2021

Frequency of Atrial Arrhythmia in Hospitalized Patients with COVID-19

There is growing evidence that COVID-19 can cause cardiovascular complications. However, there are limited data on the characteristics and importance of atrial arrhythmia (AA) in patients hospitalized with COVID-19. Data from 1029 patients diagnosed with of COVID-19 and admitted to Columbia University Medical Center between March 1st and April 15th 2020 were analyzed. The diagnosis of AA was confirmed by 12 lead electrocardiographic recordings, 24hour telemetry recordings and implantable device interrogations. Patients' history, biomarkers and hospital course were reviewed. Outcomes of death, intubation and discharge were assessed. Of 1029 patients, 82 (8%) were diagnosed with AA. Out of the 82 patients with AA. Of the AA patients, new-onset AA was seen in 46 (56%) patients, recurrent paroxysmal and chronic persistent were diagnosed in 16 (20%) and 20 (24%) individuals, respectively. Sixty-five percent of the patients diagnosed with AA (n=53) died. Patients diagnosed with AA had significantly higher mortality compared to those without AA (65% vs. 21%; p < 0.001). Predictors of mortality were older age (Odds Ratio (OR) =1.12, [95% Confidence Interval (CI), 1.04 to 1.22]); male gender (OR=6.4 [95% CI, 1.3 to 32]); azithromycin use (OR=13.4 [95% CI, 2.14 to 84]); and higher D-dimer levels (OR=2.8 [95% CI, 1.1 to7.3]). In conclusion, patients diagnosed with AA had 3.1 times significant increase in mortality rate versus patients without diagnosis of AA in COVID-19 patients. Older age, male gender, azithromycin use and higher baseline D-dimer levels were predictors of mortality.

Worldwide Survey of COVID-19 Associated Arrhythmias

Background - COVID-19 has led to over 1 million deaths worldwide and has been associated with cardiac complications including cardiac arrhythmias. The incidence and pathophysiology of these manifestations remain elusive. In this worldwide survey of patients hospitalized with COVID-19 who developed cardiac arrhythmias, we describe clinical characteristics associated with various arrhythmias, as well as global differences in modulations of routine electrophysiology practice during the pandemic.

Methods - We conducted a retrospective analysis of patients hospitalized with COVID-19 infection worldwide with and without incident cardiac arrhythmias. Patients with documented atrial fibrillation (AF), atrial flutter (AFL), supraventricular tachycardia (SVT), non-sustained or sustained ventricular tachycardia (VT), ventricular fibrillation (VF), atrioventricular block (AVB), or marked sinus bradycardia (HR<40bpm) were classified as having arrhythmia. De-identified data was provided by each institution and analyzed.

Results - Data was collected for 4,526 patients across 4 continents and 12 countries, 827 of whom had an arrhythmia. Cardiac comorbidities were common in patients with arrhythmia: 69% had hypertension, 42% diabetes mellitus, 30% had heart failure and 24% coronary artery disease. Most had no prior history of arrhythmia. Of those who did develop an arrhythmia, the majority (81.8%) developed atrial arrhythmias, 20.7% developed ventricular arrhythmias, and 22.6% had bradyarrhythmia. Regional differences suggested a lower incidence of AF in Asia compared to other continents (34% vs. 63%). Most patients in in North America and Europe received hydroxychloroquine, though the frequency of hydroxychloroquine therapy was constant across arrhythmia types. Forty-three percent of patients who developed arrhythmia were mechanically ventilated and 51% survived to hospital discharge. Many institutions reported drastic decreases in electrophysiology procedures performed.

Conclusions - Cardiac arrhythmias are common and associated with high morbidity and mortality among patients hospitalized with COVID-19 infection. There were significant regional variations in the types of arrhythmias and treatment approaches.

Metformin Is Associated with a Lower Risk of Atrial Fibrillation and Ventricular Arrhythmias Compared to Sulfonylureas: An Observational Study

Background - Type 2 diabetes (DM2) is one of the most common chronic disorders worldwide and is an important cause of cardiovascular disease. Studies investigating the risk of atrial and ventricular arrhythmias in diabetic patients taking different oral diabetes medications are sparse.

Methods - We used IBM MarketScan® Medicare Supplemental Database to examine the risk of arrhythmias for patients on different oral diabetes medications by propensity score matching.

Results - We found that patients on metformin monotherapy had significantly reduced risk of atrial arrhythmias, including atrial fibrillation, compared to monotherapy with DPP4 or TZD medications. Patients on metformin monotherapy had significantly reduced risk of atrial arrhythmias, ventricular arrhythmias, and bradycardia compared to monotherapy with sulfonylureas. Combination therapy with sulfonylureas and metformin had an increased risk of atrial arrhythmias compared to some other combinations.

Conclusions - Different oral diabetes medications have significantly different long-term risk of arrhythmia. Specifically, metformin is associated with reduced risk of atrial fibrillation and ventricular arrhythmias compared to sulfonylureas.

Integrated electrophysiology care for patients with heart failure: An envisioned future

Heart failure (HF) is a chronic, progressive, and complex disease that is increasing in prevalence with a projected 46% increase from 2012 to 2030. 

1 

Frequent hospital admissions have made HF one of the leading causes of health care expenditures, costing the system more than 30 billion US dollars a year. 

2 

Many of these patients have cardiac implantable electronic devices (CIEDs), wearable devices, and atrial and ventricular arrhythmias. There is an increasing focus on how to best manage these patients, with the recognition that an integrated care model is optimal.

EVOLUTION OF RISK STRATIFICATION AND SUDDEN DEATH PREVENTION IN HYPERTROPHIC CARDIOMYOPATHY: 20 YEARS WITH THE IMPLANTABLE CARDIOVERTER-DEFIBRILLATOR

Hypertrophic cardiomyopathy (HCM) is a relatively common inherited myocardial disorder, once regarded as largely untreatable with ominous prognosis and most visibly as a common cause of sudden death (SD) in the young. Over the last several years, HCM has been transformed into a contemporary treatable disease with management options that significantly alter the clinical course. With the use of implantable cardioverter-defibrillators (ICDs) in the HCM patient population, a new paradigm has emerged, with primary prevention device therapy reliably terminating potentially lethal ventricular tachyarrhythmias (3%–4% per year) and being largely responsible for a >10-fold decrease in disease-related mortality (to 0.5% per year), independent of age. A guideline-based clinical risk stratification algorithm has evolved, including variables identified with cardiac magnetic resonance. One or more risk markers judged major and relevant within a patient’s clinical profile can be considered sufficient to recommend a primary prevention implant (associated with a measure of physician judgment and shared decision-making). ICD decisions using the individual risk marker strategy have been associated with 95% sensitivity for identifying patients who subsequently experienced appropriate ICD therapy, albeit often delayed substantially for >5 or >10 years after implant, but without heart failure deterioration or death following device intervention. A rigid mathematically derived statistical risk model proposed by the European Society of Cardiology is associated with low sensitivity (ie, 33%) for predicting SD events. Introduction of prophylactically inserted ICDs to HCM 20 years ago has significantly altered the clinical course and landscape of this disease. SD prevention has reduced HCM mortality significantly, making preservation of life and potential for normal longevity a reality for most HCM patients.

Admission Cardiac Diagnostic Testing with Electrocardiography and Troponin Measurement Prognosticates Increased 30‐Day Mortality in COVID‐19

Background

Cardiovascular involvement in coronavirus disease 2019 (COVID‐19) is common and leads to worsened mortality. Diagnostic cardiovascular studies may be helpful for resource appropriation and identifying patients at increased risk for death.

Methods and Results

We analyzed 887 patients (aged 64±17 years) admitted with COVID‐19 from March 1 to April 3, 2020 in New York City with 12 lead electrocardiography within 2 days of diagnosis. Demographics, comorbidities, and laboratory testing, including high sensitivity cardiac troponin T (hs‐cTnT), were abstracted. At 30 days follow‐up, 556 patients (63%) were living without requiring mechanical ventilation, 123 (14%) were living and required mechanical ventilation, and 203 (23%) had expired. Electrocardiography findings included atrial fibrillation or atrial flutter (AF/AFL) in 46 (5%) and ST‐T wave changes in 306 (38%). 27 (59%) patients with AF/AFL expired as compared to 181 (21%) of 841 with other non‐life‐threatening rhythms (P<0.001). Multivariable analysis incorporating age, comorbidities, AF/AFL, QRS abnormalities, and ST‐T wave changes, and initial hs‐cTnT ≥20 ng/L showed that increased age (HR 1.04/year), elevated hs‐cTnT (HR 4.57), AF/AFL (HR 2.07), and a history of coronary artery disease (HR 1.56) and active cancer (HR 1.87) were associated with increased mortality.

Conclusions

Myocardial injury with hs‐cTnT ≥20 ng/L, in addition to cardiac conduction perturbations, especially AF/AFL, upon hospital admission for COVID‐19 infection is associated with markedly increased risk for mortality than either diagnostic abnormality alone.

Theoretical models and computational analysis of action potential dispersion for cardiac arrhythmia risk stratification

Reentrant cardiac arrhythmias such as atrial fibrillation (AF) and ventricular fibrillation (VF) are common cardiac arrhythmias that account for substantial morbidity and mortality throughout the world. However, the mechanisms and optimal ablation treatment strategies for such arrhythmias are still unclear. Using 2D optical mapping of a mouse model with AF and VF, we have identified regional heterogeneity of the action potential duration (APD) in the atria and ventricles of the heart as key drivers for the initiation and persistence of reentry. The purpose of this paper is to discuss theoretical patterns of dispersion, demonstrate patterns of dispersion seen in our mouse model and discuss the computational analysis of APD dispersion patterns. These analyses and discussions may lead to better understanding of dispersion patterns in patients with these arrhythmias, as well as help comprehend whether and how reducing …

High-density Grid Technology Aids in the Visualization of Purkinje Potentials in Fascicular Ventricular Tachycardia

A 71-year-old man with atrial fibrillation (AF), ischemic cardiomyopathy, and ventricular tachycardia (VT) presented having experienced implantable cardioverter-defibrillator (ICD) shocks. He had been previously treated with amiodarone and ICD placement for VT. His last episode of VT was several years prior to admission. About two months before admission, several appropriate shocks were recorded. Despite an increase in amiodarone, in subsequent weeks, he received several additional shocks with syncope. He was hospitalized and an unchanged ejection fraction of 35%, patent bypass grafts, and no new coronary disease were documented. He was then transferred to our institution.

High-density Grid Mapping of Micro-and Macro-reentrant Left Atrial Arrhythmias

Dr. Wan has served on the steering committee for Medtronic and Boston Scientific. Dr. Saluja has served as a consultant to Abbott and BioSense Webster. Dr. Biviano has served as a medical advisory board member for Abbott, BioSense Webster, and Boston Scientific. The other authors report no conflicts of interest for the published content.

Management of Arrhythmias Associated with COVID-19

Personalized care while balancing risk/benefit of medical or invasive therapy is necessary to improve care of patients with arrhythmias. Providers must provide thorough follow-up care and use necessary precaution while caring for COVID-19 patients.

2020

Clinical and cardiac characteristics of COVID‐19 mortalities in a diverse New York City Cohort

Introduction

Electrocardiographic characteristics in COVID‐19‐related mortality have not yet been reported, particularly in racial/ethnic minorities.

Methods and Results

We reviewed demographics, laboratory and cardiac tests, medications, and cardiac rhythm proximate to death or initiation of comfort care for patients hospitalized with a positive SARS‐CoV‐2 reverse‐transcriptase polymerase chain reaction in three New York City hospitals between March 1 and April 3, 2020 who died. We described clinical characteristics and compared factors contributing toward arrhythmic versus nonarrhythmic death. Of 1258 patients screened, 133 died and were enrolled. Of these, 55.6% (74/133) were male, 69.9% (93/133) were racial/ethnic minorities, and 88.0% (117/133) had cardiovascular disease. The last cardiac rhythm recorded was VT or fibrillation in 5.3% (7/133), pulseless electrical activity in 7.5% (10/133), unspecified bradycardia in 0.8% (1/133), and asystole in 26.3% (35/133). Most 74.4% (99/133) died receiving comfort measures only. The most common abnormalities on admission electrocardiogram included abnormal QRS axis (25.8%), atrial fibrillation/flutter (14.3%), atrial ectopy (12.0%), and right bundle branch block (11.9%). During hospitalization, an additional 17.6% developed atrial ectopy, 14.7% ventricular ectopy, 10.1% atrial fibrillation/flutter, and 7.8% a right ventricular abnormality. Arrhythmic death was confirmed or suspected in 8.3% (11/133) associated with age, coronary artery disease, asthma, vasopressor use, longer admission corrected QT interval, and left bundle branch block (LBBB).

Conclusions

Conduction, rhythm, and electrocardiographic abnormalities were common during COVID‐19‐related hospitalization. Arrhythmic death was associated with age, coronary artery disease, asthma, longer admission corrected QT interval, LBBB, ventricular ectopy, and usage of vasopressors. Most died receiving comfort measures.

The Effect of Radiofrequency Catheter Ablation of Typical Atrial Flutter on Cardiac Chambers' Size and Function

Introduction: Cavo-tricuspid isthmus (CTI) dependent atrial flutter (AFL) is one of the most common atrial arrhythmias involving the right atrium (RA) for which radiofrequency catheter ablation has been widely used as a therapy of choice. However, there is limited data on the effect of this intervention on cardiac size and function.

Hypothesis: CTI dependent ablation for patients with AFL will improve tricuspid valve function, biatrial enlargement, and ventricular function.

Methods: A retrospective study was conducted on 468 patients who underwent CTI dependent ablation for clinical typical AFL at a single institution between 2010 and 2019. After patients with congenital or rheumatic heart disease, heart transplant recipients, or those without baseline echocardiogram were excluded, 211 patients remained in the analysis. Echocardiographic data were analyzed at baseline prior to ablation, and at early follow-up within 1-year post-ablation. Follow-up echocardiographic data was available for 130 patients.

Results: Of the 211 patients with CTI-AFL, 200 had typical counterclockwise flutter. The mean age was 64.2±12.1 years old with 12% (n=26) female. The average left ventricular (LV) ejection fraction (EF) significantly improved on follow-up echo (45.55±14.26 to 49±14.4%, p=0.0075), of which 63 (48%) patients had an improvement in EF of 5% or more and 19 (25%) patients had an increased EF of 20% or more. The prevalence of moderate to severe tricuspid regurgitation (TR) was 24% (n=50) at baseline and 18% (n=22) at follow-up with no significant difference (p=0.27). However, 30% (n=39) of the patients had one grade or more improvement in their TR within the 1-year follow-up. Echocardiography also showed improvement of RA size in 48.6%, and left atrial (LA) size in 48.2% of the patients.

Conclusions: Patients who underwent CTI dependent AFL ablation showed an improvement in cardiac size and function at follow-up evaluation. Although longer-term results are unknown, these findings suggest that restoration of sinus rhythm from atrial flutter is associated with improvement in TR severity, RA size, LA size, and LVEF.

Outcome of Radiofrequency Catheter Ablation of Cavo-tricuspid Isthmus Dependent Flutter in Patients With Adult Congenital Heart Disease

Introduction: Both typical cavo-tricuspid isthmus (CTI) dependent (or its equivalent) and atypical atrial flutter (AFL) are common in adults with congenital heart disease (CHD) either due to its inherent cardiac anatomy or as a result of prior surgical procedures. Radiofrequency catheter ablation is routinely used as a therapeutic option.

Hypothesis: Patients with CHD will have an improvement in systemic ventricular ejection fraction and a decreased incidence of atrial arrhythmias after ablation.

Methods: A retrospective study was conducted on 99 patients with CHD who underwent ablation for clinical AFL at a single institution between 2010 and 2019. Of these patients, 62 had CTI-AFL. The 2 patients with unspecified CHD were excluded. CHD was divided into 3 categories according to the American College of Cardiology Task Force 1 of the 32nd Bethesda Conference - simple, moderate severity, and great complexity lesions. Outcomes of ablation at 1 year follow up were assessed.

Results: Typical counterclockwise CTI-AFL was seen in 50 patients. The mean age was 49.1±13.6 years old with 29 (48.3%) females. Of the 60 patients, 35% (n=21) had simple lesions, 51.7% (n=31) had moderate lesions, and 13.3% (n=8) had great complexity lesions. The mean left or systemic ventricular ejection fraction (EF) significantly improved on follow-up echo among patients with simple CHD (49.1±13.1 to 56.5±4.7%, p=0.018) and moderate CHD (49.5±14.9 to 54±8.5%, p=0.02), but did not change among patients with great complexity CHD (52.5±6 to 52.5±9.25%, p=0.9). There was a significantly increased incidence of atrial fibrillation (9.5% vs. 16.1% vs. 50%, p=0.04) post ablation among simple, moderate, and great complexity lesions, respectively, but no significant difference in the recurrence rate of atrial flutter (p=0.3).

Conclusions: Patients who underwent CTI-AFL ablation showed an improvement in EF in patients with simple and moderate CHD. There was also a significantly increased incidence in the development of atrial fibrillation post ablation in CHD with great complexity compared to simple or moderate CHD.

Outcomes of Radiofrequency Catheter Ablation of Atrial Arrhythmias in Lung Transplant Recipients

Introduction: Atrial arrhythmias (AA) are common after lung transplant (LT) and may impact overall mortality. The majority of arrhythmias tend to be organized flutter, amenable to ablation; however the data is limited.

Hypothesis: The purpose of this study was to investigate the outcomes of radiofrequency catheter ablation of AA in LT recipients.

Methods: All LT recipients undergoing electrophysiology study at our institution between 2011-2018 were retrospectively reviewed. A total of 20 atrial ablations were identified in 16 patients. Mean follow-up was 4 ± 2.9 years.

Results: Overall, mean age was 55 ± 13 years, 63% were male, 63% were status post bilateral (vs. single) LT, and mean LVEF was 57%. Transplant indications included interstitial lung disease (44%), COPD (19%), and cystic fibrosis (19%). Antiarrhythmics and beta blockers were used in 44% and 75%, respectively. Mean time from transplant to first ablation was 2.7 years. Of 20 ablations, macro-reentrant flutter (75%) and focal atrial tachycardia (15%) were common, particularly in double LT recipients (Figure). The most common ablation sites were pulmonary vein anastomosis/left atrial ridge (60%), mitral annulus (35%) and left atrial roof (30%). Restoration of sinus rhythm occurred in 19 of 20 procedures and only one complication occurred (e.g. small pericardial effusion without tamponade). Arrhythmia recurred in 10 (63%) patients, however, most were managed conservatively. Repeat ablation was needed in 4 patients, of which AAs originated from different locations. Beta blocker use was associated with a lower risk of SVT recurrence (p=0.04). Reduced LVEF and longer time to procedure post-transplant were associated with repeat ablation (p<0.05).

Conclusions: The majority of AAs in LT recipients are atrial flutter originating near the pulmonary vein anastomosis sites. Despite a high immediate procedural success rate, recurrence is high and 25% of patients require multiple ablation attempts.

Digital Health and the Care of the Patient With Arrhythmia: What Every Electrophysiologist Needs to Know

The field of cardiac electrophysiology has been on the cutting edge of advanced digital technologies for many years. More recently, medical device development through traditional clinical trials has been supplemented by direct to consumer products with advancement of wearables and health care apps. The rapid growth of innovation along with the mega-data generated has created challenges and opportunities. This review summarizes the regulatory landscape, applications to clinical practice, opportunities for virtual clinical trials, the use of artificial intelligence to streamline and interpret data, and integration into the electronic medical records and medical practice. Preparation of the new generation of physicians, guidance and promotion by professional societies, and advancement of research in the interpretation and application of big data and the impact of digital technologies on health outcomes will help to advance the adoption and the future of digital health care.

