Loss of the Atrial Fibrillation-Related Gene, Zfhx3, Results in Atrial Dilation and Arrhythmias.

BACKGROUND: ZFHX3 (zinc finger homeobox 3), a gene that encodes a large transcription factor, is at the second-most significantly associated locus with atrial fibrillation (AF), but its function in the heart is unknown. This study aims to identify causative genetic variation related to AF at the ZFHX3 locus and examine the impact of Zfhx3 loss on cardiac function in mice. METHODS: CRISPR-Cas9 genome editing, chromatin immunoprecipitation, and luciferase assays in pluripotent stem cell-derived cardiomyocytes were used to identify causative genetic variation related to AF at the ZFHX3 locus. Cardiac function was assessed by echocardiography, magnetic resonance imaging, electrophysiology studies, calcium imaging, and RNA sequencing in mice with heterozygous and homozygous cardiomyocyte-restricted Zfhx3 loss (Zfhx3 Het and knockout, respectively). Human cardiac single-nucleus ATAC (assay for transposase-accessible chromatin)-sequencing data was analyzed to determine which genes in atrial cardiomyocytes are directly regulated by ZFHX3. RESULTS: We found single-nucleotide polymorphism (SNP) rs12931021 modulates an enhancer regulating ZFHX3 expression, and the AF risk allele is associated with decreased ZFHX3 transcription. We observed a gene-dose response in AF susceptibility with Zfhx3 knockout mice having higher incidence, frequency, and burden of AF than Zfhx3 Het and wild-type mice, with alterations in conduction velocity, atrial action potential duration, calcium handling and the development of atrial enlargement and thrombus, and dilated cardiomyopathy. Zfhx3 loss results in atrial-specific differential effects on genes and signaling pathways involved in cardiac pathophysiology and AF. CONCLUSIONS: Our findings implicate ZFHX3 as the causative gene at the 16q22 locus for AF, and cardiac abnormalities caused by loss of cardiac Zfhx3 are due to atrial-specific dysregulation of pathways involved in AF susceptibility. Together, these data reveal a novel and important role for Zfhx3 in the control of cardiac genes and signaling pathways essential for normal atrial function.

Ketone ester supplementation suppresses cardiac inflammation and improves cardiac energetics in a swine model of acute myocardial infarction.

BACKGROUND: Myocardial infarction (MI) is a major risk factor for the development of heart failure with reduce ejection fraction (HFrEF). While previous studies have focused on HFrEF, the cardiovascular effects of ketone bodies in acute MI are unclear. We examined the effects of oral ketone supplementation as a potential treatment strategy in a swine acute MI model. METHODS: Farm pigs underwent percutaneous balloon occlusion of the LAD for 80 min followed by 72 h reperfusion period. Oral ketone ester or vehicle was administered during reperfusion and continued during the follow-up period. RESULTS: Oral KE supplementation induced ketonemia 2-3 mmol/l within 30 min after ingestion. KE increased ketone (ßHB) extraction in healthy hearts without affecting glucose and fatty acid (FA) consumption. During reperfusion, the MI hearts consumed less FA with no change in glucose consumption, whereas hearts from MI-KE-fed animals consumed more ßHB and FA, as well as improved myocardial ATP production. A significant elevation of infarct T2 values indicative of inflammation was found only in untreated MI group compared to sham. Concordantly, cardiac expression of inflammatory markers, oxidative stress, and apoptosis were reduced by KE. RNA-seq analysis identified differentially expressed genes related to mitochondrial energy metabolism and inflammation. CONCLUSIONS: Oral KE supplementation induced ketosis and enhanced myocardial ßHB extraction in both healthy and infarcted hearts. Acute oral supplementation with KE favorably altered cardiac substrate uptake and utilization, improved cardiac ATP levels, and reduced cardiac inflammation following MI.

Therapeutic hypothermia for acute myocardial infarction: a narrative review of evidence from animal and clinical studies.

