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Atrial fibrillation (AF) in the setting of heart failure (HF) with preserved ejection fraction (HFpEF) is a prevalent comorbidity and is enabled by adverse left atrial (LA) remodeling, dilation, and scar tissue formation. These changes are facilitated by poor left ventricular compliance. A growing body of clinical evidence and medical guidelines suggest that managing atrial tachyrhythms with catheter ablation (CA) is paramount to treating concomitant HF. This recommendation is complicated in that thermal CA modalities, namely radiofrequency ablation and cryoablation, are both therapeutic via inducing additional scar tissue. AF treatment with thermal CA may compound the atrial scar burden for patients who already have extensive scars secondary to HFpEF. Therefore, thermal CA could act as "gasoline" to the slowly burning "fire" within the LA, increasing the rate of AF recurrence. Pulsed-field ablation (PFA), which utilizes high-voltage irreversible electroporation, is a non-thermal CA technique that is capable of disrupting reentrant microcircuits and arrhythmogenic foci without inducing significant scar burden. PFA has the potential to mitigate the strong fibrosis response to thermal CA that predisposes to AF by serving as "water" rather than "gasoline". Thus, PFA may increase the efficacy and durability of CA for AF in HFpEF, and subsequently, may decrease the risk of procedural complications from repeat CAs. In this article, we provide a summary of the clinical concepts underlying HFpEF and AF and then summarize the data to date on the potential of PFA being a superior CA technique for AF in the setting of comorbid HFpEF., Competing Interests: Conflicts of Interest: The authors declare no relevant conflicts of interest. I.R.C. is a physician employed by Banner Health.

The field of cardio-oncology is an expanding frontier within cardiovascular medicine, and the need for evidence-based guidelines is apparent. One of the emerging focuses within cardio-oncology is the concomitant use of medications for cardioprotection in the setting of chemotherapy regimens that have known cardiovascular toxicity. While clinical trials focusing on cardioprotection during chemotherapy are sparse, an inaugural trial exploring the prophylactic potential of Sodium-Glucose Cotransporter-2 inhibitors (SGLT2is) for anthracycline (ANT)-induced cardiotoxicity has recently commenced. Proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors, though less studied in this oncology demographic, have exhibited promise in preclinical studies for conferring cardiac protection during non-ischemic toxic insults. While primarily used to reduce low-density lipoprotein, PCSK9 inhibitors exhibit pleiotropic effects, including the attenuation of inflammation, reactive oxygen species, and endothelial dysfunction. In ANT-induced cardiotoxicity, these same processes are accelerated, resulting in premature termination of treatment, chronic cardiovascular sequelae, heart failure, and/or death. This review serves a dual purpose: firstly, to provide a concise overview of the mechanisms implicated in ANT-induced cardiotoxicity, and, finally, to summarize the existing preclinical data supporting the theoretical possibility of the cardioprotective effects of PCSK9 inhibition in ANT-induced cardiotoxicity., Competing Interests: Conflicts of Interest: The authors declare no relevant conflicts of interest.

The use of catheter-based irreversible electroporation in clinical cardiac laboratories, termed pulsed-field ablation (PFA), is gaining international momentum among cardiac electrophysiology proceduralists for the non-thermal management of both atrial and ventricular tachyrhythmogenic substrates. One area of potential application for PFA is in the mitigation of ventricular tachycardia (VT) risk in the setting of ischemia-mediated myocardial fibrosis, as evidenced by recently published clinical case reports. The efficacy of tissue electroporation has been documented in other branches of science and medicine; however, ventricular PFA's potential advantages and pitfalls are less understood. This comprehensive review will briefly summarize the pathophysiological mechanisms underlying VT and then summarize the pre-clinical and adult clinical data published to date on PFA's effectiveness in treating monomorphic VT. These data will be contrasted with the effectiveness ascribed to thermal cardiac ablation modalities to treat VT, namely radiofrequency energy and liquid nitrogen-based cryoablation.