Cardiac electrophysiology consultative experience at the epicenter of the COVID-19 pandemic in the United States

Background

The COVID-19 pandemic has greatly altered the practice of cardiac electrophysiology around the world for the foreseeable future. Professional organizations have provided guidance for practitioners, but real-world examples of the consults and responsibilities cardiac electrophysiologists face during a surge of COVID-19 patients is lacking.

Methods

In this observational case series we report on 29 consecutive inpatient electrophysiology consultations at a major academic medical center in New York City, the epicenter of the pandemic in the United States, during a 2 week period from March 30-April 12, 2020, when 80% of hospital beds were occupied by COVID-19 patients, and the New York City metropolitan area accounted for 10% of COVID-19 cases worldwide.

Results

Reasons for consultation included: Atrial tachyarrhythmia (31%), cardiac implantable electronic device management (28%), bradycardia (14%), QTc prolongation (10%), ventricular arrhythmia (7%), post-transcatheter aortic valve replacement conduction abnormality (3.5%), ventricular pre-excitation (3.5%), and paroxysmal supraventricular tachycardia (3.5%). Twenty-four patients (86%) were positive for COVID-19 by nasopharyngeal swab. All elective procedures were canceled, and only one urgent device implantation was performed. Thirteen patients (45%) required in-person evaluation and the remainder were managed remotely.

Conclusion

Our experience shows that the application of a massive alteration in workflow and personnel forced by the pandemic allowed our team to efficiently address the intersection of COVID-19 with a range of electrophysiology issues. This experience will prove useful as guidance for emerging hot spots or areas affected by future waves of the pandemic.

Slow uniform electrical activation during sinus rhythm is an indicator of reentrant VT isthmus location and orientation in an experimental model of myocardial infarction

Background

To validate the predictability of reentrant circuit isthmus locations without ventricular tachycardia (VT) induction during high-definition mapping, we used computer methods to analyse sinus rhythm activation in experiments where isthmus location was subsequently verified by mapping reentrant VT circuits.

Method

In 21 experiments using a canine postinfarction model, bipolar electrograms were obtained from 196-312 recordings with 4mm spacing in the epicardial border zone during sinus rhythm and during VT. From computerized electrical activation maps of the reentrant circuit, areas of conduction block were determined and the isthmus was localized. A linear regression was computed at three different locations about the reentry isthmus using sinus rhythm electrogram activation data. From the regression analysis, the uniformity, a measure of the constancy at which the wavefront propagates, and the activation gradient, a measure that may approximate wavefront speed, were computed. The purpose was to test the hypothesis that the isthmus locates in a region of slow uniform activation bounded by areas of electrical discontinuity.

Results

Based on the regression parameters, sinus rhythm activation along the isthmus near its exit proceeded uniformly (mean r2= 0.95±0.05) and with a low magnitude gradient (mean 0.37±0.10mm/ms). Perpendicular to the isthmus long-axis across its boundaries, the activation wavefront propagated much less uniformly (mean r2= 0.76±0.24) although of similar gradient (mean 0.38±0.23mm/ms). In the opposite direction from the exit, at the isthmus entrance, there was also less uniformity (mean r2= 0.80±0.22) but a larger magnitude gradient (mean 0.50±0.25mm/ms). A theoretical ablation line drawn perpendicular to the last sinus rhythm activation site along the isthmus long-axis was predicted to prevent VT reinduction. Anatomical conduction block occurred in 7/21 experiments, but comprised only small portions of the isthmus lateral boundaries; thus detection of sinus rhythm conduction block alone was insufficient to entirely define the VT isthmus.

Conclusions

Uniform activation with a low magnitude gradient during sinus rhythm is present at the VT isthmus exit location but there is less uniformity across the isthmus lateral boundaries and at isthmus entrance locations. These factors may be useful to verify any proposed VT isthmus location, reducing the need for VT induction to ablate the isthmus. Measured computerized values similar to those determined herein could therefore be assistive to sharpen specificity when applying sinus rhythm mapping to localize EP catheter ablation sites.

Increased Incidence of Chronic Kidney Injury in African Americans Following Cardiac Transplantation

Objectives

This study examined whether African American race was associated with an elevated risk of chronic kidney disease (CKD) post-cardiac transplantation.

Background

CKD often occurs after cardiac transplantation and may require renal replacement therapy (RRT) or renal transplant. African American patients have a higher risk for kidney disease as well as worse post-cardiac transplant morbidity and mortality. It is unclear, however, if there is a propensity for African Americans to develop CKD after cardiac transplant.

Methods

The Institutional Review Board of Columbia University Medical Center approved the retrospective study of 151 adults (57 African American and 94 non-African American) who underwent single-organ heart transplant from 2013 to 2016. The primary outcome was a decrease in estimated glomerular filtration rate (eGFR), development of CKD, and end-stage renal disease (ESRD) requiring RRT after 2 years.

Results

African American patients had a significant decline in eGFR post-cardiac transplant compared to non-African American patients (− 34 ± 6 vs. − 20 ± 4 mL/min/1.73 m2, p < 0.0006). African American patients were more likely to develop CKD stage 2 or worse (eGFR < 90 mL/min/1.73 m2) than non-African American patients (81% vs. 59%, p < 0.0005).

Conclusions

This is the first study to report that African American patients are at a significantly higher risk for eGFR decline and CKD at 2 years post-cardiac transplant. Future investigation into risk reduction is necessary for this patient population.

Digital Health and the Care of the Arrhythmia Patient; What Every Electrophysiologist Needs to Know.

The field of cardiac electrophysiology has been on the cutting edge of advanced digital technologies for many years. More recently, medical device development through traditional clinical trials has been supplemented by direct to consumer products with advancement of wearables and healthcare apps. The rapid growth of innovation along with the mega-data generated has created challenges and opportunities. This review summarizes the regulatory landscape, applications to clinical practice, opportunities for virtual clinical trials, the use of artificial intelligence to streamline and interpret data, and integration into the electronic medical records and medical practice. Preparation of the new generation of physicians, guidance and promotion by professional societies, and advancement of research in the interpretation and application of big data and the impact of digital technologies on health outcomes will help to advance the adoption and the future of digital health care.

Fibroblast growth factor homologous factors tune arrhythmogenic late NaV1. 5 current in calmodulin binding–deficient channels

The Ca2+-binding protein calmodulin has emerged as a pivotal player in tuning Na+ channel function, although its impact in vivo remains to be resolved. Here, we identify the role of calmodulin and the NaV1.5 interactome in regulating late Na+ current in cardiomyocytes. We created transgenic mice with cardiac-specific expression of human NaV1.5 channels with alanine substitutions for the IQ motif (IQ/AA). The mutations rendered the channels incapable of binding calmodulin to the C-terminus. The IQ/AA transgenic mice exhibited normal ventricular repolarization without arrhythmias and an absence of increased late Na+ current. In comparison, transgenic mice expressing a lidocaine-resistant (F1759A) human NaV1.5 demonstrated increased late Na+ current and prolonged repolarization in cardiomyocytes, with spontaneous arrhythmias. To determine regulatory factors that prevent late Na+ current for the IQ/AA mutant channel, we considered fibroblast growth factor homologous factors (FHFs), which are within the NaV1.5 proteomic subdomain shown by proximity labeling in transgenic mice expressing NaV1.5 conjugated to ascorbate peroxidase. We found that FGF13 diminished late current of the IQ/AA but not F1759A mutant cardiomyocytes, suggesting that endogenous FHFs may serve to prevent late Na+ current in mouse cardiomyocytes. Leveraging endogenous mechanisms may furnish an alternative avenue for developing novel pharmacology that selectively blunts late Na+ current.

The prognostic value of electrocardiogram at presentation to emergency department in patients with COVID-19

Objective

To study whether combining vital signs and electrocardiogram (ECG) analysis can improve early prognostication.

Methods

This study analyzed 1258 adults with coronavirus disease 2019 who were seen at three hospitals in New York in March and April 2020. Electrocardiograms at presentation to the emergency department were systematically read by electrophysiologists. The primary outcome was a composite of mechanical ventilation or death 48 hours from diagnosis. The prognostic value of ECG abnormalities was assessed in a model adjusted for demographics, comorbidities, and vital signs.

Results

At 48 hours, 73 of 1258 patients (5.8%) had died and 174 of 1258 (13.8%) were alive but receiving mechanical ventilation with 277 of 1258 (22.0%) patients dying by 30 days. Early development of respiratory failure was common, with 53% of all intubations occurring within 48 hours of presentation. In a multivariable logistic regression, atrial fibrillation/flutter (odds ratio [OR], 2.5; 95% CI, 1.1 to 6.2), right ventricular strain (OR, 2.7; 95% CI, 1.3 to 6.1), and ST segment abnormalities (OR, 2.4; 95% CI, 1.5 to 3.8) were associated with death or mechanical ventilation at 48 hours. In 108 patients without these ECG abnormalities and with normal respiratory vitals (rate <20 breaths/min and saturation >95%), only 5 (4.6%) died or required mechanical ventilation by 48 hours versus 68 of 216 patients (31.5%) having both ECG and respiratory vital sign abnormalities.

Conclusion

The combination of abnormal respiratory vital signs and ECG findings of atrial fibrillation/flutter, right ventricular strain, or ST segment abnormalities accurately prognosticates early deterioration in patients with coronavirus disease 2019 and may assist with patient triage.

Cardiac arrhythmias in patients with COVID‐19

The emergence of coronavirus disease 2019 (COVID‐19), caused by the severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2) has become a major global public health concern. Although SARS‐CoV‐2 causes primarily respiratory problems, concurrent cardiac injury cannot be ignored since it may be an independent predictor for adverse outcomes. Cardiac arrhythmias are often observed in patients with COVID‐19, especially in severe cases, and more likely contribute to the high risk of adverse outcomes. Arrhythmias should be regarded as one of the main complications of COVID‐19. Mechanistically, a number of ion channels can be adversely affected in COVID‐19, leading to alterations in cardiac conduction and/or repolarization properties, as well as calcium handling, which can predispose to cardiac arrhythmogenesis. In addition, several antimicrobials that are currently used as potential therapeutic agents for COVID‐19, such as chloroquine, hydroxychloroquine and azithromycin, have uncertain benefit, and yet may induce electrocardiographic QT prolongation with potential ventricular pro‐arrhythmic effects. Continuous electrocardiogram monitoring, accurate and prompt recognition of arrhythmias are important. The present review focuses on cardiac arrhythmias in patients with COVID‐19, its underlying mechanisms, and proposed preventive and therapeutic strategies.

Indications for and findings on transthoracic echocardiography in COVID-19

Background

Despite growing evidence of cardiovascular complications associated with coronavirus disease 2019 (COVID-19), there are few data regarding the performance of transthoracic echocardiography (TTE) and the spectrum of echocardiographic findings in this disease.

Methods

A retrospective analysis was performed among adult patients admitted to a quaternary care center in New York City between March 1 and April 3, 2020. Patients were included if they underwent TTE during the hospitalization after a known positive diagnosis for COVID-19. Demographic and clinical data were obtained using chart abstraction from the electronic medical record.

Results

Of 749 patients, 72 (9.6%) underwent TTE following positive results on severe acute respiratory syndrome coronavirus-2 polymerase chain reaction testing. The most common clinical indications for TTE were concern for a major acute cardiovascular event (45.8%) and hemodynamic instability (29.2%). Although most patients had preserved biventricular function, 34.7% were found to have left ventricular ejection fractions ≤ 50%, and 13.9% had at least moderately reduced right ventricular function. Four patients had wall motion abnormalities suggestive of stress-induced cardiomyopathy. Using Spearman rank correlation, there was an inverse relationship between high-sensitivity troponin T and left ventricular ejection fraction (ρ = −0.34, P = .006). Among 20 patients with prior echocardiograms, only two (10%) had new reductions in LVEF of >10%. Clinical management was changed in eight individuals (24.2%) in whom TTE was ordered for concern for acute major cardiovascular events and three (14.3%) in whom TTE was ordered for hemodynamic evaluation.

Conclusions

This study describes the clinical indications for use and diagnostic performance of TTE, as well as findings seen on TTE, in hospitalized patients with COVID-19. In appropriately selected patients, TTE can be an invaluable tool for guiding COVID-19 clinical management.

Feasibility of near-infrared spectroscopy as a tool for anatomical mapping of the human epicardium

Epicardial ablation is necessary for the treatment of ventricular tachycardias refractory to endocardial ablation due to arrhythmic substrates involving the epicardium. The human epicardium is composed of adipose tissue and coronary vasculature embedded on the surface and within the myocardium, which can complicate electroanatomical mapping, electrogram interpretation and ablation delivery. We propose using near-infrared spectroscopy (NIRS) to decipher adipose tissue from myocardial tissue within human hearts ex vivo. Histological measurement of epicardial adipose thickness direct correlated (R = 0.884) with the adipose contrast index. These results demonstrate the potential of NIRS integrated catheters for mapping the spatial distribution of epicardial substrates and could aid in improving guidance during epicardial ablation interventions.

Atrial Arrhythmia in Hospitalized Patients with COVID-19

Introduction: There is growing evidence that COVID-19 can cause cardiovascular complications. However, there are limited data on the characteristics and importance of atrial arrhythmia (AA) in patients hospitalized with COVID-19. Methods: Data from 1029 patients diagnosed with of COVID-19 and admitted to Columbia University Medical Center between March 1st and April 15th 2020 were analyzed. The diagnosis of AA was confirmed by 12 lead electrocardiographic recordings, 24-hour telemetry recordings and implantable device interrogations. Patients’ history, biomarkers and hospital course were reviewed. Outcomes of death, intubation and discharge were assessed. Results: Of 1029 patients, 82 (8%) were diagnosed with AA. Out of the 82 patients with AA. Of the AA patients, new-onset AA was seen in 46 (56%) patients, recurrent paroxysmal and chronic persistent were diagnosed in 16 (20%) and 20 (24%) individuals, respectively. Sixty-five percent of the patients diagnosed with AA (n=53) died. Patients diagnosed with AA had significantly higher mortality compared to those without AA (65% vs. 21%; p < 0.001). Predictors of mortality were older age (Odds Ratio (OR) =1.12, [95% Confidence Interval (CI), 1.04 to 1.22]); male gender (OR=6.4 [95% CI, 1.3 to 32]); azithromycin use (OR=13.4 [95% CI, 2.14 to 84]); and higher D-dimer levels (OR=2.8 [95% CI, 1.1 to7.3]). Conclusions: Patients diagnosed with AA had 3.1 times significant increase in mortality rate versus patients without diagnosis of AA in COVID-19 patients. Older age, male gender, azithromycin use and higher baseline D-dimer levels were predictors of mortality.

Non-invasive systems and methods for rendering of cardiac electromechanical activation

Systems and methods for generating an electromechanical map are disclosed herein. The methods includes obtaining ultrasound data comprising a series of consecutive image frames and radio frequency (RF) signals corresponding to the location in the heart; measuring displacements and strains based on the ultrasound data to determine an electromechanical activation in the location; converting the ultrasound data into a series of isochrone maps; and combining the series of isochrone maps to generate the electromechanical map. The electromechanical map illustrates the electromechanical activation and internal wall structures of the heart.

Survey of current perspectives on consumer-available digital health devices for detecting atrial fibrillation

Background

Many digital health technologies capable of atrial fibrillation (AF) detection are directly available to patients. However, adaptation into clinical practice by heart rhythm healthcare practitioners (HCPs) is unclear.

Objective

To examine HCP perspectives on use of commercial technologies for AF detection and management.

Methods

We created an electronic survey for HCPs assessing practice demographics and perspectives on digital devices for AF detection and management. The survey was distributed electronically to all members of 3 heart rhythm professional societies.

Results

We received 1601 responses out of 73,563 e-mails sent, with 43.6% from cardiac electrophysiologists, 12.8% from fellows, and 11.6% from advanced practice practitioners. Most respondents (62.3%) reported having recommended patient use of a digital device for AF detection. Those who did not had concerns about their accuracy (29.6%), clinical utility of results (22.8%), and integration into electronic health records (19.8%). Results from a 30-second single-lead electrocardiogram were sufficient for 42.7% of HCPs to recommend oral anticoagulation for patients at high risk for stroke. Respondents wanted more data comparing the accuracy of digital devices to conventional devices for AF monitoring (64.9%). A quarter (27.3%) of HCPs had no reservations recommending digital devices for AF detection, and most (53.4%) wanted guidelines from their professional societies providing guidance on their optimal use.

Conclusion

Many HCPs have already integrated digital devices into their clinical practice. However, HCPs reported facing challenges when using digital technologies for AF detection, and professional society recommendations on their use are needed.

Extrapulmonary manifestations of COVID-19

Although COVID-19 is most well known for causing substantial respiratory pathology, it can also result in several extrapulmonary manifestations. These conditions include thrombotic complications, myocardial dysfunction and arrhythmia, acute coronary syndromes, acute kidney injury, gastrointestinal symptoms, hepatocellular injury, hyperglycemia and ketosis, neurologic illnesses, ocular symptoms, and dermatologic complications. Given that ACE2, the entry receptor for the causative coronavirus SARS-CoV-2, is expressed in multiple extrapulmonary tissues, direct viral tissue damage is a plausible mechanism of injury. In addition, endothelial damage and thromboinflammation, dysregulation of immune responses, and maladaptation of ACE2-related pathways might all contribute to these extrapulmonary manifestations of COVID-19. Here we review the extrapulmonary organ-specific pathophysiology, presentations and management considerations for patients with COVID-19 to aid clinicians and scientists in recognizing and monitoring the spectrum of manifestations, and in developing research priorities and therapeutic strategies for all organ systems involved.

Restructuring Structural Heart Disease Practice During the COVID-19 Pandemic: JACC Review Topic of the Week

Patients with structural heart disease are at increased risk of adverse outcomes from the coronavirus disease-2019 (COVID-19) due to advanced age and comorbidity. In the midst of a global pandemic of a novel infectious disease, reality-based considerations comprise an important starting point for formulating clinical management pathways. The aims of these “crisis-driven” recommendations are: 1) to ensure appropriate and timely treatment of structural heart disease patients; 2) to minimize the risk of COVID-19 exposure to patients and health care workers; and 3) to limit resource utilization under conditions of constraint. Although the degree of disruption to usual practice will vary across the United States and elsewhere, we hope that early experiences from a heart team operating in the current global epicenter of COVID-19 may prove useful for others adapting their practice in advance of local surges of COVID-19.

Derived telemetry-based electrocardiograms in the intensive care unit: insights from a COVID-19 epicenter

Introduction: Severely ill inpatients with SARS-CoV-2 infection, Coronavirus Disease 2019 (COVID-19) require close electrocardiographic (ECG) monitoring due to frequent cardiac involvement of the disease and cardiovascular side effects of therapies. This study aimed to compare ECG parameters measured from conventional 12-lead ECGs to those from a telemetry-generated 7-lead or single lead ECG to determine if the latter may be an alternative for screening and monitoring patients, particularly during a pandemic. Methods and Results: We identified 33 patients with respiratory failure due to COVID-19 undergoing telemetry monitoring in the intensive care unit. Each received a 12-lead ECG utilizing standard lead placement. A concurrent 7-lead ECG and single lead (lead II) tracing were obtained using the central telemetry system. Each ECG was interpreted and intervals manually measured by 2 cardiologists with disagreements adjudicated by a third. Compared to the 12-lead ECG measurement, the 7-lead ECG underestimated the corrected QT by on average 13.45±32.05 msec, and the single lead ECG underestimated corrected QT by 19.62±33.19 msec (Bazett, p < 0.05). Bland Altman analysis also demonstrated evidence of a positive bias, suggesting that the telemetry-derived tracings underestimated the QT interval. The presence of T wave abnormalities and ST segment changes were overestimated by the telemetry-derived tracings as compared to standard ECGs. Conclusion: Though telemetry-derived ECGs may be useful in screening patients for significant ECG abnormalities, they likely do not represent a reliable replacement of the standard 12-lead ECG in the routine diagnosis and management of critically ill patients.