Myocardial infarction (MI) is the leading cause of death from coronary heart disease and requires immediate reperfusion therapy with thrombolysis, primary percutaneous coronary intervention, or coronary artery bypass grafting. However, myocardial reperfusion therapy is often accompanied by cardiac ischemia/reperfusion (I/R) injury, which leads to myocardial injury with detrimental consequences. The causes of I/R injury are unclear, but are multifactorial, including free radicals, reactive oxygen species, calcium overload, mitochondria dysfunction, inflammation, and neutrophil-mediated vascular injury. Mild hypothermia has been introduced as one of the potential inhibitors of myocardial I/R injury. Although animal studies have demonstrated that mild hypothermia significantly reduces or delays I/R myocardium damage, human trials have not shown clinical benefits in acute MI (AMI). In addition, the practice of hypothermia treatment is increasing in various fields such as surgical anesthesia and intensive care units. Adequate sedation for anesthetic procedures and protection from body shivering has become essential during therapeutic hypothermia. Therefore, anesthesiologists should be aware of the effects of therapeutic hypothermia on the metabolism of anesthetic drugs. In this paper, we review the existing data on the use of therapeutic hypothermia for AMI in animal models and human clinical trials to better understand the discrepancy between perceived benefits in preclinical animal models and the absence thereof in clinical trials thus far.

Virtual multidisciplinary care for heart failure patients with cardiac resynchronization therapy devices during the Coronavirus Disease 2019 pandemic.

BACKGROUND: Heart failure (HF) patients with CRT devices are a vulnerable patient population during the Coronavirus Disease 2019 (COVID-19) Pandemic. It is important to develop innovative virtual care models to deliver multidisciplinary care while minimizing the risk of SARS-CoV2 exposure. OBJECTIVE: We aim to provide a description of how HF patients with CRT devices were assessed and managed in our virtual multidisciplinary clinic during the COVID-19 Pandemic. Clinical outcomes between this group of patients seen in virtual clinic and a historical cohort followed by in-person multi-disciplinary clinic prior to the pandemic were compared. METHOD: This is a retrospective cohort study of HF patients with CRT implants who were seen in the virtual multidisciplinary clinic from March 18th, 2020 to May 27th, 2020 (Virtual Visit Group, N = 43). A historical cohort of HF patients with CRT devices seen in the ReACT clinic in person during the same calendar time period in 2019 was used as a control group (In-Person Visit Group, N = 39). Both groups were followed until July 1st of the same calendar year (2020 or 2019) for clinical events. The primary outcome measure was a combined outcome of all-cause mortality and HF- or device-related hospitalizations during follow-up. The secondary outcome measures included patient satisfaction, COVID-19 infection, and other cardiovascular events. RESULTS: In the Virtual-Visit Group, 21 patients (48.8%) had their initial ReACT clinic visit (first visit after CRT implant) as a virtual visit; 22 patients (51.2%) had prior in-person ReACT clinic visits before the first virtual visit. During the virtual visits, 12 patients had either potential cardiac symptoms or significant device interrogation findings that required clinical intervention. In post-virtual clinic patient satisfaction survey, all 22 patients surveyed (100%) reported being very satisfied or satisfied with the overall experience of the virtual clinic, and every patient (100%) said they would like to use telemedicine again. During a median follow-up period of 82 days (interquartile range [IQR] 61-96 days), one patient died from pneumonia of unclear etiology at an outside hospital, without documentation of COVID-19 positivity. No patient was hospitalized for HF- or arrhythmia-related complications. No patient was diagnosed with COVID-19. Compared with the In-Person Visit Group, there was no significant increase in mortality or major cardiovascular events in the Virtual-Visit Group (2.3% versus 5.1%, P = 0.60). CONCLUSIONS AND RELEVANCE: Virtual multidisciplinary care was feasible for HF patients with cardiac resynchronization therapy devices and achieved good patient satisfaction. Virtual care was not associated with short-term increase in adverse events for HF patients with CRT device during the COVID-19 Pandemic. This virtual care model could help promote the adoption of digital health methodology for high-risk patients with multiple cardiac comorbidities.