Background: The therapeutic use of irreversible electroporation in clinical cardiac laboratories, termed pulsed field ablation (PFA), is gaining pre-regulatory approval momentum among rhythm specialists for the mitigation of arrhythmogenic substrate without increased procedural risk. Though electroporation has been utilized in other branches of science and medicine for decades, apprehension regarding all the possible off-target complications of PFA have yet to be thoroughly identified and investigated., Methods: This brief review will summarize the preclinical and adult clinical data published to date on PFA's effects on the autonomic system that interplays closely with the cardiovascular system, termed the neurocardiovascular system. These data are contrasted with the findings of efferent destruction secondary to thermal cardiac ablation modalities, namely radiofrequency energy and liquid nitrogen-based cryoablation., Results: In vitro neurocardiology findings, in vivo neurocardiology findings, and clinical neurocardiology findings to date nearly unanimously support the preservation of a critical mass of perineural structures and extracellular matrices to allow for long-term nervous regeneration in both cardiac and non-cardiac settings., Conclusions: Limited histopathologic data exist for neurocardiovascular outcomes post-PFA. Neuron damage is not only theoretically possible, but has been observed with irreversible electroporation, however regeneration is almost always concomitantly described., Competing Interests: Conflict of Interest The authors declare no conflict of interest.

The clinical use of irreversible electroporation in invasive cardiac laboratories, termed pulsed field ablation (PFA), is gaining early enthusiasm among electrophysiologists for the management of both atrial and ventricular arrhythmogenic substrates. Though electroporation is regularly employed in other branches of science and medicine, concerns regarding the acute and permanent vascular effects of PFA remain. This comprehensive review aims to summarize the preclinical and adult clinical data published to date on PFA's effects on pulmonary veins and coronary arteries. These data will be contrasted with the incidences of iatrogenic pulmonary vein stenosis and coronary artery injury secondary to thermal cardiac ablation modalities, namely radiofrequency energy, laser energy, and liquid nitrogen-based cryoablation., Competing Interests: Conflicts of interest All authors declare no conflicts of interest.

In swine models, there are well-established protocols for creating a closed-chest myocardial infarction (MI) as well as protocols for characterization of cardiac function with cardiac magnetic resonance (CMR). This methods manuscript outlines a novel technique in CMR data acquisition utilizing smart-signal gradient recalled echo (GRE)-based array sequences in a free-breathing swine heart failure model allowing for both high spatial and temporal resolution imaging. Nine male Yucatan mini swine weighing 48.7 ± 1.6 kg at 58.2 ± 3.1 weeks old underwent the outlined imaging protocol before and 1-month after undergoing closed chest left anterior descending coronary artery (LAD) occlusion/reperfusion. The left ventricular ejection fraction (LVEF) at baseline was 59.3 ± 2.4% and decreased to 48.1 ± 3.7% 1-month post MI (P = 0.029). The average end-diastolic volume (EDV) at baseline was 55.2 ± 1.7 ml and increased to 74.2 ± 4.2 ml at 1-month post MI (P = 0.001). The resulting images from this novel technique and post-imaging analysis are presented and discussed. In a Yucatan swine model of heart failure via closed chest left anterior descending coronary artery (LAD) occlusion/reperfusion, we found that CMR with GRE-based array sequences produced clinical-grade images with high spatial and temporal resolution in the free-breathing setting., (© 2022. The Author(s).)

Purpose of Review: Heart failure often progresses despite optimal medical and device therapies, and advanced mechanical circulatory support has limited availability and substantial associated morbidity. Cardiac contractility modulation (CCM) provides nonexcitatory stimulation to ventricular myocardium which increases cardiac contractility without increasing oxygen demand. This review describes the emerging role of CCM in heart failure treatment., Recent Findings: The FIX-HF-5C2 study demonstrated similar safety and efficacy profile of the two-lead Optimizer device in comparison with the prior three-lead system, thereby decreasing procedural complexity and minimizing endocardial hardware. The FIX-HF-5C trial underscored the benefit of CCM in patients with mild-moderate left ventricular dysfunction (ejection fraction, 25-45%) with New York Heart Association (NYHA) Class III symptoms. The summarized randomized trial data show consistent improvements in peak VO2, 6-min walk distance, and NYHA functional class with CCM. Future trials are planned to determine the role of CCM in heart failure patients with preserved ejection fraction, obligate ventricular pacing, and atrial arrhythmias., Summary: Nonexcitatory extracellular electric potentials can facilitate inotropic improvements in the failing heart. The mechanism of CCM does not increase myocardial oxygen consumption and has been shown to mitigate heart failure symptoms, decrease hospitalizations, and work in synergy with guideline-directed therapy for heart failure., (Copyright © 2021 Wolters Kluwer Health, Inc. All rights reserved.)