Year in Review in Cardiac Electrophysiology

In the past year, there have been numerous advances in our understanding of arrhythmia mechanisms, diagnosis, and new therapies. We have seen advances in basic cardiac electrophysiology with data suggesting that secretoneurin may be a biomarker for patients at risk of ventricular arrhythmias, and we have learned of the potential role of an NPR-C (natriuretic peptide receptor-C) in atrial fibrosis and the role of an atrial specific 2-pore potassium channel TASK-1 as a therapeutic target for atrial fibrillation. We have seen studies demonstrating the role of sensory neurons in sleep apnea–related atrial fibrillation and the association between bariatric surgery and atrial fibrillation ablation outcomes. Artificial intelligence applied to electrocardiography has yielded estimates of age, sex, and overall health. We have seen new tools for collection of patient-centered outcomes following catheter ablation. There have been significant advances in the ability to identify ventricular tachycardia termination sites through high-density mapping of deceleration zones. We have learned that right ventricular dysfunction may be a predictor of survival benefit after implantable cardioverter-defibrillator implantation in patients with nonischemic cardiomyopathy. We have seen further insights into the role of His bundle pacing on improving outcomes. As our understanding of cardiac laminopathies advances, we may have new tools to predict arrhythmic event rates in gene carriers. Finally, we have seen numerous advances in the treatment of arrhythmias in patients with congenital heart disease.

Cardiac arrhythmias in COVID-19 infection

Severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2), the virus that causes COVID-19, has affected >1 million people worldwide.1 As of this writing, >60 000 people have died as a result of this virus in the United States alone,2 and New York City has over 167 000 confirmed coronavirus disease 2019 (COVID-19) cases, the highest number of any city in the United States. New York City is now considered a COVID-19 epicenter. While this disease predominantly affects the lungs, often leading to pneumonia and acute respiratory distress syndrome, adverse effects on the heart have also been described.3 Electrophysiological issues are increasingly recognized as a disease manifestation, with one study reporting arrhythmias in 44% of individuals with severe illness.4 Sudden cardiac death has also been described anecdotally.5 However, the type and severity of arrhythmias associated with COVID-19 have not been described. In this article, we present 4 cases that highlight the spectrum of arrhythmias observed in patients with COVID-19 infection. New York-Presbyterian/Columbia University Irving Medical Center is located in the New York City COVID-19 epicenter and herein, we describe the clinical presentations we have seen and discuss decision-making regarding therapeutic options, acknowledging difficulties pertaining to resource conservation and healthcare worker safety.

This study was approved by the Columbia University Institutional Review Board, and procedures followed were in accordance with institutional guidelines. Due to the nature of the study, written informed consent was not required. The authors declare that all supporting data are available within the article.

Performance of electrophysiology procedures at an academic medical center amidst the 2020 coronavirus (COVID‐19) pandemic

A global coronavirus (COVID‐19) pandemic occurred at the start of 2020 and is already responsible for more than 74 000 deaths worldwide, just over 100 years after the influenza pandemic of 1918. At the center of the crisis is the highly infectious and deadly SARS‐CoV‐2, which has altered everything from individual daily lives to the global economy and our collective consciousness. Aside from the pulmonary manifestations of disease, there are likely to be several electrophysiologic (EP) sequelae of COVID‐19 infection and its treatment, due to consequences of myocarditis and the use of QT‐prolonging drugs. Most crucially, the surge in COVID‐19 positive patients that have already overwhelmed the New York City hospital system requires conservation of hospital resources including personal protective equipment (PPE), reassignment of personnel, and reorganization of institutions, including the EP laboratory. In this proposal, we detail the specific protocol changes that our EP department has adopted during the COVID‐19 pandemic, including performance of only urgent/emergent procedures, after hours/7‐day per week laboratory operation, single attending‐only cases to preserve PPE, appropriate use of PPE, telemedicine and video chat follow‐up appointments, and daily conferences to collectively manage the clinical and ethical dilemmas to come. We discuss also discuss how we perform EP procedures on presumed COVID positive and COVID tested positive patients to highlight issues that others in the EP community may soon face in their own institution as the virus continues to spread nationally and internationally.

Systems and methods for mechanical mapping of cardiac rhythm

(63) Continuation of application No. 14/682.980, filed on locations over the series of images. The periodicity corre-Apr. 9, 2015, now Pat. No. 10517.564, which is a sponds to an electromechanical signal of the heart in the continuation-in-part of application No. PCT/US13/region corresponding to the measured one or more pixel 64377, filed on Oct. 10, 2013. locations.

Guidance for Cardiac Electrophysiology During the COVID-19 Pandemic from the Heart Rhythm Society COVID-19

Task Force; Electrophysiology Section of the American College of Cardiology; and the Electrocardiography and Arrhythmias Committee of the Council on Clinical Cardiology, American Heart Association

Coronavirus disease 2019 (COVID-19) is a global pandemic that is wreaking havoc on the health and economy of much of human civilization. Electrophysiologists have been impacted personally and professionally by this global catastrophe. In this joint article from representatives of the Heart Rhythm Society, the American College of Cardiology, and the American Heart Association, we identify the potential risks of exposure to patients, allied healthcare staff, industry representatives, and hospital administrators. We also describe the impact of COVID-19 on cardiac arrhythmias and methods of triage based on acuity and patient comorbidities. We provide guidance for managing invasive and noninvasive electrophysiology procedures, clinic visits, and cardiac device interrogations. In addition, we discuss resource conservation and the role of telemedicine in remote patient care along with management strategies for affected patients.

Restructuring electrophysiology during the COVID-19 pandemic: a practical guide from a New York City hospital network

The coronavirus disease 2019 crisis is a global pandemic of a novel infectious disease with far-ranging public health implications. With regard to cardiac electrophysiology (EP) services, we discuss the “real-world” challenges and solutions that have been essential for efficient and successful (1) ramping down of standard clinical practice patterns and (2) pivoting of workflow processes to meet the demands of this pandemic. The aims of these recommendations are to outline: (1) essential practical steps to approaching procedures, as well as outpatient and inpatient care of EP patients, with relevant examples, (2) successful strategies to minimize exposure risk to patients and clinical staff while also balancing resource utilization, (3) challenges related to redeployment and restructuring of clinical and support staff, and (4) considerations regarding continued collaboration with clinical and administrative colleagues to implement these changes. While process changes will vary across practices and hospital systems, we believe that these experiences from 4 different EP sections in a large New York City hospital network currently based in the global epicenter of the coronavirus disease 2019 pandemic will prove useful for other EP practices adapting their own practices in preparation for local surges.

Catheter ablation lesion visualization with intracardiac strain imaging in canines and humans

Catheter ablation is a common treatment for arrhythmia, but can fail if lesion lines are noncontiguous. Identification of gaps and nontransmural lesions can reduce the likelihood of treatment failure and recurrent arrhythmia. Intracardiac myocardial elastography (IME) is a strain imaging technique that provides visualization of the lesion line. Estimation of lesion size and gap resolution were evaluated in an open-chest canine model (n = 3), and clinical feasibility was investigated in patients undergoing ablation to treat typical cavotricuspid isthmus (CTI) atrial flutter (n = 5). A lesion line consisting of three lesions and two gaps was generated on the canine left ventricle via epicardial ablation. One lesion was generated in one canine right ventricle. Average lesion and gap areas were measured with high agreement (33 ± 14 and 30 ± 15 mm 2 , respectively) when compared against gross pathology (34 ± 19 and 26 ± 11 mm 2 , respectively). Gaps as small as 11 mm 2 (3.6 mm on epicardial surface) were identifiable. Absolute error and relative error in estimated lesion area were 9.3 ± 8.4 mm 2 and 31% ± 34%; error in estimated gap area was 11 ± 9.0 mm 2 and 40% ± 29%. Flutter patients were imaged throughout the procedure. Strain was shown to be capable of differentiating between baseline and after ablation completion as confirmed by conduction block. In all patients, strain decreased in the CTI after ablation (mean paired difference of -17% ± 11%, p <; 0.05). IME could potentially become a useful ablation monitoring tool in health facilities.

Guidance for cardiac electrophysiology during the COVID-19 pandemic from the Heart Rhythm Society COVID-19

Task Force; Electrophysiology Section of the American College of Cardiology; and the Electrocardiography and Arrhythmias Committee of the Council on Clinical Cardiology, American Heart Association

Coronavirus disease 2019 (COVID-19) is a global pandemic that is wreaking havoc on the health and economy of much of human civilization. Electrophysiologists have been impacted personally and professionally by this global catastrophe. In this joint article from representatives of the Heart Rhythm Society, the American College of Cardiology, and the American Heart Association, we identify the potential risks of exposure to patients, allied healthcare staff, industry representatives, and hospital administrators. We also describe the impact of COVID-19 on cardiac arrhythmias and methods of triage based on acuity and patient comorbidities. We provide guidance for managing invasive and noninvasive electrophysiology procedures, clinic visits, and cardiac device interrogations. In addition, we discuss resource conservation and the role of telemedicine in remote patient care along with management strategies for affected patients.

Noninvasive localization of cardiac arrhythmias using electromechanical wave imaging

Cardiac arrhythmias are a major cause of morbidity and mortality worldwide. The 12-lead electrocardiogram (ECG) is the current noninvasive clinical tool used to diagnose and localize cardiac arrhythmias. However, it has limited accuracy and is subject to operator bias. Here, we present electromechanical wave imaging (EWI), a high–frame rate ultrasound technique that can noninvasively map with high accuracy the electromechanical activation of atrial and ventricular arrhythmias in adult patients. This study evaluates the accuracy of EWI for localization of various arrhythmias in all four chambers of the heart before catheter ablation. Fifty-five patients with an accessory pathway (AP) with Wolff-Parkinson-White (WPW) syndrome, premature ventricular complexes (PVCs), atrial tachycardia (AT), or atrial flutter (AFL) underwent transthoracic EWI and 12-lead ECG. Three-dimensional (3D) rendered EWI isochrones and 12-lead ECG predictions by six electrophysiologists were applied to a standardized segmented cardiac model and subsequently compared to the region of successful ablation on 3D electroanatomical maps generated by invasive catheter mapping. There was significant interobserver variability among 12-lead ECG reads by expert electrophysiologists. EWI correctly predicted 96% of arrhythmia locations as compared with 71% for 12-lead ECG analyses [unadjusted for arrhythmia type: odds ratio (OR), 11.8; 95% confidence interval (CI), 2.2 to 63.2; P = 0.004; adjusted for arrhythmia type: OR, 12.1; 95% CI, 2.3 to 63.2; P = 0.003]. This double-blinded clinical study demonstrates that EWI can localize atrial and ventricular arrhythmias including WPW, PVC, AT, and AFL. EWI when used with ECG may allow for improved treatment for patients with arrhythmias.

Rapid optical spectroscopic quantification and mapping of human epicardial adipose tissue and lesion deposition (Conference Presentation)

Epicardial catheter ablation has been increasingly recognized as an important adjunct in treating ventricular arrhythmias unamenable by endocardial ablation alone. The presence of epicardial adipose tissue (EAT) is a primary cause for ineffective ablation energy delivery and electrogram misinterpretation. To address this need, we propose a catheter-based near-infrared spectroscopic technique for mapping EAT and lesion deposition, and validate it within excised human donor hearts. We introduce a new parameter, the adipose contrast index (ACI), for rapid lipid assessment. Strong correspondence was observed between values derived from interpolated 3-dimensional ACI maps and histologically-determined EAT layer thickness (Pearson’s, R = 0.903).

Leadless Pacemakers after Cardiac Transplantation

We would like to thank Dr. Araj for his thoughtful response to our article, “Conduction Abnormalities Associated with Tricuspid Annuloplasty in Cardiac Transplantation,” wherein we highlighted increased permanent pacemaker (PPM) implantation and conduction abnormalities in orthotopic heart transplant (OHT) recipients receiving prophylactic tricuspid annuloplasty of the donor heart.1

In his letter to the editor, Dr. Araj reinforces the infectious and mechanical risks of PPM placement in the high-risk period shortly after heart transplantation. He astutely frames a peri-transplant PPM requirement within the context of the recently changed transplant allocation system which predisposes to less ideal donor hearts. He cites concomitant electrophysiology advancements like the leadless pacemaker (LPM), Micra (Medtronic Inc, Minneapolis, MN), which may be implemented to counterbalance the “necessary evil” of an occasional post-OHT PPM.2

In our experience at Columbia University, LPM implantation is associated with decreased tricuspid regurgitation and infectious risk when compared with single-chamber pacemakers placed in post-transcatheter aortic valve replacement patients.3

Because of the single-chamber pacing limitation and its use in patients with high infection risk and permanent atrial fibrillation, LPMs tend to be implanted in sicker patients. We have implanted one LPM in a post-OHT patient who had profound recurrent vagally mediated sinus bradycardia and atrioventricular block during dialysis. A follow-up echocardiogram showed trace tricuspid regurgitation, although he later died of pneumonia and respiratory failure 9 months after device placement. As Dr. Araj suggests, in light of potentially intermittent low levels of ventricular pacing in OHT patients receiving PPMs, LPM placement ought to be considered in this special clinical context to mitigate device-related complications.2 However, LPM implantation in patients with sinus rhythm and atrioventricular block will lead to atrioventricular dyssynchrony because of lack of atrial sensing. Peripheral vascular abnormalities in cardiac transplant patients such as venous tortuosity or arteriovenous fistula may also limit ability to insert and advance the transcatheter pacing system for LPM placement. Future developments in leadless pacing such as dual chamber sensing and pacing systems with smaller delivery systems will offer more options to a broader patient population, including cardiac transplant patients.

Dietary Saturated Fat Promotes Arrhythmia by Activating NOX2 (NADPH Oxidase 2).

BACKGROUND: Obesity and diets high in saturated fat increase the risk of arrhythmias and sudden cardiac death. However, the molecular mechanisms are not well understood. We hypothesized that an increase in dietary saturated fat could lead to abnormalities of calcium homeostasis and heart rhythm by a NOX2 (NADPH oxidase 2)-dependent mechanism.

METHODS: We investigated this hypothesis by feeding mice highfat diets. In vivo heart rhythm telemetry, optical mapping, and isolated cardiac myocyte imaging were used to quantify arrhythmias, repolarization, calcium transients, and intracellular calcium sparks.

RESULTS: We found that saturated fat activates NOX (NADPH oxidase), whereas polyunsaturated fat does not. The high saturated fat diet increased repolarization heterogeneity and ventricular tachycardia inducibility in perfused hearts. Pharmacological inhibition or genetic deletion of NOX2 …

Dietary Saturated Fat Promotes Arrhythmia by Activating NOX2 (NADPH Prevalence and Electronic Health Record-Based Phenotype of Loss-of-Function

کتابخانه الکترونیک ارتقاء مستمر کمی وکیفی ارائه خدمات کتابداری و اطلاع رسانی به مراجه کنندگان در امر آموزش وپژوهش بوده که در نهایت موجب ارتقاء سطح رضایتمندی و توانمند سازی مراجعه کنندگان از طریق تسهيل امکانات دسترسي از راه دور به منابع، اطلاعات علمي، اخبار و... با ارائه روزآمدترين و دقيق ترين خدمات وفناوري ها به مراجعان خواهد گرديد.

2019

Systems and methods for mechanical mapping of cardiac rhythm

Techniques for mapping behavior of a heart include acquiring a series of two or more images of the heart. The series of images is taken at one or more pixel locations, each pixel location corresponding to a region of the heart. Image data corresponding to the pixel locations can be obtained, and a periodicity of the image data measured for each of the pixel locations over the series of images. The periodicity corresponds to an electromechanical signal of the heart in the region corresponding to the measured one or more pixel locations.

Atrial Fibrillation is Associated With Recurrent Ventricular Arrhythmias After Lvad Implant: Incidence and Impact in a Consecutive Series

Introduction: Left ventricular assist devices (LVADs) are pivotal treatments for end-stage congestive heart failure (CHF) patients as destination or bridge to heart transplantation therapy. Atrial fibrillation (AF) is highly prevalent and associated with worse clinical outcomes in LVAD patients. Less is known regarding the association between AF and recurrent VAs in post-LVAD patients. This study examined a cohort of LVAD patients who had manifested pre-LVAD ventricular arrhythmias (VAs) in order to determine: (1) the rate of recurrent post-LVAD VAs, as well as (2) the incidence and impact of atrial fibrillation (AF) on recurrent post-LVAD VAs.

Methods: Medical records of 195 patients who received a LVAD were reviewed. Descriptive statistics were generated and logistic regression was used to assess the association of clinical variables with the presence of VAs.

Results: 47% of 195 CHF patients who received an LVAD manifested significant VAs prior to LVAD implant (82%-Heartmate II, 14%-HVAD, 4%-other) and were followed for an average of 17 months post-LVAD. Of patients with pre-LVAD VAs, 41% continued to manifest recurrent VAs (92%-VT, 3%-VF, and 5%-VT&VF) after LVAD implantation. By multivariable logistic regression, a history of AF (present in 57% of recurrent VA patients) was associated with recurrent VAs after LVAD (OR=4.99; 95% CI 1.67, 14.96; p=0.004).

Conclusions: AF is not only prevalent in over half of LVAD patients with recurrent VAs, but is also in independent predictor of recurrent VAs. Further studies regarding the effect of AF treatment on recurrent VAs are warranted.

Real-World Use of Implantable Loop Recorder Following Cryptogenic Stroke: Who Actually Benefits From Long Term Monitoring and How Long Should They Remain Implanted?

Introduction: Insertion of implantable loop recorder (ILR) after cryptogenic stroke for detection of AF has increased since CRYSTAL-AF. However, it is unclear which patients actually benefit from long term monitoring and how long ILRs should remain implanted.

Hypothesis: To provide real-world data of ILR use at a high-volume tertiary medical center, and determine the characteristics of patients who benefit most from ILR placement after cryptogenic stroke.

Methods: After IRB approval, medical records of 123 patients with cryptogenic stroke and insertion of ILRs between 2015 and 2017 were reviewed. Basic demographic information, components of CHA2DS2-VASc score, AF detection, heart rate variability (HRV), and echo data were collected.

Results: A total of 123 patients (mean age 67.96 years +/- 13.71, 61 % male) were followed for at least 3 months, and 26 patients (21%) were found to have AF (defined as greater than 10 seconds of AF). Median time to AF detection was 95 days (range 3 days to 3.6 years). Univariable and multivariable analysis showed that age, race, CHA2DS2-VASc and HRV were not predictive of AF. The mean duration of implantation was 454 days. Patients with detected AF had a longer implantation duration than those who did not, mean of 585 days vs. 419 days (p=0.01). None of the 13 patients who suffered recurrent CVA after index event had AF.