Evolving Cardiac Electrical Therapies for Advanced Heart Failure Patients.

Symptomatic heart failure (HF) patients despite optimal medical therapy and advances such as invasive hemodynamic monitoring remain challenging to manage. While cardiac resynchronization therapy remains a highly effective therapy for a subset of HF patients with wide QRS, a majority of symptomatic HF patients are poor candidates for such. Recently, cardiac contractility modulation, neuromodulation based on carotid baroreceptor stimulation, and phrenic nerve stimulation have been approved by the US Food and Drug Administration and are emerging as therapeutic options for symptomatic HF patients. This state-of-the-art review examines the role of these evolving electrical therapies in advanced HF.

Comparison between TightRail rotating dilator sheath and GlideLight laser sheath for transvenous lead extraction.

BACKGROUND: There are limited data on the comparative analyses of TightRail rotating dilator sheath (Philips) and laser sheath for lead extraction. OBJECTIVE: To evaluate the effectiveness and safety of the TightRail sheath as a primary or secondary tool for transvenous lead extraction (TLE). METHODS: Retrospective cohort analysis of 202 consecutive patients who underwent TLE using either TightRail sheath and/or GlideLight laser sheath (Philips) in our hospital. The study population was divided into three groups: Group A underwent TLE with laser sheath only (N = 157), Group B with TightRail sheath only (N = 22), and Group C with both sheaths (N = 23). RESULTS: During this period, 375 leads in 202 patients were extracted, including 297 leads extracted by laser sheath alone, 45 leads by TightRail sheath alone, and 33 by both TightRail sheath and laser sheaths. The most common indications included device infection (44.6%) and lead-related complications (44.1%). The median age of leads was 8.9 years. TightRail sheath (Group B) achieved similar efficacy as a primary extraction tool compared with laser sheath (Group A), with complete procedure success rate of 93.3% (vs. 96.6%, P = .263) and clinical success rate of 100.0% (vs. 98.1%, P = .513). Among 32 leads in which Tightrail was used after laser had failed (Group C), the complete procedure success rate was 75.8%. No significant difference in procedural adverse events was observed. CONCLUSION: Our single-center experience confirms that the TightRail system is an effective first-line and second-line method for TLE. Further investigation is required to guide the selection of mechanical and laser sheaths in lead extraction cases.

Identification of two preclinical canine models of atrial fibrillation to facilitate drug discovery.

BACKGROUND: Atrial fibrillation (AF) is the most common arrhythmia occurring in humans, and new treatment strategies are critically needed. The lack of reliable preclinical animal models of AF is a major limitation to drug development of novel antiarrhythmic compounds. OBJECTIVE: The purpose of this study was to provide a comprehensive head-to-head assessment of 5 canine AF models. METHODS: Five canine models were evaluated for the efficacy of AF induction and AF duration. We tested 2 acute models: short-term atrial tachypacing (AT) for 6 hours with analysis of AF at hourly increments, and carbachol injection into a cardiac fat pad followed by short-term AT. We also tested 3 chronic models: pacemaker implantation followed by either 4 weeks of AT and subsequent atrial burst pacing or intermittent long-term AT for up to 4-5 months to generate AF ≥4.5 hours, and finally ventricular tachypacing to induce heart failure followed by atrial burst pacing to induce AF. RESULTS: Careful evaluation showed that acute AT, AT for 4 weeks, and the heart failure model all were unsuccessful in generating reproducible AF episodes of sufficient duration to study antiarrhythmic drugs. In contrast, intermittent long-term AT generated AF lasting ≥4.5 hours in ∼30% of animals. The acute model using carbachol and short-term AT resulted in AF induction of ≥15 minutes in ≥75% of animals, thus enabling testing of antiarrhythmic drugs. CONCLUSION: Intermittent long-term AT and the combination of local carbachol injection with successive short-term AT may contribute to future drug development efforts for AF treatment.