Conclusions: CHA2DS2-VASc, LA size and HRV were not predictive of AF detection by ILR. Patients <40 of years, patients with a CHA2DS2-VASc of 0 and patients with recurrent strokes despite anticoagulation rarely had AF detected and did not benefit from ILRs. The first 3 months were the greatest yield for AF detection, however longer monitoring allowed capture of more AF events.

Increased Age, Left Atrial Size, and Body Mass Index in Patients With Atrial Fibrillation Alters Intracardiac Electrogram Morphology

Introduction: There are limited studies evaluating whether patients of increased age, left atrial size (LA size), and body mass index (BMI) with AF have altered intracardiac electrogram (EGM) morphology.

Methods: With Columbia University IRB approval, we analyzed left atrial intracardiac EGMs acquired during invasive electrophysiology study in 55 patients with persistent AF (mean age = 63.4 years, with 73% male). Risk factors for AF including age, left atrial size and BMI were correlated with EGM morphology: amplitude and width, dominant frequency (DF), and spectral complexity (level of heterogeneity in the normalized power spectrum). Means (in mV for amplitude and width, and Hz for frequency), standard deviations, and correlation coefficients (r) were calculated for each EGM feature. All variables were treated as continuous variables and linear regressions were used to determine correlations.

Results:Increasing age was associated with EGMs of: (1) lower amplitude (n = 51, mean = .021 ± .02, r = -.65, p < .001), (2) decreased width (n = 51, mean = 3.24 ± .483, r = -.57, p < .001); and (3) greater spectral complexity (n = 43, mean = .287 ± .0890, r = .488, p < .001). Increasing LA size (N = 27) was associated with: (1) lower amplitude (mean = .013 ± .016, r = -.42, p = .03), (2) decreased width (mean = 2.77 ± .45, r = -.48, p = .01), (3) higher DF (mean = 5.25 ± .87, r = .47, p = .01), and (4) greater spectral complexity (mean = .32 ± .11, r = .48, p = .01). Increasing BMI (N = 41) correlated with: (1) higher DF (mean = 5.30 ± 1.01, r = .406, p = .008) and (2) greater spectral complexity (mean = .32 ± .08, r = 392, p = .01).

Conclusions: As AF patients, and increase LA size and/or BMI, atrial EGMs decrease inamplitude and width and increased in frequency and spectral complexity. These findings suggest that atrial remodeling due to increased age, left atrial size, and BMI leads to (1) reduced local atrial activation, (2) decreased refractoriness and (3) more heterogeneous activation. Altered EGM morphology in these patients may skew interpretation by operating electrophysiologists, thereby reducing success of ablation in patients with these risk factors.

Catheter Ablation Lesion Mapping With Intracardiac Echocardiography in Canines and Humans

Introduction: Arrhythmia recurrence following catheter ablations is associated with lesion gaps or non-transmurality. Lesion visualization could increase procedural success and avoid repeat treatments.

Hypothesis: Intracardiac Myocardial Elastography (IME) is an ICE-based strain (ε) imaging technique that can be used to monitor catheter ablation.

Methods: We used intracardiac echocardiography to visualize epicardial ventricular ablations in a canine. A line composed of 3 epicardial lesions (6-7 mm diameter) separated by 3 mm gaps were generated on an open-chest canine (n=1) left ventricle. After the heart was excised, the lesion line was sliced in half stained with 10% tetrazolium chloride (TTC). ROC curves were generated to compare sensitivity/specificity of IME when compared to gross pathology. We used intracardiac echocardiography to visualize cavotricuspid isthmus (CTI) ablation in patients with atrial flutter. Five patients (80±4.9 y/o, 40% male) undergoing ablation for atrial flutter were imaged with IME. ICE field-of-view was set to the CTI region distal to the IVC ridge. Images were obtained before ablation and until conduction block was achieved.

Results: In the canine, IME accurately visualized the lesion gaps in the ventricle (Fig 1a). When defining a lesion as any region with ε of less than 2.5%, lesion diameter and gap size was 5.4±1.7 and 4.3±2.4 mm, respectively. Compared to pathological inspection (Fig 1b), IME was able to identify lesions in the canine ventricle with high sensitivity/specificity (ROC AUC 94%). During CTI ablation, IME effectively mapped lesion formation (Fig 1c-e). CTI bidirectional conduction block was verified by differential pacing in all five patients, a finding which correlated with a mean decrease in ε at the CTI by 17±11% after ablation.

Conclusions: IME was capable of mapping epicardial lesions in the canine ventricle, and can accurately visualize completion of CTI line conduction block in typical flutter patients.

Atrial fibrillation is associated with recurrent ventricular arrhythmias after LVAD implant: Incidence and impact in a consecutive series

This study examined left-ventricular assist device (LVAD) patients with pre-LVAD ventricular arrhythmias (VAs) to determine the rate of recurrent post-LVAD VAs and the impact of pre-LVAD atrial fibrillation (AF) on recurrent post-LVAD VAs. Medical records of 195 consecutive LVAD patients were reviewed. Descriptive statistics were generated and Cox proportional hazard models were used to assess the association of clinical variables with the time to recurrent VA. Forty-seven percent of 195 CHF patients who received LVAD-manifested significant VAs prior to LVAD implant (82% Heartmate II, 14% HVAD, 4% other; median follow-up = 17 months), 41% of whom manifested recurrent post-LVAD VAs. Pre-LVAD AF was associated with recurrent VAs (hazard ratio = 3.73; 95% CI 1.33, 10.48; p = 0.012). Recurrent VAs were associated with increased mortality (hazard ratio = 3.06; 95% CI 1.17, 7.98; p = 0.023). A history of AF is prevalent in over half of LVAD patients with recurrent VAs and is associated with time to recurrence of VA.

Real-World Use of Implantable Loop Recorder Following Cryptogenic Stroke: Who Actually Benefits From Long Term Monitoring and How Long Should They Remain Implanted?

Introduction: Insertion of implantable loop recorder (ILR) after cryptogenic stroke for detection of AF has increased since CRYSTAL-AF. However, it is unclear which patients actually benefit from long term monitoring and how long ILRs should remain implanted.

Hypothesis: To provide real-world data of ILR use at a high-volume tertiary medical center, and determine the characteristics of patients who benefit most from ILR placement after cryptogenic stroke.

Methods: After IRB approval, medical records of 123 patients with cryptogenic stroke and insertion of ILRs between 2015 and 2017 were reviewed. Basic demographic information, components of CHA2DS2-VASc score, AF detection, heart rate variability (HRV), and echo data were collected.

Results: A total of 123 patients (mean age 67.96 years +/- 13.71, 61 % male) were followed for at least 3 months, and 26 patients (21%) were found to have AF (defined as greater than 10 seconds of AF). Median time to AF detection was 95 days (range 3 days to 3.6 years). Univariable and multivariable analysis showed that age, race, CHA2DS2-VASc and HRV were not predictive of AF. The mean duration of implantation was 454 days. Patients with detected AF had a longer implantation duration than those who did not, mean of 585 days vs. 419 days (p=0.01). None of the 13 patients who suffered recurrent CVA after index event had AF.

Conclusions: CHA2DS2-VASc, LA size and HRV were not predictive of AF detection by ILR. Patients <40 of years, patients with a CHA2DS2-VASc of 0 and patients with recurrent strokes despite anticoagulation rarely had AF detected and did not benefit from ILRs. The first 3 months were the greatest yield for AF detection, however longer monitoring allowed capture of more AF events.

Increased Age, Left Atrial Size, and Body Mass Index in Patients With Atrial Fibrillation Alters Intracardiac Electrogram Morphology

Introduction: There are limited studies evaluating whether patients of increased age, left atrial size (LA size), and body mass index (BMI) with AF have altered intracardiac electrogram (EGM) morphology.

Methods: With Columbia University IRB approval, we analyzed left atrial intracardiac EGMs acquired during invasive electrophysiology study in 55 patients with persistent AF (mean age = 63.4 years, with 73% male). Risk factors for AF including age, left atrial size and BMI were correlated with EGM morphology: amplitude and width, dominant frequency (DF), and spectral complexity (level of heterogeneity in the normalized power spectrum). Means (in mV for amplitude and width, and Hz for frequency), standard deviations, and correlation coefficients (r) were calculated for each EGM feature. All variables were treated as continuous variables and linear regressions were used to determine correlations.

Results:Increasing age was associated with EGMs of: (1) lower amplitude (n = 51, mean = .021 ± .02, r = -.65, p < .001), (2) decreased width (n = 51, mean = 3.24 ± .483, r = -.57, p < .001); and (3) greater spectral complexity (n = 43, mean = .287 ± .0890, r = .488, p < .001). Increasing LA size (N = 27) was associated with: (1) lower amplitude (mean = .013 ± .016, r = -.42, p = .03), (2) decreased width (mean = 2.77 ± .45, r = -.48, p = .01), (3) higher DF (mean = 5.25 ± .87, r = .47, p = .01), and (4) greater spectral complexity (mean = .32 ± .11, r = .48, p = .01). Increasing BMI (N = 41) correlated with: (1) higher DF (mean = 5.30 ± 1.01, r = .406, p = .008) and (2) greater spectral complexity (mean = .32 ± .08, r = 392, p = .01).

Conclusions: As AF patients, and increase LA size and/or BMI, atrial EGMs decrease inamplitude and width and increased in frequency and spectral complexity. These findings suggest that atrial remodeling due to increased age, left atrial size, and BMI leads to (1) reduced local atrial activation, (2) decreased refractoriness and (3) more heterogeneous activation. Altered EGM morphology in these patients may skew interpretation by operating electrophysiologists, thereby reducing success of ablation in patients with these risk factors.

Catheter Ablation Lesion Mapping With Intracardiac Echocardiography in Canines and Humans

Introduction: Arrhythmia recurrence following catheter ablations is associated with lesion gaps or non-transmurality. Lesion visualization could increase procedural success and avoid repeat treatments.

Hypothesis: Intracardiac Myocardial Elastography (IME) is an ICE-based strain (ε) imaging technique that can be used to monitor catheter ablation.

Methods: We used intracardiac echocardiography to visualize epicardial ventricular ablations in a canine. A line composed of 3 epicardial lesions (6-7 mm diameter) separated by 3 mm gaps were generated on an open-chest canine (n=1) left ventricle. After the heart was excised, the lesion line was sliced in half stained with 10% tetrazolium chloride (TTC). ROC curves were generated to compare sensitivity/specificity of IME when compared to gross pathology. We used intracardiac echocardiography to visualize cavotricuspid isthmus (CTI) ablation in patients with atrial flutter. Five patients (80±4.9 y/o, 40% male) undergoing ablation for atrial flutter were imaged with IME. ICE field-of-view was set to the CTI region distal to the IVC ridge. Images were obtained before ablation and until conduction block was achieved.

Results: In the canine, IME accurately visualized the lesion gaps in the ventricle (Fig 1a). When defining a lesion as any region with ε of less than 2.5%, lesion diameter and gap size was 5.4±1.7 and 4.3±2.4 mm, respectively. Compared to pathological inspection (Fig 1b), IME was able to identify lesions in the canine ventricle with high sensitivity/specificity (ROC AUC 94%). During CTI ablation, IME effectively mapped lesion formation (Fig 1c-e). CTI bidirectional conduction block was verified by differential pacing in all five patients, a finding which correlated with a mean decrease in ε at the CTI by 17±11% after ablation.

Conclusions: IME was capable of mapping epicardial lesions in the canine ventricle, and can accurately visualize completion of CTI line conduction block in typical flutter patients.

Atrial fibrillation is associated with recurrent ventricular arrhythmias after LVAD implant: Incidence and impact in a consecutive series

This study examined left-ventricular assist device (LVAD) patients with pre-LVAD ventricular arrhythmias (VAs) to determine the rate of recurrent post-LVAD VAs and the impact of pre-LVAD atrial fibrillation (AF) on recurrent post-LVAD VAs. Medical records of 195 consecutive LVAD patients were reviewed. Descriptive statistics were generated and Cox proportional hazard models were used to assess the association of clinical variables with the time to recurrent VA. Forty-seven percent of 195 CHF patients who received LVAD-manifested significant VAs prior to LVAD implant (82% Heartmate II, 14% HVAD, 4% other; median follow-up = 17 months), 41% of whom manifested recurrent post-LVAD VAs. Pre-LVAD AF was associated with recurrent VAs (hazard ratio = 3.73; 95% CI 1.33, 10.48; p = 0.012). Recurrent VAs were associated with increased mortality (hazard ratio = 3.06; 95% CI 1.17, 7.98; p = 0.023). A history of AF is prevalent in over half of LVAD patients with recurrent VAs and is associated with time to recurrence of VA.

 

 

Dietary saturated fat promotes arrhythmia by activating NOX2 (nadph oxidase 2)

Background:

Obesity and diets high in saturated fat increase the risk of arrhythmias and sudden cardiac death. However, the molecular mechanisms are not well understood. We hypothesized that an increase in dietary saturated fat could lead to abnormalities of calcium homeostasis and heart rhythm by a NOX2 (NADPH oxidase 2)-dependent mechanism.

Methods:

We investigated this hypothesis by feeding mice high-fat diets. In vivo heart rhythm telemetry, optical mapping, and isolated cardiac myocyte imaging were used to quantify arrhythmias, repolarization, calcium transients, and intracellular calcium sparks.

Results:

We found that saturated fat activates NOX (NADPH oxidase), whereas polyunsaturated fat does not. The high saturated fat diet increased repolarization heterogeneity and ventricular tachycardia inducibility in perfused hearts. Pharmacological inhibition or genetic deletion of NOX2 prevented arrhythmogenic abnormalities in vivo during high statured fat diet and resulted in less inducible ventricular tachycardia. High saturated fat diet activates CaMK (Ca2+/calmodulin-dependent protein kinase) in the heart, which contributes to abnormal calcium handling, promoting arrhythmia.

Conclusions:

We conclude that NOX2 deletion or pharmacological inhibition prevents the arrhythmogenic effects of a high saturated fat diet, in part mediated by activation of CaMK. This work reveals a molecular mechanism linking cardiac metabolism to arrhythmia and suggests that NOX2 inhibitors could be a novel therapy for heart rhythm abnormalities caused by cardiac lipid overload.

A nurse-led approach to improving cardiac lifestyle modification in an atrial fibrillation population

Atrial fibrillation (AF) is a major public health problem and the most common cardiac arrhythmia encountered in clinical practice at this time. AF is associated with numerous symptoms such as palpitations, shortness of breath, and fatigue, which can significantly reduce health-related quality of life and result in serious adverse cardiac outcomes. In light of this, the aim of the present pilot study was to test the feasibility of implementing a mobile health (mHealth) lifestyle intervention titled “Atrial Fibrillation and Cardiac Health: Targeting Improving Outcomes via a Nurse-Led Intervention (ACTION),” with the goal of improving cardiac health measures, AF symptom recognition, and self-management. As part of this study, participants self-identified cardiac health goals at enrollment. The nurse used web-based resources from the American Heart Association (Dallas, TX, USA), which included the Life’s Simple 7® My Life Check® assessment, to quantify current lifestyle behavior change needs. Furthermore, on the My AFib Experience™ website (American Heart Association, Dallas, TX, USA), the patient used a symptom tracker tool to capture the date, time, frequency, and type of AF symptoms, and these data were subsequently reviewed by the cardiac nurse. Throughout the six-month intervention period, the cardiac nurse used a motivational interviewing approach to support participants’ cardiac health goals. Ultimately, the ACTION intervention was tested in 53 individuals with AF (mean age: 59 ± 11 years; 76% male). Participants were predominantly overweight/obese (79%), had a history of hypertension (62%) or hyperlipidemia (61%), and reported being physically inactive/not preforming any type of regular exercise (52%). The majority (88%) of the participants had one or more Life’s Simple 7® measures that could be improved. Most of the participants (98%) liked having a dedicated nurse to work with them on a biweekly basis via the mHealth portal. The most commonly self-reported symptoms were palpitations, fatigue/exercise intolerance, and dyspnea. Seventy percent of the participants had an improvement in their weight and blood pressure as documented within the electronic health record as well as a corresponding improvement in their Life’s Simple 7® score at six months. On average, there was a three-pound (1.36-kg) decrease in weight and a 5-mmHg decrease in systolic blood pressure between baseline and at six months. In conclusion, this pilot work provides initial evidence regarding the feasibility of implementing the ACTION intervention and supports testing the ACTION intervention in a larger cohort of AF patients to inform existing AF guidelines and build an evidence base for reducing AF burden through lifestyle modification.

Addressing challenges of quantitative methodologies and event interpretation in the study of atrial fibrillation

Atrial fibrillation (AF) is the commonest arrhythmia, yet the mechanisms of its onset and persistence are incompletely known. Although techniques for quantitative assessment have been investigated, there have been few attempts to integrate this information to advance disease treatment protocols. In this review, key quantitative methods for AF analysis are described, and suggestions are provided for the coordination of the available information, and to develop foci and directions for future research efforts. Quantitative biologists may have an interest in this topic in order to develop machine learning and tools for arrhythmia characterization, but they may perhaps have a minimal background in the clinical methodology and in the types of observed events and mechanistic hypotheses that have thus far been developed. We attempt to address these issues via exploration of the published literature. Although no new data is presented in this review, examples are shown of current lines of investigation, and in particular, how electrogram analysis and whole-chamber quantitative modeling of the left atrium may be useful to characterize fibrillatory patterns of activity, so as to propose avenues for more efficacious acquisition and interpretation of AF data.

Conduction abnormalities associated with tricuspid annuloplasty in cardiac transplantation

Prophylactic DeVega tricuspid annuloplasty (DVA) of the donor heart has been reported to improve tricuspid regurgitation (TR), renal dysfunction, and mortality in cardiac transplant recipients. This is the first study to investigate the electrical, as well as, hemodynamic effects of DVA during orthotopic heart transplantation (OHT). Electrocardiographic, echocardiographic, and hemodynamic data of 76 patients with DVA and 104 patients without DVA who underwent OHT between 2013 and 2017 at Columbia University Medical Center (New York, NY) were studied. Patients with DVA were older (56.5 ± 1.2 vs. 52.4 ± 1.0 years of age; p = 0.017) and predominantly men (78% vs. 68%; p = 0.02). There were no significant differences in right ventricular function and TR. Patients with DVA had increased incidence of right bundle branch block compared with without DVA (37% ± 5.9% vs. 9% ± 2.9%; p < 0.001). Three patients with DVA developed complete heart block (CHB), whereas no patients without DVA developed CHB (p = 0.04). Four patients with DVA received a pacemaker (PPM), whereas only one patient in the without DVA group received a PPM. Complete heart block was significantly increased in patients who received prophylactic DVA. Possible risk of conduction abnormalities should be considered with performance of DVA annuloplasty in cardiac transplant recipients.

3D-rendered Electromechanical Wave Imaging for Localization of Accessory Pathways in Wolff-Parkinson-White Minors*

Arrhythmia localization prior to catheter ablation is critical for clinical decision making and treatment planning. The current standard lies in 12-lead electrocardiogram (ECG) interpretation, but this method is non-specific and anatomically limited. Accurate localization requires intracardiac catheter mapping prior to ablation. Electromechanical Wave Imaging (EWI) is a high frame-rate ultrasound modality capable of non-invasively mapping the electromechanical activation in all cardiac chambers in vivo. In this study, we evaluate 3D-rendered EWI as a technique for consistently localizing the accessory pathway (AP) in Wolff-Parkinson-White (WPW) pediatric patients. A 2000 Hz EWI diverging sequence was used to transthoracically image 13 patients with evidence of ECG pre-excitation, immediately prior to catheter ablation and after successful ablation whenever possible. 3D-rendered activation maps were generated by co-registering and interpolating the 4 resulting multi-2D isochrones. A blinded electrophysiologist predicted the AP location on 12-lead ECG prior to ablation. Double-blinded EWI isochrones and clinician assessments were compared to the successful ablation site as confirmed by intracardiac mapping using a segmented template of the heart with 19 ventricular regions. 3D-rendered EWI was shown capable of consistently localizing AP in all the WPW cases. Clinical ECG interpretation correctly predicted the origin with an accuracy of 53.8%, respectively 84.6% when considering predictions in immediately adjacent segments correct. Our method was also capable of assessing the difference in activation pattern from before to after successful ablation on the same patient. These findings indicate that EWI could inform current diagnosis and expedite treatment planning of WPW ablation procedures.

Heterogeneity of the action potential duration is required for sustained atrial fibrillation

Atrial fibrillation (AF) is the most common cardiac arrhythmia and accounts for substantial morbidity and mortality. Recently, we created a mouse model with spontaneous and sustained AF caused by a mutation in the NaV1.5 channel (F1759A) that enhances persistent Na+ current, thereby enabling the investigation of molecular mechanisms that cause AF and the identification of potentially novel treatment strategies. The mice have regional heterogeneity of action potential duration of the atria similar to observations in patients with AF. In these mice, we found that the initiation and persistence of the rotational reentrant AF arrhythmias, known as spiral waves or rotors, were dependent upon action potential duration heterogeneity. The centers of the rotors were localized to regions of greatest heterogeneity of the action potential duration. Pharmacologically attenuating the action potential duration heterogeneity reduced both spontaneous and pacing-induced AF. Computer-based simulations also demonstrated that the action potential duration heterogeneity is required to generate rotors that manifest as AF. Taken together, these findings suggest that action potential duration heterogeneity in mice and humans is one mechanism by which AF is initiated and that reducing action potential duration heterogeneity can lessen the burden of AF.

Towards real-time multispectral endoscopic imaging for cardiac lesion quality assessment

Atrial fibrillation (Afib) can lead to life threatening conditions such as heart failure and stroke. During Afib treatment, clinicians aim to repress unusual electrical activity by electrically isolating the pulmonary veins (PV) from the left atrium (LA) using radiofrequency ablation. However, current clinical tools are limited in reliably assessing transmurality of the ablation lesions and detecting the presence of gaps within ablation lines, which can warrant repeat procedures. In this study, we developed an endoscopic multispectral reflectance imaging (eMSI) system for enhanced discrimination of tissue treatment at the PV junction. The system enables direct visualization of cardiac lesions through an endoscope at acquisition rates up to 25 Hz. Five narrowband, high-power LEDs were used to illuminate the sample (450, 530, 625, 810 and 940nm) and combinatory parameters were calculated based on their relative reflectance. A stitching algorithm was employed to generate large field-of-view, multispectral mosaics of the ablated PV junction from individual eMSI images. A total of 79 lesions from 15 swine hearts were imaged, ex vivo. Statistical analysis of the acquired five spectral data sets and ratiometric maps revealed significant differences between transmural lesions, non-transmural lesions around the venoatrial junctions, unablated posterior wall of left atrium tissue, and pulmonary vein (p < 0.0001). A pixel-based quadratic discriminant analysis classifier was applied to distinguish four tissue types: PV, untreated LA, non-transmural and transmural lesions. We demonstrate tissue type classification accuracies of 80.2% and 92.1% for non-transmural and transmural lesions, and 95.0% and 92.8% for PV and untreated LA sites, respectively. These findings showcase the potential of eMSI for lesion validation and may help to improve AFib treatment efficacy.

Leadless pacemaker implantation: a feasible and reasonable option in transcatheter heart valve replacement patients

Background

Leadless pacemakers (LPMs) have been shown to have lower postoperative complications than traditional permanent pacemakers but there have been no studies on the outcomes of LPMs in patients with transcatheter heart valve replacements (THVRs). This study determined outcomes of LPMs compared to transvenous single‐chamber pacemakers (SCPs) post‐THVR.

Methods

This is a retrospective single‐center study including 10 patients who received LPMs post‐THVR between February 2017 and August 2018 and a comparison group of 23 patients who received SCP post‐THVR between July 2008 and August 2018. LPM or SCP was implanted at the discretion of electrophysiologists for atrial fibrillation with slow ventricular response or sinus node dysfunction with need for single‐chamber pacing only.

Results

LPMs were associated with decreased tricuspid regurgitation (P = 0.04) and decreased blood loss during implantation (7.5 ± 2.5 cc for LPMs vs 16.8 ± 3.2 cc for SCPs, P = 0.03). Five LPM patients had devices positioned in the right ventricular septum as seen on transthoracic echocardiogram. Frequency of ventricular pacing was similar between LPM and SCP groups. In the LPM group, one case was complicated by a pseudoaneurysm and one death was due to noncardiac causes. There was one pneumothorax and one pocket infection in the SCP group.

Conclusions

In this small retrospective study, LPMs were feasible post‐THVR and found to perform as well as SCPs, had less intraprocedural blood loss, and were associated with less tricuspid regurgitation. Further, larger studies are required to follow longer‐term outcomes and complications.

Localization of accessory pathways in pediatric patients with Wolff-Parkinson-White syndrome using 3D-rendered electromechanical wave imaging

Objectives:

This study sought to demonstrate the feasibility of electromechanical wave imaging (EWI) for localization of accessory pathways (AP) prior to catheter ablation in a pediatric population.

Background:

Prediction of AP locations in patients with Wolff-Parkinson-White syndrome is currently based on analysis of 12-lead electrocardiography (ECG). In the pediatric population, specific algorithms have been developed to aid in localization, but these can be unreliable. EWI is a noninvasive imaging modality relying on a high frame rate ultrasound sequence capable of visualizing cardiac electromechanical activation.

Methods:

Pediatric patients with ventricular pre-excitation presenting for catheter ablation were imaged with EWI immediately prior to the start of the procedure. Two clinical pediatric electrophysiologists predicted the location of the AP based on ECG. Both EWI and ECG predictions were blinded to the results of catheter ablation. EWI and ECG localizations were subsequently compared with the site of successful ablation.

Results:

Fifteen patients were imaged with EWI. One patient was excluded for poor echocardiographic windows and the inability to image the entire ventricular myocardium. EWI correctly predicted the location of the AP in all 14 patients. ECG analysis correctly predicted 11 of 14 (78.6%) of the AP locations.

Conclusions:

EWI was shown to be capable of consistently localizing accessory pathways. EWI predicted the site of successful ablation more frequently than analysis of 12-lead ECG. EWI isochrones also provide anatomical visualization of ventricular pre-excitation. These findings suggest that EWI can predict AP locations, and EWI may have the potential to better inform clinical electrophysiologists prior to catheter ablation procedures.

2018

Increased Kidney Injury in Black Patients After Cardiac Transplant

Introduction: Kidney Injury is common in heart transplant (HT) patients and may lead to end stage renal disease and increased morbidity and mortality. Advanced age, diabetes, ischemic vascular disease, calcineurin inhibitor use, and baseline chronic kidney injury (CKI) are known risk factors for kidney injury, but it is unclear if there are other outstanding factors such as race.

Hypothesis: Black patients experience higher rates of chronic kidney injury post-HT compared to non-black patients.

Methods: With Institutional Review Board approval, we retrospectively studied 156 patients (57 black and 99 non-black) who underwent HT from 2013 to 2016. The primary predictor of interest was race, dichotomized as black and non-black. The primary outcome was absolute change in estimated glomerular filtration rate (eGFR), calculated using the Modification of Diet in Renal Disease formula, at time of HT and 2 year follow-up. The secondary outcome was stage 3 CKI (eGFR < 60 mL/min/1.73 m2). Continuous group differences were evaluated with Student’s t-test and categorical differences with the χ2 test.

Results: The prevalence of baseline CKI was 12% among black patients and 25% among non-black patients. Black patients had a significant decline in eGFR post-HT compared to non-black patients (30.8 ± 3.3 vs 17.6 ± 1.9 mL/min/1.73 m2, p < 0.004), and were 2.4 times more likely to develop CKI (95% CI 1.19-4.86) at 2 years post-HT. Factors known to predict post-HT CKI such as diabetes, age, and sex were similar between groups but black patients were less likely to have ischemic cardiomyopathy (ICM) and required higher maintenance tacrolimus doses. In a multivariable model containing baseline CKI, ICM, diabetes, sex and tacrolimus dose at 2 years post-transplant, black race remained a significant predictor of eGFR decline at 2 years post-HT.

Conclusions: Black patients are at significantly higher risk for developing CKI post-HT, which may lead to increased post-HT complications.

Non-invasive characterization of focal arrhythmia with electromechanical wave imaging in vivo

There is currently no established method for the non-invasive characterization of arrhythmia and differentiation between endocardial and epicardial triggers at the point of care. Electromechanical wave imaging (EWI) is a novel ultrasound-based imaging technique based on time-domain transient strain estimation that can map and characterize electromechanical activation in the heart in vivo. The objectives of this initial feasibility study were to determine that EWI is capable of differentiating between endocardial and epicardial sources of focal rhythm and, as a proof-of-concept, that EWI could characterize focal arrhythmia in one patient with premature ventricular contractions (PVCs) before radiofrequency (RF) ablation treatment. First, validation of EWI for differentiation of surface of origin was performed in seven (n = 7) adult dogs using four epicardial and four endocardial pacing protocols. Second, one (n = 1) adult patient diagnosed with PVC was imaged with EWI before the scheduled RF ablation procedure, and EWI results were compared with mapping procedure results. In dogs, EWI was capable of detecting whether pacing was of endocardial or epicardial origin in six of seven cases (86% success rate). In the PVC patient, EWI correctly identified both regions and surface of origin, as confirmed by results from the electrical mapping obtained from the RF ablation procedure. These results reveal that EWI can map the electromechanical activation across the myocardium and indicate that EWI could serve as a valuable pre-treatment planning tool in the clinic.

Year in review in cardiac electrophysiology

In the past year, there have been key advances in our understanding of arrhythmia mechanisms and diagnosis and important new therapies. We have seen advances in basic cardiac electrophysiology with demonstration of optogenetic targeting of atrial fibrillation (AF) rotors, induced pluripotent stem cell–based biological pacemakers, small-conductance Ca2+-activated K+ (SK) channels as targets for AF treatment, and reductions in inward rectifier potassium current in promoting ventricular fibrillation. Hand-held ECG devices and implantable loop recorders have been shown to detect subclinical AF. Catheter ablation of AF in patients with left ventricular dysfunction improves outcomes compared with medical therapy. Both hybrid thoracoscopic surgical and catheter ablation procedures and off-pump surgery for AF have demonstrated efficacy. Anticoagulation with uninterrupted dabigatran had a lower major bleeding rate compared with uninterrupted warfarin after AF ablation. Studies have examined optimizing access to automatic external defibrillators by identifying optimal locations for placement and possibility of using a drone delivery network. In long-QT syndrome, there are advances in understanding of ECG predictors of arrhythmic events, the role of the role of gene variants in conferring arrhythmic risk, and effect of age and sex on QTc interval. There are numerous advances in the treatment of ventricular tachycardia, including noninvasive cardiac radiation. Catheter ablation and implantable devices continue to demonstrate effectiveness in patients with congenital heart disease.

Sk and ik channel agonists for treatment of heart failure

The present invention provides compounds that are improved potassium channel agonists. Pharmaceutical compositions including a pharmaceutically acceptable carrier and a compound of the present invention are also provided. Methods and kits for treating or ameliorating the effects of heart failure syndrome, high blood pressure and diabetes also are provided. Methods, kits and compositions which include compounds of the present invention also are provided.

Clinical Outcomes After Tricuspid Annuloplasty Prior to Cardiac Transplantation: A Single Center Experience

Purpose

Allograft tricuspid regurgitation (TR) occurs after orthotopic heart transplantation (OHT) and is associated with significant morbidity. Prophylactic tricuspid repair with DeVega annuloplasty (DVA) of the donor heart has been reported to improve TR, renal dysfunction and mortality in cardiac transplant recipients. This is the first study to investigate the electrical and hemodynamic effects of DVA during OHT.

Methods

Patients who underwent OHT between 2013-2017 were included in our analysis to study clinical outcomes before and after incorporation of DVA into the transplant surgical protocol. 76 with DVA patients and 104 without DVA patients were included in the analysis. Electrocardiographic, echocardiographic and hemodynamic data were collected over one year after OHT. From the time period each patient received cardiac transplant to initial endomyocardial biopsy, all electrograms were assessed by two blinded reviewers.

Results

Patients in the group with DVA were older (56.5±1.2 vs 52.4 ±1.0 years of age, p=0.017) and predominantly men (78% vs 68%. p=0.02). TR severity and right ventricular (RV) dysfunction measured by echocardiography or intracardiac hemodynamics was similar between the two groups 3 and 12 months after transplant. Patients with DVA had increased incidence of right bundle branch block (RBBB) (37% ± 5.9 vs. 9% ± 2.9, p<0.001). 3 patients with DVA developed complete heart block, whereas no patients in the group without DVA developed complete heart block during index hospitalization (p=0.04). Four patients in the group with DVA received a pacemaker during the first month after OHT, whereas only one patient in the group without DVA received a pacemaker. All patients who received a pacemaker for complete heart block had a low level of ventricular pacing one year after transplant.

Conclusion

There was a significant increase in complete heart block early after cardiac transplantation in patients who received prophylactic DVA. There were no significant differences in RV dysfunction and the degree of TR between patients with and without DVA. Our institution has since discontinued the use of DVA in the transplant surgical protocol after two years due to the results of our study.

NOVEL 3D NONINVASIVE ULTRASOUND IMAGING LOCALIZES ACCESSORY PATHWAYS IN ADULTS AND ADOLESCENTS WITH WOLFF-PARKINSON-WHITE SYNDROME

Background

Electromechanical Wave Imaging (EWI) is a novel non-invasive imaging modality utilizing high frame rate ultrasound to visualize cardiac electromechanical activation. This is the first study to utilize EWI to localize accessory pathways (AP) in patients with Wolff-Parkinson-White (WPW) syndrome.

Methods

Ten patients with evidence of ventricular pre-excitation on resting EKG underwent transthoracic EWI prior to mapping and catheter ablation. Four clinical electrophysiologists predicted the location of the AP with 12-lead ECG using a standardized segmented template of both ventricles. AP locations predicted by a 3D EWI map and by electrophysiologists were compared to the subsequent catheter mapping. Each arm of the study was blinded to the results of the other.

Results

Mean age was 23.0±3.1 years and 6 were male. Catheter mapping located APs in 10 patients: 3 anteroseptal, 3 posteroseptal, 2 left lateral, 1 left anterolateral, and 1 fasciculoventricular pathway. Interpretation of 12-lead ECG by clinicians using the standardized template correctly identified 72.5±4.8% of the AP locations. EWI using the same template correctly predicted 100% of the AP locations. A representative image is shown in Fig. 1.

Conclusion

EWI is a novel noninvasive imaging tool which may be more accurate than EKG for localization of APs in WPW syndrome.

CARDIAC RESYNCHRONIZATION THERAPY IN 3D USING ELECTROMECHANICAL WAVE IMAGING: A NOVEL NON INVASIVE ULTRASOUND-BASED IMAGING TECHNIQUE

Background

Immediate effect of cardiac resynchronization therapy (CRT) after biventricular pacemaker implantation is commonly based on narrowing of the QRS complex. Electromechanical Wave Imaging (EWI) is a high frame-rate ultrasound imaging technique that can provide a 3D ventricular activation map and assess the extent of myocardial resynchronization (MR).

Methods

8 patients with heart failure, decreased left ventricular ejection fraction (LVEF), and left bundle branch block (LBBB) or RV pacing with planned CRT underwent EWI on the day of implantation with and without CRT. The percentage of MR within 120ms was calculated based on 3D rendered images of EWI results. QRS duration was assessed with 12 lead EKG before and after CRT.

Results

Mean age was 69±4.2 years of age, 75% were male, with mean LVEF of 22±1.7%. Presenting rhythm was sinus with LBBB in 5 patients and RV pacing in 3 patients. There was no significant difference in mean QRS duration with and without CRT (160.8±7.9 ms vs. 142±8.6 ms, p=0.08). There was significant change in MR detected with EWI: mean MR was 52±4.8% without CRT vs. 84.9±4.9% with CRT, p<0.01.

Conclusion

EWI may be an effective tool for 3D quantification of ventricular response to CRT. MR is able to detect immediate changes in ventricular activation patterns that are not reflected in QRS shortening.

2017

Electromechanical wave imaging and electromechanical wave velocity estimation in a large animal model of myocardial infarction

Echocardiography is often used in the clinic for detection and characterization of myocardial infarction. Electromechanical wave imaging (EWI) is a non-invasive ultrasound-based imaging technique based on time-domain incremental motion and strain estimation that can evaluate changes in contractility in the heart. In this study, electromechanical activation is assessed in infarcted heart to determine whether EWI is capable of detecting and monitoring infarct formation. Additionally, methods for estimating electromechanical wave (EW) velocity are presented, and changes in the EW propagation velocity after infarct formation are studied.

Attenuating Mitochondrial ROS Reduces AF in Mice With Persistent Na+ Current

Introduction: Atrial fibrillation (AF) in humans is associated with increased reactive oxygen species (ROS). Using a mouse model of spontaneous and persistent AF, we demonstrated that increased persistent Na+ current is sufficient to increase mitochondrial ROS and induce AF.

Hypothesis: Increased persistent Na+ current in the atria causes mitochondrial injury and increased ROS. We hypothesize that attenuating the injury and ROS can reduce the incidence AF in mice.

Methods: Transthoracic echocardiography and electron microscopic (EM) images were performed on F1759A-AF mice and control littermates. Hearts from 4-11 month old mice were sectioned and analyzed for intracellular (DCF, 20 μM) and mitochondrial oxidative stress (mitosox, 5mM). Four mice were treated with antioxidant mitotempo (0.7 mg/kg, IP, qd) for 6 weeks.

Results: F1759A-AF mice at 20-30 days of age, the left ventricular (LV) ejection fraction was reduced non-significantly by 14% compared to controls. LV ejection fraction modestly decreased, with a 27% and 35% relative reduction at 41-50 days and 51-80 days respectively (p<0.05, N=10). EM analysis showed that F1759A-AF mice had swollen mitochondria and ruptured outer membranes. There was a significant decrease in mitochondrial density in the mice with AF compared to littermate controls with normal sinus rhythm (74.2 ± 0.8 vs. 89.5 ± 0.2 %, p <0.05, N=4 AF, 2 control; over ~500 mitochondria analyzed in each group). Intracellular and mitochondrial ROS levels in the F1759A-AF mice were markedly increased 4.8 fold compared to control mice. Mitotempo treatment significantly decreased oxidative stress significantly by more than 50%, p<0.05, N=3 each group). Mitotempo reduced the incidence of spontaneous and sustained AF and converted 25% of mice to permanent normal sinus rhythm (n=4).

Conclusions: Increased persistent Na+ current can cause mitochondrial injury and increased ROS in mice with AF. 6-week treatment with mitotempo significantly decreased oxidative stress and reduced AF burden. Targeting mitochondrial injury can be a novel therapeutic pathway for treatment of AF caused by persistent Na+ current.