Animal Models of Atrial Fibrillation.

Atrial fibrillation (AF) is the most common sustained arrhythmia encountered in humans and is a significant source of morbidity and mortality. Despite its prevalence, our mechanistic understanding is incomplete, the therapeutic options have limited efficacy, and are often fraught with risks. A better biological understanding of AF is needed to spearhead novel therapeutic avenues. Although "natural" AF is nearly nonexistent in most species, animal models have contributed significantly to our understanding of AF and some therapeutic options. However, the impediments of animal models are also apparent and stem largely from the differences in basic physiology as well as the complexities underlying human AF; these preclude the creation of a "perfect" animal model and have obviated the translation of animal findings. Herein, we review the vast array of AF models available, spanning the mouse heart (weighing 1/1000th of a human heart) to the horse heart (10× heavier than the human heart). We attempt to highlight the features of each model that bring value to our understanding of AF but also the shortcomings and pitfalls. Finally, we borrowed the concept of a SWOT analysis from the business community (which stands for strengths, weaknesses, opportunities, and threats) and applied this introspective type of analysis to animal models for AF. We identify unmet needs and stress that is in the context of rapidly advancing technologies, these present opportunities for the future use of animal models.

WATCHMAN implantation in patients with a history of atrial fibrillation and intracranial hemorrhage.

PURPOSE: Use of oral anticoagulation (OAC) in patients with a history of intracranial hemorrhage (ICH) is often considered high risk as OAC-related ICH is associated with high mortality rates. Left atrial appendage closure with a WATCHMAN device is an alternative management strategy to OAC to decrease thrombotic risk in atrial fibrillation patients; however use of OAC followed by dual antiplatelet therapy (DAPT) or DAPT therapy alone is required for 6 months post-procedurally. In this study, we examined the safety of WATCHMAN implantation followed by 6 months of anti-thrombotic therapy in patients with a history of ICH. METHODS: This is a retrospective analysis of 63 patients with a history of ICH prior to WATCHMAN implantation (Group I) and 95 patients without a history of ICH who underwent WATCHMAN placement (Group II). The primary outcome was death, stroke, or major bleeding within 6 months of WATCHMAN placement. RESULTS: The average CHA2DS2-VASc of Group I was 4.9 ± 1.7 vs 4.7 ± 1.4 for Group II (p = 0.34). The most common type of ICH in Group I was an intracerebral hemorrhage (57%). The median time between ICH and WATCHMAN implantation in Group I patients was 212 days. A total of 19% of Group I patients were managed with DAPT alone post-procedurally vs. 3% in Group II (p < 0.001). Similar to 89% of Group II (p = 0.19), 95% of Group I patients were free of the primary outcome at 6 months. No Group I patients had recurrent ICH within 6 months after WATCHMAN implantation. CONCLUSION: In a retrospective, multicenter series of patients with a history of ICH prior to WATCHMAN implantation, WATCHMAN placement was performed safely with 6-month outcomes that were similar to patients without a history of ICH, encompassing the time during which a patient with a history of ICH would need antithrombotic therapy to facilitate WATCHMAN placement.

Common Coding Variants in SCN10A Are Associated With the Nav1.8 Late Current and Cardiac Conduction.