Sexual Dimorphic Characteristics in a Mouse Model of Atrial Fibrillation

Introduction: The incidence of atrial fibrillation (AF) is higher in men than in women. There is currently a lack of an animal model to study the gender-specific pathophysiology of spontaneous and persistent AF.

Hypothesis: We hypothesize that there are gender specific structural and electrophysiological modifications due to AF.

Methods: F1759A-NaV1.5 transgenic mice with spontaneous persistent AF were used to study gender specific structural and ultrastructural changes. Telemetry devices were implanted. Hearts were stained with Masson’s trichrome and mitosox. Analysis was performed on transmission electron microscopic (EM) images. Optical mapping was performed on the Langendorff perfused mouse hearts

Results: Spontaneous AF was detected in telemetry in 100% of 8 F1759A-AF mice. AF burden/20 hours recording was decreased in females (2.8 ± 0.5 hrs, N= 3) vs. males (8.5 ±1.6 hrs, N=5), p <0.05. QTc was shorter in females (69.5±10.7 ms, N=12) vs. males (83.2 ± 11.8 ms, N=19, p <0.002). Males (N=9) had increased right (RA) and left atrial (LA) fibrosis compared to females (N=8): RA: 4.1 ± 0.9% vs. 1.8 ± 0.3%, p<0.05 and LA: 4.2 ± 1.1% vs. 1.6 ± 0.7%. Mitosox staining showed increased oxidative stress in males (11.2 ± 1.8 A.U in males vs. 8.9 ± 1.4 A.U in females, N=5 each group). EM showed higher atrial mitochondrial density (9.1% increase), diameter (13.4% increase) and area (17.7% increase) in males than in females (n=3 each group), p<0.001. Optically mapped hearts (N=6 males, 10 females) showed higher dominant frequency, DFmax (33.9 ± 0.2 vs. 23.5 ±5.2 Hz, p<0.05), action potential duration, APD50 max (43.1 ±5.3 vs. 33.7 ±4.8 ms, p<0.05) and lower conduction velocity, CV (0.6 ± 0.2 vs. 1.1 ± 0.5 m/s, p<0.05) in males than compared to females.

Conclusions: Female mice had decreased atrial fibrosis, mitochondrial oxidative stress, and mitochondrial dysfunction. Higher QTc, APD and DFmax in males lead to increased AF burden, while increased fibrosis lead to lower CV. F1759A-AF mice may offer a means to understand and develop sex specific AF therapeutics.

Spatiotemporal Gradients are Necessary for Initiation and Maintenance of Atrial Fibrillation in Mice

Introduction: Aberrant sodium influx in F1759A-NaV1.5 mice is sufficient to cause spontaneous atrial fibrillation (AF), as well as, similar electrophysiological and structural changes seen in humans with AF.

Hypothesis: We hypothesize that APD heterogeneity is necessary for initiation and maintenance of AF.

Methods: Hearts from 3-12 month old F1759A-AF mice and control mice were isolated and Langendorff perfused. High resolution epicardial optical voltage mapping was performed using a CMOS camera and voltage sensitive dye, Di4ANEPPS.

Results: Atrial APD dispersion was 10 fold higher in F1759A-AF hearts compared to control mice in sinus rhythm ( p<0.05, N=4 control, 7 AF mice). Triggered activations were observed in F1759A-AF hearts arising from multiple atrial regions. Multiple wave breaks and reentry points were seen in AF hearts that lead to either a fibrillatory conduction or organized dominant meandering rotational activity. Singularity point density (SPD) maps demonstrated that wave breaks and rotational activity have an increased propensity to anchor at the regions of higher APD dispersion (N=7). Ranolazine (100-500μM) and ATX II (10-20nM) perfusion in the F1759A-AF hearts significantly reduced the APD dispersion by 74.3% (N=7). Ranolazine and ATXII homogenized APD dispersion and reduced AF inducibility by 100% and 80% respectively, p<0.05, N=4).

Conclusions: Wavebreaks and rotational reentrant circuits were anchored at border zones of increased spatiotemporal APD gradients. Lowering these gradients resulted in lower AF inducibilty. Thus, aiming to homogenize spatiotemporal APD gradients may be a new therapeutic target for AF in humans.

Cardiac Lesion Mapping In Vivo Using Intracardiac Myocardial Elastography

Radio frequency (RF) ablation of the myocardium is used to treat various cardiac arrhythmias. The size, spacing, and transmurality of lesions have been shown to affect the success of the ablation procedure; however, there is currently no method to directly image the size and formation of ablation lesions in real time. Intracardiac myocardial elastography (ME) has been previously used to image the decrease in cardiac strain during systole in the ablated region as a result of the lesion formation. However, the feasibility of imaging multiple lesions and identifying the presence of gaps between lesions has not yet been investigated. In this paper, RF ablation lesions (n = 7) were generated in the left ventricular epicardium in three anesthetized canines. Two sets of two lesions each were created in close proximity to one another with small gaps (1.5 and 4 cm), while one set of two lesions was created directly next to each other with no gap. A clinical intracardiac echocardiography system was programmed to transmit a custom diverging beam sequence at 600 Hz and used to image the ablation site before and after the induction of ablation lesions. Cumulative strains were estimated over systole using a normalized cross-correlational displacement algorithm and a least-squares strain kernel. Afterward, lesions were excised and subjected to tetrazolium chloride staining. Results indicate that intracardiac ME was capable of imaging the reduction in systolic strain associated with the formation of an ablation lesion. Furthermore, lesion sets containing gaps were able to be distinguished from lesion sets created with no gaps. These results indicate that the end-systolic strain measured using intracardiac ME may be used to image the formation of lesions induced during an RF ablation procedure, in order to provide critical assessment of lesion viability during the interventional procedure.

A 3‐D rendering algorithm for electromechanical wave imaging of a beating heart

Purpose

Arrhythmias can be treated by ablating the heart tissue in the regions of abnormal contraction. The current clinical standard provides electroanatomic 3‐D maps to visualize the electrical activation and locate the arrhythmogenic sources. However, the procedure is time‐consuming and invasive. Electromechanical wave imaging is an ultrasound‐based noninvasive technique that can provide 2‐D maps of the electromechanical activation of the heart. In order to fully visualize the complex 3‐D pattern of activation, several 2‐D views are acquired and processed separately. They are then manually registered with a 3‐D rendering software to generate a pseudo‐3‐D map. However, this last step is operator‐dependent and time‐consuming.

Methods

This paper presents a method to generate a full 3‐D map of the electromechanical activation using multiple 2‐D images. Two canine models were considered to illustrate the method: one in normal sinus rhythm and one paced from the lateral region of the heart. Four standard echographic views of each canine heart were acquired. Electromechanical wave imaging was applied to generate four 2‐D activation maps of the left ventricle. The radial positions and activation timings of the walls were automatically extracted from those maps. In each slice, from apex to base, these values were interpolated around the circumference to generate a full 3‐D map.

Results

In both cases, a 3‐D activation map and a cine‐loop of the propagation of the electromechanical wave were automatically generated. The 3‐D map showing the electromechanical activation timings overlaid on realistic anatomy assists with the visualization of the sources of earlier activation (which are potential arrhythmogenic sources). The earliest sources of activation corresponded to the expected ones: septum for the normal rhythm and lateral for the pacing case.

Conclusions

The proposed technique provides, automatically, a 3‐D electromechanical activation map with a realistic anatomy. This represents a step towards a noninvasive tool to efficiently localize arrhythmias in 3‐D.

Early Detection and Mapping of Ischemia using Myocardial Elastography

Objective

PUBLIC HEALTH RELEVANCE: Cardiovascular diseases rank as America's primary killer in both men and women, claiming the lives of over 41% of more than 2.4 million Americans who die each year. Myocardial elastography is a unique technique that can noninvasively map both the mechanical and electrical properties of the myocardium for early detection of disease.

Development of an automaton model of rotational activity driving atrial fibrillation

Background

Atrial fibrillation (AF) is difficult to treat effectively, owing to uncertainty in where to best ablate to eliminate arrhythmogenic substrate. A model providing insight into the electrical activation events would be useful to guide catheter ablation strategy.

Method

A two-dimensional, 576×576 node automaton was developed to simulate atrial electrical activity. The substrate field was altered by the presence of differing refractory period at varying locations. Fibrosis was added in the form of short, randomly positioned lines of conduction block. Larger areas of block were used to simulate ablation lesions. Anisotropy was imposed in a 2:1 ratio. A premature electrical impulse from one of four grid corners was utilized to initiate activation.

Results

Rotational activity was uninducible when refractory patch dimensions were less than 20×20 mm. For larger refractory regions, a single premature stimulus was capable of inducing an average of 1.19±1.10 rotors, which often formed near the patch edges. A maximum of 5 rotors formed when refractory patch dimensions approached the size of the entire left atrial virtual field. Rotors formed along a refractory patch edge, after wavefront arrival was delayed at turning points or due to the presence of a fiber cluster of sufficient size. However, rotational activity could also occur around a large fiber cluster without the need of spatially variable refractoriness. When obstacles to conduction were lacking in size, nascent rotors drifted and either extinguished, or stabilized upon anchoring at a sufficiently large fiber cluster elsewhere in the field. Transient rotors terminated when traversing a region with differing refractory periods, if no obstacle to conduction was present to sufficiently delay wavefront arrival beyond the longest refractory period. Other rotors were annihilated when a nearby rotor with faster spin rate gradually interrupted the activation pathway. Elimination of anchors by removal, or by simulated ablation over a sufficient region, prevented rotor onset at a particular location where it would otherwise form.

Conclusions

The presence of obstacles to conduction and spatial differences in refractory period are important parameters for initiating and maintaining rotational activity in this simulation of an atrial substrate.

Gender differences in atrial fibrillation

The Sexually Dimorphic Characteristics of the Pathophysiology and Treatment of Atrial Fibrillation

Cardiac arrhythmias are a prevalent clinical problem as it increases risk of stroke, heart failure, and overall morbidity. Treatment of arrhythmias may include blood thinners, rhythm control, as well as surgical ablation. In this chapter, we discuss the differences in diagnosis, prognosis, and treatment of cardiac arrhythmias in men and women. Further understanding of the gender specific differences of various cardiac arrhythmias including atrial fibrillation, long QT syndrome, and supraventricular arrhythmias may be helpful for more delivery of more personalized medicine.

2016

Increased Cardiac Conduction Abnormalities After Tricuspid Annuloplasty During Cardiac Transplantation: A Single Center 3 Year Retrospective Review

Introduction: Tricuspid annuloplasty (TA) performed in donor hearts at time of orthotopic cardiac transplantation to reduce tricuspid regurgitation and preserve right ventricular function in transplant recipients has been shown to improve transplant outcomes. However, after incorporation of TA into our surgical protocol, we have observed an increased incidence of conduction abnormalities including right bundle branch block and heart block suggestive of AV nodal injury after incorporation of TA into the transplant surgical protocol.

Methods: We conducted a retrospective review of medical charts of 97 adult cardiac transplantation recipients, as well as, information available on the donor hearts over a three year time period from 2014 to 2016 at Columbia University Medical Center, New York, NY.

Results: No donor hearts had RBBB prior to harvest. Before vs. after incorporation of the TA procedure into the transplant protocol: the mean age of transplant recipients was 52 ± 1.7 s.e.m years of age vs. 57 ± 1.3 s.e.m years of age. 6 patients (11.8%, n=51) vs. 19 TA patients (42.2%, n=45) had RBBB postoperatively (p<0.005). Development of RBBB was increased in 27 mm (52%) vs 25 mm TA (35%), p=NS. Only 1 recipient (1.9%, n=51) vs. 4 TA recipients (8.8 %, n=45) had complete heart block within 30 days postoperatively (p=0.19), two of whom went on to receive implantation of permanent pacemakers. One of the two patients ultimately recovered AV conduction.

Conclusions: There was a 3.6 fold increase in RBBB and 4.6 fold increase in incidence of AV block after incorporation of TA to the transplant surgical protocol at our center. Our results suggest that TA may cause injury to the conduction system of the donor heart. This is the first retrospective study demonstrating significant conduction abnormalities after incorporation of TA into the transplant surgical protocol.

3D Myocardial Elastography In Vivo

Strain evaluation is of major interest in clinical cardiology as it can quantify the cardiac function. Myocardial elastography, a radio-frequency (RF)-based crosscorrelation method, has been developed to evaluate the local strain distribution in the heart in vivo. However, inhomogeneities such as RF ablation lesions or infarction require a three-dimensional approach to be measured accurately. In addition, acquisitions at high volume rate are essential to evaluate the cardiac strain in three dimensions. Conventional focused transmit schemes using 2D matrix arrays, trade off sufficient volume rate for beam density or sector size to image rapid moving structure such as the heart, which lowers accuracy and precision in the strain estimation. In this study, we developed 3D myocardial elastography at high volume rates using diverging wave transmits to evaluate the local axial strain distribution in three dimensions in three open-chest canines before and after radio-frequency ablation. Acquisitions were performed with a 2.5 MHz 2D matrix array fully programmable used to emit 2000 diverging waves at 2000 volumes/s. Incremental displacements and strains enabled the visualization of rapid events during the QRS complex along with the different phases of the cardiac cycle in entire volumes. Cumulative displacement and strain volumes depict high contrast between non-ablated and ablated myocardium at the lesion location, mapping the tissue coagulation. 3D myocardial strain elastography could thus become an important technique to measure the regional strain distribution in three dimensions in humans.

Validation of electromechanical wave imaging in a canine model during pacing and sinus rhythm

Background

Accurate determination of regional areas of arrhythmic triggers is of key interest to diagnose arrhythmias and optimize their treatment. Electromechanical wave imaging (EWI) is an ultrasound technique that can image the transient deformation in the myocardium after electrical activation and therefore has the potential to detect and characterize location of triggers of arrhythmias.

Objectives

The objectives of this study were to investigate the relationship between the electromechanical and the electrical activation of the left ventricular (LV) endocardial surface during epicardial and endocardial pacing and during sinus rhythm as well as to map the distribution of electromechanical delays.

Methods

In this study, 6 canines were investigated. Two external electrodes were sutured onto the epicardial surface of the LV. A 64-electrode basket catheter was inserted through the apex of the LV. Ultrasound channel data were acquired at 2000 frames/s during epicardial and endocardial pacing and during sinus rhythm. Electromechanical and electrical activation maps were synchronously obtained from the ultrasound data and the basket catheter, respectively.

Results

The mean correlation coefficient between electromechanical and electrical activation was 0.81 for epicardial anterior pacing, 0.79 for epicardial lateral pacing, 0.69 for endocardial pacing, and 0.56 for sinus rhythm.

Conclusion

The electromechanical activation sequence determined by EWI follows the electrical activation sequence and more specifically in the case of pacing. This finding is of key interest in the role that EWI can play in the detection of the anatomical source of arrhythmias and the planning of pacing therapies such as cardiovascular resynchronization therapy.

Electromechanical wave imaging (EWI) validation in all four cardiac chambers with 3D electroanatomic mapping in canines in vivo

Characterization and mapping of arrhythmias is currently performed through invasive insertion and manipulation of cardiac catheters. Electromechanical wave imaging (EWI) is a non-invasive ultrasound-based imaging technique, which tracks the electromechanical activation that immediately follows electrical activation. Electrical and electromechanical activations were previously found to be linearly correlated in the left ventricle, but the relationship has not yet been investigated in the three other chambers of the heart. The objective of this study was to investigate the relationship between electrical and electromechanical activations and validate EWI in all four chambers of the heart with conventional 3D electroanatomical mapping. Six (n  =  6) normal adult canines were used in this study. The electrical activation sequence was mapped in all four chambers of the heart, both endocardially and epicardially using the St Jude's EnSite 3D mapping system (St. Jude Medical, Secaucus, NJ). EWI acquisitions were performed in all four chambers during normal sinus rhythm, and during pacing in the left ventricle. Isochrones of the electromechanical activation were generated from standard echocardiographic imaging views. Electrical and electromechanical activation maps were co-registered and compared, and electrical and electromechanical activation times were plotted against each other and linear regression was performed for each pair of activation maps. Electromechanical and electrical activations were found to be directly correlated with slopes of the correlation ranging from 0.77 to 1.83, electromechanical delays between 9 and 58 ms and R2 values from 0.71 to 0.92. The linear correlation between electrical and electromechanical activations and the agreement between the activation maps indicate that the electromechanical activation follows the pattern of propagation of the electrical activation. This suggests that EWI may be used as a novel non-invasive method to accurately characterize and localize sources of arrhythmias.

Intracardiac myocardial elastography for lesion quantification in cardiac radiofrequency ablation

Radiofrequency ablation of the myocardium is used to treat various cardiac arrhythmias. The size, spacing, and transmurality of lesions have been shown to affect the success of the ablation procedure; however, there is currently no method to directly image the size and formation of ablation lesions in real time. Intracardiac myocardial elastrography has been used previously to image the reduction in end-systolic strain in the ablated region as a result of the lesion formation. However, the relationship between end-systolic strain change and lesion size has not been investigated. In this study, a large animal model is used to establish a relationship between the area affected by the strain reduction and lesion volume. Ablation lesions (n=10) were created in the left ventricular epicardium in five anesthetized canines. A clinical intracardiac echocardiography machine was programmed to emit a custom diverging beam sequence at 600 Hz and used to image the ablation site before and after the induction of a lesion. Cumulative strains were estimated over systole using a normalized cross-correlation displacement algorithm and a Savitzky-Golay strain kernel. The reduction in strain as a result of the ablation was computed by comparing cumulative end-systolic strains before and after ablation. Lesion volume was also measured ex vivo and compared to the area of significant strain change (>8% reduction) for each lesion. A good correlation was found between the area of significant strain change and lesion volume (r 2 = 0.86). These results indicate that end-systolic strain measured using ME can be used to estimate the size of lesions induced during an RF ablation procedure, potentially assisting clinicians in lesion formation assessment during the procedure.

176-20: Cryoballoon ablation as treatment of recent paroxysmal atrial fibrillation. Data from a large cohort of patients followed in a real world multicenter experience

Introduction: Atrial tachycardia (AT) is an atrial arrhythmia that be treated by ablation of the focal site triggering the arrhythmia. Electromechanical wave imaging (EWI) is a novel, non-invasive, ultrasound imaging technique, used to map the transmural electromechanical activation in vivo in all four cardiac chambers in canine models. In this study, we validate EWI against 3D electroanatomical mapping and use EWI to non-invasively localize focal atrial pacing sites in right and left atria.

Methods: In six (N = 6) normal adult male dogs, electrical activation maps in normal sinus rhythm in all four chambers were obtained using a 3D electroanatomical mapping system (Ensite Velocity, St. Jude Medical, Secaucus, NJ, USA). These maps were compared to electromechanical activation maps, or isochrones, obtained with EWI. A Verasonics ultrasound system (Verasonics, Redmond, WA, USA) with a 2.5-MHz phased array and an unfocused beam sequence at 2000 frames/s in the standard apical views was used for EWI. Axial incremental displacements and strains were estimated using high-precision, RF-based speckle tracking. The myocardium was segmented and pseudo-3D isochrones of the electromechanical activation were generated. EWI isochrones were also obtained in four additional open-chest canines (N = 4) while pacing from several right and left atrial locations.

Results: There was a direct correlation between electrical and electromechanical activations obtained in all four chambers with linear regression slopes from 0.77 to 1.83, intercepts from 17.8 ms to 58.6 ms and R2 values from 0.71 to 0.92. Isochrones obtained using EWI all showed the earliest activation located at the region of pacing and correlated directly with 3D electroanatomical maps generated during pacing.

Conclusions: Direct linear correlation between electrical and electromechanical activations in all four chambers suggests that the electromechanical activation follows the path of the electrical activation. EWI may be used as a non-invasive tool capable of correctly detecting the origin of right and left focal AT. This suggests that EWI, a non-invasive, cost-effective, ultrasound-based technique may be used in the clinical assessment of arrhythmia in humans.

49-03: Arrhythmogenic Features of Channels of Surviving Myocytes in Post-Infarct Patients With and Without Spontaneous VT

Aims: In ventricular scar, the impulse spread is slow as it traverses multiple split and zigzag channels of surviving muscle. We aimed to evaluate electrograms in the scar to determine their local delay in relation to the onset of ventricular activation (activation time) and inequality in voltage splitting (entropy), and their relationship to channels. We reasoned that unlike innocuous bystander channels, which are often short with multiple side branches, ventricular tachycardia (VT) supporting channels have very slow impulse spread and possess low entropy due to their longer protected length and relative lack of side branching.

Methods: Patients with ischemic cardiomyopathy and multiple inducible VT were studied. In the initial mapping stage (16 patients, 58 VTs), left ventricular endocardial mapping was performed in sinus rhythm. Detailed pace mapping was used to identify VT channels, and confirmed, when feasible, by entrainment. The scar electrograms were analyzed in time- and voltage-domains to determine mean activation time, dispersion in activation time and entropy. The predictive performances of these properties to detect VT channels were tested. In the application stage (7 patients, 20 VTs), these properties were prospectively tested to guide catheter ablation.

Results: A mean of 763 ± 203 sampling points per-patient were taken, 451 ± 145 points in dense scar. From 1770 pace maps, 174 channels were identified, and 47 corresponded to inducible VTs. A combination of scar electrograms with the latest mean activation time and minimum entropy, in a high activation dispersion region, accurately recognized regions containing VT channels (kappa = 0.89, sensitivity = 86%, specificity = 100%, positive predictive value = 93%, and negative predictive value = 100%). Finally, focused ablation within the prospective channel regions eliminated 18/20 inducible VTs.

Conclusion: Activation time and entropy mapping in the scar accurately identifies VT channels during sinus rhythm. This can expedite recognition of VT channels without pace mapping or mapping during VT and minimize extensive ablation.

29-06: Inducibility of Atrial Fibrillation After Epicardial Injection of the new pharmaceutical composition containing botulinum toxin into epicardial fat pads

Background: Prior clinical and animal studies suggest that botulinum toxin injection into the epicardial fat pads can suppress atrial fibrillation (AF) recurrences and inducibility. However, currently known botulinum toxin compositions do not have a prolonged action, nor increase the therapeutic effect of botulinum toxin and are not intended to treat cardiac arrhythmias.

Objective: The aim of the present study was to assess the efficacy and safety of the new pharmaceutical composition containing botulinum toxin and mucopolysaccharide injection into epicardial fat pads for prevention of AF.

Methods: Twenty-four dogs were separated into 3 groups: epicardial approach for the new pharmaceutical composition containing botulinum toxin and mucopolysaccharide (chitosan; WO2014184746 A1) injection into 3 main epicardial fat pads, epicardial approach for placebo (normal saline) injection (control 1; n = 8) and epicardial approach for pure botulinum toxin injection (control 2; n = 8).

Results: 3 epicardial injections (50 unit of botulinum toxin per 1 mL at each) were administrated into 3 main left atrial autonomic nervous system projection of each animal. Injections of all forms botulinum toxin demonstrated dramatic prolongation of ERP in all PV-atrial junctions and vagal stimulation shortened ERP was less pronounced. Suppression of AF inducibility was observed at day 7 after all forms botulinum toxin group injections. The reduction of AF inducibility after pure botulinum toxin injection was: at 7 day - 57% (p < 0.001 vs placebo; p < 0.001 vs baseline); at 14 day - 61% (p < 0.001 vs placebo; p < 0.001 vs baseline); at 1 month - 38% (p < 0.001 vs placebo; p < 0.001 vs baseline); at 3 month - 23% (p = 0.003; p = 0.06 vs baseline). Composition containing botulinum toxin and mucopolysaccharide showed the lowest AF inducibility and prolonged effect: at 7 day - 86% (p < 0.05 vs pure form); at 14 day - 75% (p < 0.05 vs pure form); at 1 month - 71% (p < 0.05 vs pure form); at 3 month - 65% (p < 0.05 vs pure form). No cardiac suppressive effect or significant procedure-related complications occurred.

Conclusions: Composition containing botulinum toxin and mucopolysaccharide injection into epicardial fat pads was feasible and safe, increased and prolonged effect of complete abolition of cardiac vagal responses and significant AF suppression.

ABERRANT SODIUM INFLUX IS SUFFICIENT TO CAUSE CARDIOMYOPATHY AND SPONTANEOUS SUSTAINED ATRIAL FIBRILLATION IN MICE

Background

Increased sodium influx via incomplete inactivation of NaV1.5 is correlated with an increased incidence of atrial fibrillation (AF) in humans. We created mice expressing F1759A-NaV1.5, and demonstrate that incomplete Na+ channel inactivation is sufficient to cause a novel mouse model with spontaneous and prolonged episodes of AF.

Methods

A modified α-myosin heavy chain (α-MHC) promoter was used as the responder, and mice were crossed with α-MHC-reverse tet-transactivator protein (rtTA) mice. Double TG (dTG) mice with doxycycline-regulated cardiac-specific expression of FLAG-F1759A-NaV1.5 and rtTA had spontaneous and prolonged AF. Whole cell patch and calcium imaging was performed on cardiomyocytes. Echocardiography, histology, transmission electron microscopy (TEM), and optical mapping were performed on whole hearts. Telemeters were implanted. Mice were given IP injection of NCX inhibitor, SEA 0400.

Results

Cardiomyocytes from dTG mice have increased persistent sodium current in the atria and ventricles. dTG mice had decreased heart function with increased atrial size and fibrosis. TEM of dTG mice showed myofibril disarray, mitochondrial necrosis, and increased T-tubule size. Optical mapping demonstrated dTG murine hearts are capable of sustaining rotors with high dominant frequency with high regularity indices, and suggests that rotors meander in areas of high spatiotemporal gradients. The mean reduction in AF burden after IP injection of NCX inhibitor, SEA 0400, during the 20-hour recording period mice was 59% (n=5).

Conclusions

Increased persistent sodium current caused heterogeneously prolonged action potential duration and rotors, wave and wavelets in the atria, mimicking the mechanistic theories for AF in humans. Targeting the downstream effects of enhanced sodium entry by acutely inhibiting the sodium-calcium exchanger markedly reduced the burden of AF and ventricular arrhythmias in vivo, identifying a new therapeutic approach for AF.

Aberrant sodium influx causes cardiomyopathy and atrial fibrillation in mice

Increased sodium influx via incomplete inactivation of the major cardiac sodium channel NaV1.5 is correlated with an increased incidence of atrial fibrillation (AF) in humans. Here, we sought to determine whether increased sodium entry is sufficient to cause the structural and electrophysiological perturbations that are required to initiate and sustain AF. We used mice expressing a human NaV1.5 variant with a mutation in the anesthetic-binding site (F1759A-NaV1.5) and demonstrated that incomplete Na+ channel inactivation is sufficient to drive structural alterations, including atrial and ventricular enlargement, myofibril disarray, fibrosis and mitochondrial injury, and electrophysiological dysfunctions that together lead to spontaneous and prolonged episodes of AF in these mice. Using this model, we determined that the increase in a persistent sodium current causes heterogeneously prolonged action potential duration and rotors, as well as wave and wavelets in the atria, and thereby mimics mechanistic theories that have been proposed for AF in humans. Acute inhibition of the sodium-calcium exchanger, which targets the downstream effects of enhanced sodium entry, markedly reduced the burden of AF and ventricular arrhythmias in this model, suggesting a potential therapeutic approach for AF. Together, our results indicate that these mice will be important for assessing the cellular mechanisms and potential effectiveness of antiarrhythmic therapies.

Diagnosis, treatment, and mechanisms of long QT syndrome

Molecular genetic studies have linked gene mutations to several inherited cardiovascular diseases, the prototypic example being ion channelopathies causing delayed cardiac repolarization. Congenital long QT syndrome (LQTS) is an inherited arrhythmia syndrome characterized by prolonged QT interval, and an increased risk of polymorphic ventricular tachycardia and sudden cardiac death. The identification and in-depth scientific study of gene mutations associated with this syndrome have enabled novel insights into the mechanisms of the cardiac action potential and cardiac arrhythmias. In this review, we summarize the most recent advances in the diagnosis and treatment of LQTS as well as the mechanisms responsible for this disorder.

2015

Preclinical evidence that trametinib enhances the response to antiangiogenic tyrosine kinase inhibitors in renal cell carcinoma

Sunitinib and pazopanib are antiangiogenic tyrosine kinase inhibitors (TKI) used to treat metastatic renal cell carcinoma (RCC). However, the ability of these drugs to extend progression-free and overall survival in this patient population is limited by drug resistance. It is possible that treatment outcomes in RCC patients could be improved by rationally combining TKIs with other agents. Here, we address whether inhibition of the Ras-Raf-MEK-ERK1/2 pathway is a rational means to improve the response to TKIs in RCC. Using a xenograft model of RCC, we found that tumors that are resistant to sunitinib have a significantly increased angiogenic response compared with tumors that are sensitive to sunitinib in vivo. We also observed significantly increased levels of phosphorylated ERK1/2 in the vasculature of resistant tumors, when compared with sensitive tumors. These data suggested that the Ras-Raf-MEK-ERK1/2 pathway, an important driver of angiogenesis in endothelial cells, remains active in the vasculature of TKI-resistant tumors. Using an in vitro angiogenesis assay, we identified that the MEK inhibitor (MEKI) trametinib has potent antiangiogenic activity. We then show that, when trametinib is combined with a TKI in vivo, more effective suppression of tumor growth and tumor angiogenesis is achieved than when either drug is utilized alone. In conclusion, we provide preclinical evidence that combining a TKI, such as sunitinib or pazopanib, with a MEKI, such as trametinib, is a rational and efficacious treatment regimen for RCC

Matter of fat: are lipids antiarrhythmic?

1314 Circ Arrhythm Electrophysiol December 2015 initiation (triggers) in the same hearts. After an MI, cells within the region of infarction are in different stages of depolarization. In the center of the ischemic zone, cells depolarize and die, whereas in the periphery, cells may be partially depolarized and, therefore, may be more excitable. During the acute time period post MI, the surge in catecholamines is thought to trigger ventricular arrhythmias through activation of endothelin-1. Thus, it is possible that these events still occur. Furthermore, in the presence of enhanced Ca2+ currents in the LDLr−/− and ApoA1−/− myocytes, delayed afterdepolarizations and early afterdepolarizations are more likely to occur.

Atrial tachycardias after atrial fibrillation ablation manifest different waveform characteristics: implications for characterizing tachycardias

Introduction

Atrial fibrillation (AF) ablation patients often manifest atrial tachycardias (AT) with atypical ECG morphologies that preclude accurate localization and mechanism. Diagnostic maneuvers used to define ATs during electrophysiology studies can be limited by tachycardia termination or transformation. Additional methods of characterizing post‐AF ablation ATs are required.

Methods and Results

We evaluated the utility of noninvasive ECG signal analytics in postablation AF patients for the following features: (1) Localization of ATs (i.e., right vs. left atrium), and (2) Identification of common left AT mechanisms (i.e., focal vs. macroreentrant). Atrial waveforms from the surface ECG were used to analyze (1) spectral organization, including dominant amplitude (DA) and mean spectral profile (MP), and (2) temporospatial variability, using temporospatial correlation coefficients.

We studied 94 ATs in 71 patients who had undergone prior pulmonary vein isolation for AF and returned for a second ablation: (1) right atrial cavotricuspid‐isthmus dependent (CTI) ATs (n = 21); (2) left atrial macroreentrant ATs (n = 41) and focal ATs (n = 32). Right CTI ATs manifested higher DAs and lower MPs than left ATs, indicative of greater stability and less complexity in the frequency spectrum. Left macroreentrant ATs possessed higher temporospatial organization than left focal ATs.

Conclusions

Noninvasively recorded atrial waveform signal analyses show that right ATs possess more stable activation properties than left ATs, and left macroreentrant ATs manifest higher temporospatial organization than left focal ATs. Further prospective analyses evaluating the role these novel ECG‐derived tools can play to help localize and identify mechanisms of common ATs in AF ablation patients are warranted.

Parsing a perplexing paroxysmal pathway

Catheter ablation is an effective and often preferred treatment for supraventricular tachycardia (SVT). Successful ablation is predicated on a precise diagnosis of the arrhythmia mechanism.1 The initial pacing maneuvers during electrophysiologic study (EPS) are often able to narrow the differential diagnosis immediately.2 We report an unusual case of SVT in which the initial findings at EPS were inconsistent with the eventual mechanism of the tachycardia.

Assessing the atrial electromechanical coupling during atrial focal tachycardia, flutter, and fibrillation using electromechanical wave imaging in humans

Minimally-invasive treatments of cardiac arrhythmias such as radio-frequency ablation are gradually gaining importance in clinical practice but still lack a noninvasive imaging modality which provides insight into the source or focus of an arrhythmia. Cardiac deformations imaged at high temporal and spatial resolution can be used to elucidate the electrical activation sequence in normal and paced human subjects non-invasively and could potentially aid to better plan and monitor ablation-based arrhythmia treatments. In this study, a novel ultrasound-based method is presented that can be used to quantitatively characterize focal and reentrant arrhythmias. Spatio-temporal maps of the full-view of the atrial and ventricular mechanics were obtained in a single heartbeat, revealing with otherwise unobtainable detail the electromechanical patterns of atrial flutter, fibrillation, and tachycardia in humans. During focal arrhythmias such as premature ventricular complex and focal atrial tachycardia, the previously developed electromechanical wave imaging methodology is hereby shown capable of identifying the location of the focal zone and the subsequent propagation of cardiac activation. During reentrant arrhythmias such as atrial flutter and fibrillation, Fourier analysis of the strains revealed highly correlated mechanical and electrical cycle lengths and propagation patterns. High frame rate ultrasound imaging of the heart can be used non-invasively and in real time, to characterize the lesser-known mechanical aspects of atrial and ventricular arrhythmias, also potentially assisting treatment planning for intraoperative and longitudinal monitoring of arrhythmias.

Secondhand smoking is associated with vascular inflammation

BACKGROUND

The relative risk for cardiovascular diseases in passive smokers is similar to that of active smokers despite almost a 100-fold lower dose of inhaled cigarette smoke. However, the mechanisms underlying the surprising susceptibility of the vascular tissue to the toxins in secondhand smoke (SHS) have not been directly investigated. The aim of this study was to investigate directly vascular endothelial cell function in passive smokers.

METHODS

Using a minimally invasive method of endothelial biopsy, we investigated directly the vascular endothelium in 23 healthy passive smokers, 25 healthy active smokers, and 23 healthy control subjects who had never smoked and had no regular exposure to SHS. Endothelial nitric oxide synthase (eNOS) function (expression of basal eNOS and activated eNOS [phosphorylated eNOS at serine1177 (P-eNOS)]) and expression of markers of inflammation (nuclear factor-κB [NF-κB]) and oxidative stress (nitrotyrosine) were assessed in freshly harvested venous endothelial cells by quantitative immunofluorescence.

RESULTS

Expression of eNOS and P-eNOS was similarly reduced and expression of NF-κB was similarly increased in passive and active smokers compared with control subjects. Expression of nitrotyrosine was greater in active smokers than control subjects and similar in passive and active smokers. Brachial artery flow-mediated dilation was similarly reduced in passive and active smokers compared with control subjects, consistent with reduced endothelial NO bioavailability.

CONCLUSIONS

Secondhand smoking increases vascular endothelial inflammation and reduces active eNOS to a similar extent as active cigarette smoking, indicating direct toxic effects of SHS on the vasculature.

Intracardiac myocardial elastography in canines and humans in vivo

Intracardiac echocardiography (ICE) is a useful imaging modality which is used during RF ablation procedures to identify anatomical structures. Utilizing ICE in conjunction with myocardial elastography (ME) can provide additional information on the mechanical properties of cardiac tissue and provide information on mechanical changes caused by ablation. The objective of this study was to demonstrate that ICE can be used at high frame rate using a diverging beam transmit sequence to image myocardial strain and differentiate myocardial tissue properties before, during, and after ablation for a clinical ablation procedure. In this feasibility study, three normal canines and eight patients with atrial fibrillation (AF) were studied in vivo. A 5.8-MHz ICE transducer was used to image the heart with a diverging beam transmit method achieving 1200 frames per second (fps). Cumulative axial displacement estimation was performed using 1-D cross-correlation with a window size of 2.7 mm and 95% overlap. Axial cumulative strains were estimated in the left atrium (LA) and right atrium (RA) using a least-squares estimator with a kernel of 2 mm on the axial displacements. In the canine case, radial thickening was detected in the lateral wall and in the interatrial septum during LA emptying. For AF patients, the mean absolute strain in the ablated region was lower (6.7 ± 3.1%) than before the ablation (17.4 ± 9.3%) in LA at the end of the LA emptying phase. In the cavotricuspid isthmus (CTI) region, mean absolute strain magnitude at the end of the RA emptying phase was found to be higher during ablation (43.0 ± 18.1%) compared with after ablation (33.7 ± 15.8%). Myocardial strains in the LA of an AF patient were approximately 2.6 times lower in the ablated region than before ablation. This initial feasibility indicates that ME can be used as a new imaging modality in conjunction with ICE in RF ablation guidance and lesion monitoring.

The PDZ motif of the α1C subunit is not required for surface trafficking and adrenergic modulation of CaV1. 2 channel in the heart

Voltage-gated Ca2+ channels play a key role in initiating muscle excitation-contraction coupling, neurotransmitter release, gene expression, and hormone secretion. The association of CaV1.2 with a supramolecular complex impacts trafficking, localization, turnover, and, most importantly, multifaceted regulation of its function in the heart. Several studies hint at an important role for the C terminus of the α1C subunit as a hub for multidimensional regulation of CaV1.2 channel trafficking and function. Recent studies have demonstrated an important role for the four-residue PDZ binding motif at the C terminus of α1C in interacting with scaffold proteins containing PDZ domains, in the subcellular localization of CaV1.2 in neurons, and in the efficient signaling to cAMP-response element-binding protein in neurons. However, the role of the α1C PDZ ligand domain in the heart is not known. To determine whether the α1C PDZ motif is critical for CaV1.2 trafficking and function in cardiomyocytes, we generated transgenic mice with inducible expression of an N-terminal FLAG epitope-tagged dihydropyridine-resistant α1C with the PDZ motif deleted (ΔPDZ). These mice were crossed with α-myosin heavy chain reverse transcriptional transactivator transgenic mice, and the double-transgenic mice were fed doxycycline. The ΔPDZ channels expressed, trafficked to the membrane, and supported robust excitation-contraction coupling in the presence of nisoldipine, a dihydropyridine Ca2+ channel blocker, providing functional evidence that they appropriately target to dyads. The ΔPDZ Ca2+ channels were appropriately regulated by isoproterenol and forskolin. These data indicate that the α1C PDZ motif is not required for surface trafficking, localization to the dyad, or adrenergic stimulation of CaV1.2 in adult cardiomyocytes.The mechanisms responsible for CaV1.2 regulation by the α1C C terminus are unknown.