BACKGROUND: Genetic variants at the SCN5A/SCN10A locus are strongly associated with electrocardiographic PR and QRS intervals. While SCN5A is the canonical cardiac sodium channel gene, the role of SCN10A in cardiac conduction is less well characterized. METHODS: We sequenced the SCN10A locus in 3699 European-ancestry individuals to identify variants associated with cardiac conduction, and replicated our findings in 21,000 individuals of European ancestry. We examined association with expression in human atrial tissue. We explored the biophysical effect of variation on channel function using cellular electrophysiology. RESULTS: We identified 2 intronic single nucleotide polymorphisms in high linkage disequilibrium (r 2=0.86) with each other to be the strongest signals for PR (rs10428132, ß=-4.74, P=1.52×10-14) and QRS intervals (rs6599251, QRS ß=-0.73; P=1.2×10-4), respectively. Although these variants were not associated with SCN5A or SCN10A expression in human atrial tissue (n=490), they were in high linkage disequilibrium (r 2≥0.72) with a common SCN10A missense variant, rs6795970 (V1073A). In total, we identified 7 missense variants, 4 of which (I962V, P1045T, V1073A, and L1092P) were associated with cardiac conduction. These 4 missense variants cluster in the cytoplasmic linker of the second and third domains of the SCN10A protein and together form 6 common haplotypes. Using cellular electrophysiology, we found that haplotypes associated with shorter PR intervals had a significantly larger percentage of late current compared with wild-type (I962V+V1073A+L1092P, 20.2±3.3%, P=0.03, and I962V+V1073A, 22.4±0.8%, P=0.0004 versus wild-type 11.7±1.6%), and the haplotype associated with the longest PR interval had a significantly smaller late current percentage (P1045T, 6.4±1.2%, P=0.03). CONCLUSIONS: Our findings suggest an association between genetic variation in SCN10A, the late sodium current, and alterations in cardiac conduction.

Experience With Wearable Cardioverter-Defibrillators at 2 Academic Medical Centers.

OBJECTIVES: This study sought to characterize the experience in a cohort of patients prescribed a wearable cardioverter-defibrillator (WCD) over a 2-year interval at 2 academic medical centers. BACKGROUND: The WCD is available for patients felt to be at high risk of sudden cardiac death. However, there is a lack of randomized data to guide its use and prescribing patterns vary. METHODS: We retrospectively reviewed indications and therapies of all WCD prescriptions over a 2-year period from 2 large academic medical centers. Data on compliance and treatment events of patients wearing the WCD were reviewed. RESULTS: Among the 147 patients prescribed a WCD, 80% were male with an age of 59 ± 14 years. The WCD was prescribed for the following reasons: primary prevention in the setting of a left ventricular ejection fraction ≤35% (53%), secondary prevention when an implantable cardioverter-defibrillator was not implanted (16%), implantable cardioverter-defibrillator explantation (23%), and other high-risk scenarios for arrhythmic sudden death (9%). The median wear duration was 50 days (interquartile range [IQR]: 25 to 85 days) with a median of 21.0 h of wear per day (IQR: 15.0 to 22.8 h). High-voltage treatment was delivered in 3 separate patients, 2 of whom died. The third patient received 3 WCD shocks without restoration of a perfusing rhythm and ultimately was resuscitated by emergency responders. No patients received inappropriate therapies. CONCLUSIONS: Events requiring therapy were rare and no lives were directly saved by the WCD. Future efforts are needed to improve identification of patients most likely to benefit from a WCD.

Diminished PRRX1 Expression Is Associated With Increased Risk of Atrial Fibrillation and Shortening of the Cardiac Action Potential.

BACKGROUND: Atrial fibrillation (AF) affects over 33 million individuals worldwide. Genome-wide association studies have identified at least 30 AF loci, but the mechanisms through which individual variants lead to altered disease risk have remained unclear for the majority of these loci. At the 1q24 locus, we hypothesized that the transcription factor PRRX1 could be a strong candidate gene as it is expressed in the pulmonary veins, a source of AF in many individuals. We sought to identify the molecular mechanism, whereby variation at 1q24 may lead to AF susceptibility. METHODS AND RESULTS: We sequenced a ≈158 kb region encompassing PRRX1 in 962 individuals with and without AF. We identified a broad region of association with AF at the 1q24 locus. Using in silico prediction and functional validation, we identified an enhancer that interacts with the promoter of PRRX1 in cells of cardiac lineage. Within this enhancer, we identified a single-nucleotide polymorphism, rs577676, which alters enhancer activity in a mouse atrial cell line and in embryonic zebrafish and differentially regulates PRRX1 expression in human left atria. We found that suppression of PRRX1 in human embryonic stem cell-derived cardiomyocytes and embryonic zebrafish resulted in shortening of the atrial action potential duration, a hallmark of AF. CONCLUSIONS: We have identified a functional genetic variant that alters PRRX1 expression, ultimately resulting in electrophysiological alterations in atrial myocytes that may promote AF.