2014

Novel Method Using Intracardiac Myocardial Elastography Provides Real-time Assessment of Right and Left Atrial Radiofrequency Ablation Lesions in Humans

Introduction: Radiofrequency (RF) ablation is an effective method for treatment of cardiac arrhythmias; however, current assessment of RF lesion formation by measuring impedance changes, electrogram dimunition, power and catheter temperature are indirect and may be inaccurate. We present a novel, imaging modality, myocardial elastography (ME), which when used in adjunct with intracardiac echocardiography (ICE) may provide real-time assessment of RF lesion formation, and changes in tissue mechanics after lesion delivery.

Methods: 7 patients (mean age 64.3 +/- 14 years) underwent imaging of their left atrium with a 5.8-MHz ICE probe before and after RF ablation with an irrigated catheter at high frame rates (1200 Hz). The channel data was acquired on a clinical ultrasound system, image reconstruction and motion tracking were performed, and cumulative axial strains were obtained from displacement estimations. The location of the ablation lesion was confirmed using ICE imaging, electroanatomic mapping and fluoroscopy. ICE images were acquired before and after 7 RF ablations (mean power of 31 ± 3 W, mean of 38 ± 14 secs, mean impedance of 112 ± 5 Ω, catheter temperature of 31 ± 3 degrees Celsius). One ICE image was obtained as a control with the ablation catheter apposed to the atrial myocardium without RF delivery.

Results: When RF was not used, ME showed a mean absolute strain of 15.1±5.1 % before, and 16.7±7.5 % (p=NS) after catheter positioning, thus demonstrating no difference in strain due to catheter contact. ME showed a mean absolute strain of 17.1 ± 9.7 % before and 8.3 ± 6.3 % after ablation (p<0.05). This demonstrates that ME can detect changes in mechanical deformation due to RF, and that ablated regions have lower strains. After RF delivery, changes in strain were apparent when reviewed by three blinded independent operators.

Conclusions: This pilot study shows that ME, a novel imaging modality, may be used during ablation for real-time assessment of cardiac mechanical deformation and functional myocardial changes due to RF lesion delivery.

2013

Intracardiac myocardial elastography in humans in vivo during radio-frequency ablation

Intracardiac echocardiography (ICE) is commonly used during radio-frequency (RF) ablation procedures for procedural guidance. Besides its imaging function, ICE could be used to assess mechanical properties of the myocardium to improve the ablation outcome. The objective of this study was to demonstrate the feasibility of imaging myocardial strains in vivo within the same imaging plane as ICE at high temporal resolution. A 5.8-MHz center frequency ICE probe was used to image the heart of two humans with atrial arrhythmias in vivo before and after RF ablation at high frame rates (1200 Hz), and the channel data were acquired on a clinical ultrasound system. The RF signals were reconstructed on a 9cm depth and 90° field of view region and axial cumulative displacement estimation was performed using 1-D cross-correlation using a window size of 2.6 mm and 95% overlap. Cumulative axial strains were obtained from the displacements using a least-squares estimator with a kernel of 5.1 mm. Cumulative axial strains in the left atrium during systole were 23% and 18% in the two subjects before ablation, changing to 8% and 11% in the same location after ablation. Myocardial elastography could thus provide some quantitative methods for monitoring the generation of thermal lesions.

 

 

Enhanced efferocytosis of apoptotic cardiomyocytes through MER tyrosine kinase links acute inflammation resolution to cardiac repair after infarction

Rationale

Efficient clearance of apoptotic cells (efferocytosis) is a prerequisite for inflammation resolution and tissue repair. Following myocardial infarction (MI), phagocytes are recruited to the heart and promote clearance of dying cardiomyocytes (CMs). The molecular mechanisms of efferocytosis of CMs and in the myocardium are unknown. The injured heart provides a unique model to examine relationships between efferocytosis and subsequent inflammation resolution, tissue remodeling, and organ function.

Objective

We set out to identify mechanisms of dying cardiomyocyte (CM) engulfment by phagocytes and to for the first time assess the causal significance of disrupting efferocytosis during MI.

Methods and Results

In contrast to other apoptotic cell receptors, macrophage MER tyrosine kinase (MER-TK) was necessary and sufficient for efferocytosis of CMs ex vivo. In mice, Mertk was specifically induced in Ly6cLO myocardial phagocytes after experimental coronary occlusion. Mertk deficiency led to an accumulation of apoptotic CMs, independent of changes in non-CMs, and a reduced index of in vivo efferocytosis. Importantly, suppressed efferocytosis preceded increases in myocardial infarct size and led to delayed inflammation resolution and reduced systolic performance. Reduced cardiac function was reproduced in chimeric mice deficient in bone marrow Mertk; reciprocal transplantation of Mertk+/+ marrow into Mertk-/- mice corrected systolic dysfunction. Interestingly, an inactivated form of MERTK, known as solMER, was identified in infarcted myocardium, implicating a natural mechanism of MERTK inactivation post MI.

Conclusions

These data collectively and directly link efferocytosis to wound healing in the heart and identify Mertk as a significant link between acute inflammation resolution and organ function.

Enhanced efferocytosis of apoptotic cardiomyocytes through myeloid-epithelial-reproductive tyrosine kinase links acute inflammation resolution to cardiac repair after infarction

Rationale:

Efficient clearance of apoptotic cells (efferocytosis) is a prerequisite for inflammation resolution and tissue repair. After myocardial infarction, phagocytes are recruited to the heart and promote clearance of dying cardiomyocytes. The molecular mechanisms of efferocytosis of cardiomyocytes and in the myocardium are unknown. The injured heart provides a unique model to examine relationships between efferocytosis and subsequent inflammation resolution, tissue remodeling, and organ function.

Objective:

We set out to identify mechanisms of dying cardiomyocyte engulfment by phagocytes and, for the first time, to assess the causal significance of disrupting efferocytosis during myocardial infarction

Methods and Results:

In contrast to other apoptotic cell receptors, macrophage myeloid-epithelial-reproductive tyrosine kinase was necessary and sufficient for efferocytosis of cardiomyocytes ex vivo. In mice, Mertk was specifically induced in Ly6cLO myocardial phagocytes after experimental coronary occlusion. Mertk deficiency led to an accumulation of apoptotic cardiomyocytes, independently of changes in noncardiomyocytes, and a reduced index of in vivo efferocytosis. Importantly, suppressed efferocytosis preceded increases in myocardial infarct size and led to delayed inflammation resolution and reduced systolic performance. Reduced cardiac function was reproduced in chimeric mice deficient in bone marrow Mertk; reciprocal transplantation of Mertk+/+ marrow into Mertk−/− mice corrected systolic dysfunction. Interestingly, an inactivated form of myeloid-epithelial-reproductive tyrosine kinase, known as solMER, was identified in infarcted myocardium, implicating a natural mechanism of myeloid-epithelial-reproductive tyrosine kinase inactivation after myocardial infarction.

Conclusions:

These data collectively and directly link efferocytosis to wound healing in the heart and identify Mertk as a significant link between acute inflammation resolution and organ function.

Diet-induced obesity causes long QT and reduces transcription of voltage-gated potassium channels

In humans, obesity is associated with long QT, increased frequency of premature ventricular complexes, and sudden cardiac death. The mechanisms of the pro-arrhythmic electrophysiologic remodeling of obesity are poorly understood. We tested the hypothesis that there is decreased expression of voltage-gated potassium channels in the obese heart, leading to long QT. Using implanted telemeters, we found that diet-induced obese (DIO) wild-type mice have impaired cardiac repolarization, demonstrated by long QT, as well as more frequent ventricular ectopy, similar to obese humans. DIO mice have reduced protein and mRNA levels of the potassium channel Kv1.5 caused by a reduction of the transcription factor cyclic AMP response element binding protein (CREB) in DIO hearts. We found that CREB knock-down by siRNA reduces Kv1.5, CREB binds to the Kv1.5 promoter in the heart, and CREB increases transcription of mouse and human Kv1.5 promoters. The reduction in CREB protein during lipotoxicity can be rescued by inhibiting protein kinase D (PKD). Our results identify a mechanism for obesity-induced electrophysiologic remodeling in the heart, namely PKD-induced reduction of CREB, which in turn decreases expression of the potassium channel Kv1.5.

Reduced vascular smooth muscle BK channel current underlies heart failure‐induced vasoconstriction in mice

Excessively increased peripheral vasoconstriction is a hallmark of heart failure (HF). Here, we show that in mice with systolic HF post–myocardial infarction, the myogenic tone of third‐order mesenteric resistance vessels is increased, the vascular smooth muscle (VSM) membrane potential is depolarized by ~20 mV, and vessel wall intracellular [Ca2+] is elevated relative to that in sham‐operated control mice. Despite the increased [Ca2+], the frequency and amplitude of spontaneous transient outward currents (STOCs), mediated by large conductance, Ca2+‐activated BK channels, were reduced by nearly 80% (P<0.01) and 25% (P<0.05), respectively, in HF. The expression of the BK α and β1 subunits was reduced in HF mice compared to controls (65 and 82% lower, respectively, P<0.01). Consistent with the importance of a reduction in BK channel expression and function in mediating the HF‐induced increase in myogenic tone are two further findings: a blunting of paxilline‐induced increase in myogenic tone in HF mice compared to controls (0.9 vs. 10.9%, respectively), and that HF does not alter the increased myogenic tone of BK β1‐null mice. These findings identify electrical dysregulation within VSM, specifically the reduction of BK currents, as a key molecular mechanism sensitizing resistance vessels to pressure‐induced vasoconstriction in systolic HF.—Wan, E., Kushner, J. S., Zakharov, S., Nui, X‐W., Chudasama, N., Kelly, C., Waase, M., Doshi, D., Liu, G., Iwata, S., Shiomi, T., Katchman, A., D'Armiento, J., Homma, S., Marx, S. O. Reduced vascular smooth muscle BK channel current underlies heart failure‐induced vasoconstriction in mice

The MER Tyrosine Kinase Limits Apoptotic Cell Accumulation in the Heart and Attenuates Ventricular Dysfunction Post Myocardial Infarction

Post myocardial infarction (MI), phagocytes are recruited to the heart to promote tissue repair and phagocytic clearance of necrotic and apoptotic cells. The molecular pathways required for apoptotic cell clearance (efferocytosis) in the heart are unknown, as well as if efferocytosis per se affects ventricular remodeling and cardiac function. MERTK is a receptor for apoptotic cells that is expressed on the surface of recruited macrophage phagocytes. Previously we showed that MERTK is required for efferocytosis and reduced apoptotic cell accumulation in atherosclerosis. Given the evidence that clearance pathways are linked to resolution of inflammation and ensuing tissue repair, we hypothesized that the efficiency of efferocytosis post MI contributes to the extent of subsequent heart repair. To test this, control and Mertk deficient mice were subjected to MI by ligation of the left anterior descending (LAD) coronary artery. In control animals, we discovered that Mertk mRNA and protein levels were significantly elevated in the heart post LAD ligation. By flow cytometry, MERTK protein was also detected on the surface of newly recruited F4/80+ phagocyte subsets. Relative to control, whole body Mertk knockout and myeloid Mertk deficiency from bone marrow chimeras, led to increased accumulation of TUNEL positive apoptotic cells (2.4+/-0.3% vs 4.5+/-0.7% in chimeras, p<0.01) in infarct border zones. In addition, TNFα and IL-6 levels were elevated in knockouts while IL-10 was reduced. Initial infarct sizes as a percentage of ischemic area at risk were similar between both groups. However, infarct size in Mertk-/- mice subsequently expanded signficantly relative to control. At later time points, hearts from Mertk-/- mice had elevated scarring and ventricular wall thinning by histology. Echocardiography indicated that Mertk-/- hearts displayed significantly exaggerated LV dysfunction, including reduced ejection fraction. Taken together, these findings suggest that efferocytosis pathways have the capacity to regulate cardiac remodeling and heart function after a heart attack. Strategies that target optimal dead cell clearance and associated inflammation resolution and repair pathways may be of benefit in helping to heal the heart. .

Venous congestion and endothelial cell activation in acute decompensated heart failure

Despite accumulating clinical evidence supporting a key role for venous congestion in the development of acute decompensated heart failure (ADHF), there remain several gaps in our knowledge of the pathophysiology of ADHF. Specifically, the biomechanically driven effects of venous congestion on the vascular endothelium (the largest endocrine/ paracrine organ of the body), on neurohormonal activation, and on renal and cardiac dysfunction remain largely unexplored. We propose that venous congestion is a fundamental, hemodynamic stimulus for vascular inflammation, which plays a key role in the development and possibly the resolution of ADHF through vascular, humoral, renal, and cardiac mechanisms. A better understanding of the role of venous congestion and endothelial activation in the pathophysiology of ADHF may provide a strong rationale for near-future testing of treatment strategies that target biomechanically driven inflammation. Targeting vascular and systemic inflammation before symptoms arise may prevent progression to overt clinical decompensation in the ADHF syndrome.

Off-pump epicardial atrial fibrillation surgery utilizing a novel bipolar radiofrequency system.

BACKGROUND:

Over the past several years, pulmonary vein isolation for the treatment of atrial fibrillation has gained significant popularity. This study was undertaken to evaluate a novel radiofrequency (RF)-enabled clamp system designed to create transmural lesions epicardially on the beating heart using bipolar RF.

METHODS:

A set of differently shaped clamps modified to deliver bipolar RF energy were used to create a series of lesions in a beating heart canine model. The pulmonary veins and atrial appendages of 6 dogs were electrically isolated using bipolar RF energy. The right and left atrial appendages served as controls for the right and left pulmonary veins, respectively. Temperature-controlled RF energy was delivered to maintain a tissue temperature of 80 degrees C for 15 seconds. Electrical isolation was assessed acutely and after 4 weeks by a bipolar pacing protocol.

RESULTS:

A total of 24 circumferential lesions were created. By pacing analysis, 100%(24/24) of these lesions were electrically isolated acutely and 95%(19/20) were still isolated 4 weeks later. At 4 weeks, 92%(22/24) of lesions were transmural by histologic analysis, and 96%(23/24) demonstrated endocardial continuity. One animal experienced a fatal cardiac arrhythmia during initiation of the post-survival procedure, prior to electrophysiologic evaluation, accounting for the reduced number of potential electrically isolated lesions.

CONCLUSION:

Bipolar RF ablation utilizing a novel bipolar RF clamp device results in electrical isolation and histologic transmurality in an off-pump epicardial model.

Magnetic surgical instrument system

The present invention provides a magnetic surgical instrument system for use in transmural surgical operations. The system includes at least two magnetic probes including magnetic components, such as a permanent magnet, an electromagnet, and a metal attracted to a magnet that attracts the magnetic probes to provide therewith a magnetic clamping force for clamping the wall of anatomical structures. The system may also include a driving device, which provides the driving signal to produce electromagnetic force and energy for various embodiments of the present invention, such as RF, microwave, laser, and cryogenic energy. The magnetic surgical system may also be adopted to ablate, cut, stable, and inject anatomical structure tissue clamped between the magnetic probes.

Coexistence of CD14-dependent and independent pathways for stimulation of human monocytes by gram-positive bacteria.

The cell wall is a key inflammatory agent of gram-positive bacteria. Possible receptors mediating cell wall-induced inflammation include CD14 and platelet-activating factor (PAF) receptor. To delineate the conditions under which these various receptors might be used, human monocytic THP-1 cells and heparinized whole human blood were stimulated with lipopolysaccharide (LPS), intact Streptococcus pneumoniae bacteria, or purified pneumococcal cell wall. THP-1 culture supernatant or cell-free plasma was analyzed for the presence of tumor necrosis factor, interleukin-1beta (IL-1beta), and IL-6. For the cultured monocytes, anti-CD14 inhibited induction of the inflammatory cytokines by the cell wall and LPS but not by intact pneumococcal bacteria. Despite the difference in CD-14 usage, the intracellular pathways induced by the three agents demonstrated similarities, as revealed in the presence of specific signal transduction inhibitors such as cholera toxin, pertussis toxin, and genistein. Cytokine production in whole human blood indicated that anti-CD14 failed to block responses to cell wall and intact pneumococci, whereas while LPS-induced responses were inhibited. PAF receptor antagonist had no effect under any conditions in both assays. These results indicate that although cell walls bind to both CD14 and PAF receptor, only CD14 appears to engender a cytokine response under restricted conditions. Furthermore, host cell responses to intact pneumococci are consistently independent of CD14 and PAF receptor.

Extrapulmonary manifestations of COVID-19

Although COVID-19 is most well known for causing substantial respiratory pathology, it can also result in several extrapulmonary manifestations. These conditions include thrombotic complications, myocardial dysfunction and arrhythmia, acute coronary syndromes, acute kidney injury, gastrointestinal symptoms, hepatocellular injury, hyperglycemia and ketosis, neurologic illnesses, ocular symptoms, and dermatologic complications. Given that ACE2, the entry receptor for the causative coronavirus SARS-CoV-2, is expressed in multiple extrapulmonary tissues, direct viral tissue damage is a plausible mechanism of injury. In addition, endothelial damage and thromboinflammation, dysregulation of immune responses, and maladaptation of ACE2-related pathways might all contribute to these extrapulmonary manifestations of COVID-19. Here we review the extrapulmonary organ-specific pathophysiology, presentations and management considerations for patients with COVID-19 to aid clinicians and scientists in recognizing and monitoring the spectrum of manifestations, and in developing research priorities and therapeutic strategies for all organ systems involved.

Intracardiac Myocardial Elastography for Assessment of Right and Left Atrial Radiofrequency Ablation Lesions in Humans

Radiofrequency (RF) ablation is an effective method for treatment of cardiac arrhythmias; however, current assessment of RF lesion formation by measuring impedance changes, electrogram dimunition, power and catheter temperature are indirect and may be inaccurate. We present a novel, imaging modality, myocardial elastography (ME), which when used in adjunct with intracardiac echocardiography (ICE) may provide real-time assessment of RF lesion formation, and changes in tissue mechanics after lesion delivery [1-4].

Preclinical Evidence That Trametinib Enhances the Response to Antiangiogenic Tyrosine Kinase Inhibitors in Renal Cell Carcinoma..

Sunitinib and pazopanib are anti-angiogenic tyrosine kinase inhibitors (TKIs) used to treat metastatic renal cell carcinoma (RCC). However, the ability of these drugs to extend progression-free and overall survival in this patient population is limited by drug resistance. It is possible that treatment outcomes in RCC patients could be improved by rationally combining TKIs with other agents. Here, we address whether inhibition of the Ras-Raf-MEK-ERK1/2 pathway is a rational means to improve the response to TKIs in RCC. Using a xenograft model of RCC, we found that tumors which are resistant to sunitinib have a significantly increased angiogenic response compared to tumors which are sensitive to sunitinib in vivo. We also observed significantly increased levels of phosphorylated ERK1/2 in the vasculature of resistant tumors, when compared to sensitive tumors. These data suggested that the Ras-RafMEK-ERK1/2 pathway, an important driver of angiogenesis in endothelial cells, remains active in the vasculature of TKI-resistant tumors. Using an in vitro angiogenesis assay, we identified that the MEK inhibitor (MEKI) trametinib has potent anti-angiogenic activity. We then show that, when trametinib is combined with a TKI in vivo, more effective suppresion of tumor growth and tumor angiogenesis is achieved than when either drug is utilized alone. In conclusion, we provide preclinical evidence that combining a TKI, such as sunitinib or pazopanib, with a MEKI, such as trametinib, is a rational and efficacious treatment regimen for RCC.