Macrophages Facilitate Electrical Conduction in the Heart.

Organ-specific functions of tissue-resident macrophages in the steady-state heart are unknown. Here, we show that cardiac macrophages facilitate electrical conduction through the distal atrioventricular node, where conducting cells densely intersperse with elongated macrophages expressing connexin 43. When coupled to spontaneously beating cardiomyocytes via connexin-43-containing gap junctions, cardiac macrophages have a negative resting membrane potential and depolarize in synchrony with cardiomyocytes. Conversely, macrophages render the resting membrane potential of cardiomyocytes more positive and, according to computational modeling, accelerate their repolarization. Photostimulation of channelrhodopsin-2-expressing macrophages improves atrioventricular conduction, whereas conditional deletion of connexin 43 in macrophages and congenital lack of macrophages delay atrioventricular conduction. In the Cd11bDTR mouse, macrophage ablation induces progressive atrioventricular block. These observations implicate macrophages in normal and aberrant cardiac conduction.

Improving Atrial Fibrillation Therapy: Is There a Gene for That?

Atrial fibrillation (AF) is an all-too-common and often challenging reality of clinical care. AF leads to significant morbidity and mortality; however, currently available treatments for AF have modest efficacy and high recurrence rates. In recent years, genetic therapy approaches have been explored in preclinical models of AF, and offer potential as a treatment modality with targeted delivery, tissue specificity, and therapy tailored to address mechanisms underlying the arrhythmia. However, many challenges remain before gene therapy can advance to a clinically relevant AF treatment. In this review, we summarize the available published data on gene therapy and discuss the challenges, opportunities, and limitations of this approach.

2017 ACC Expert Consensus Decision Pathway for Periprocedural Management of Anticoagulation in Patients With Nonvalvular Atrial Fibrillation: A Report of the American College of Cardiology Clinical Expert Consensus Document Task Force.

Periprocedural management of anticoagulation is a common clinical conundrum that involves a multidisciplinary team, cuts across many specialties, and varies greatly between institutions in the way it is practiced. Nowhere is this more evident than in the management of patients with nonvalvular atrial fibrillation. Although they have been found to improve patient outcomes, standardized evidence-based protocols are infrequently in place. The frequency of anticoagulant interruption in preparation for a procedure is high, with an estimated 250,000 patients undergoing temporary interruption annually in North America alone. Knowledge about risk of bleeding and short-term thrombotic risk resides in many specialties, further complicating the issue. Our goal in creating this pathway is to help guide clinicians in the complex decision making in this area. In this document, we aim to: 1) validate the appropriateness of the decision to chronically anticoagulate; 2) guide clinicians in the decision of whether to interrupt anticoagulation; 3) provide direction on how to interrupt anticoagulation with specific guidance for vitamin K antagonists and direct-acting oral anticoagulants; 4) evaluate whether to bridge with a parenteral agent periprocedurally; 5) offer advice on how to bridge; and 6) outline the process of restarting anticoagulation post-procedure.

Atrial Fibrillation Genetics: Is There a Practical Clinical Value Now or in the Future?

Atrial fibrillation (AF) is the most common sustained arrhythmia and has significant clinical impact. Over the last decade, our understanding of the genetics of AF has expanded dramatically. After a heritable predisposition for AF was identified, many investigators have in turn identified both common and rare variants associated with AF. Ongoing work is focused on translating these variants into disease pathways and novel therapeutic modalities. In this review, we focus on our understanding of the current concepts behind the genetics of AF and outline a vision for the incorporation of genetic data into clinical practice.