Background: Human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) are under preclinical investigation as a cell-based therapy for heart failure post-myocardial infarction. In a previous study, tissue-engineered cardiac grafts were found to improve hosts' cardiac electrical and mechanical functions. However, the durability of effect, immune response, and in vitro properties of the tissue graft remained uncharacterized. This present study is aimed at confirming the graft therapeutic efficacy in an immune-competent chronic heart failure (CHF) model and providing evaluation of the in vitro properties of the tissue graft., Methods: hiPSC-CMs and human dermal fibroblasts were cultured into a synthetic bioabsorbable scaffold. The engineered grafts underwent epicardial implantation in infarcted immune-competent male Sprague-Dawley rats. Plasma samples were collected throughout the study to quantify antibody titers. At the study endpoint, all cohorts underwent echocardiographic, hemodynamic, electrophysiologic, and histopathologic assessments., Results: The epicardially placed tissue graft therapy improved ( p < 0.05) in vivo and ex vivo cardiac function compared to the untreated CHF cohort. Total IgM and IgG increased for both the untreated and graft-treated CHF cohorts. An immune response to the grafts was detected after seven days in graft-treated CHF rats only. In vitro , engineered grafts exhibited responsiveness to beta-adrenergic receptor agonism/antagonism and SERCA inhibition and elicited complex molecular profiles., Conclusions: This hiPSC-CM-derived cardiac graft improved systolic and diastolic cardiac function in immune-competent CHF rats. The improvements were detectable at seven weeks post-graft implantation despite an antibody response beginning at week one and peaking at week three. This suggests that non-integrating cell-based therapy delivered by a bioengineered tissue graft for ischemic cardiomyopathy is a viable treatment option., Competing Interests: The work outlined in this report was the basis for forming the commercial entity Avery Therapeutics, Inc. Drs. Goldman, Koevary, Lancaster, and Ms. Sherry Daugherty have disclosed a financial interest in Avery Therapeutics to the University of Arizona. In addition, the University of Arizona has a financial interest in Avery Therapeutics. These interests have been reviewed and are being managed by the University of Arizona in accordance with its policies on outside interests. All other authors have no relevant conflicts to disclose., (Copyright © 2021 Ikeotunye Royal Chinyere et al.)

Patients diagnosed with heart failure with reduced ejection fraction (HFrEF) are at increased risk of monomorphic ventricular tachycardia (VT) and ventricular fibrillation. The presence of myocardial fibrosis provides both anatomical and functional barriers that promote arrhythmias in these patients. Propagation of VT in a reentrant circuit depends on the presence of excitable myocardium and the refractoriness of the circuit. We hypothesize that myocardial refractoriness can be modulated surgically in a model of HFrEF, leading to decreased susceptibility to VT.Male Sprague-Dawley rats were infarcted via permanent left coronary artery ligation. At 3 weeks post-infarction, engineered grafts composed of human dermal fibroblasts cultured into a polyglactin-910 biomaterial were implanted onto the epicardium to cover the area of infarction. Three weeks post-graft treatment, all rats underwent a terminal electrophysiologic study to compare monophasic action potential electroanatomic maps and susceptibility to inducible monomorphic VT.HFrEF rats (n=29) demonstrated a longer (p=0.0191) ventricular effective refractory period (ERP) and a greater (p=0.0394) VT inducibility compared with sham (n=7). HFrEF rats treated with the graft (n=12) exhibited no change in capture threshold (p=0.3220), but had a longer ventricular ERP (p=0.0029) compared with HFrEF. No statistically significant change in VT incidence was found between HFrEF rats treated with the graft and untreated HFrEF rats (p=0.0834).Surgical deployment of a fibroblast-containing biomaterial in a rodent ischemic cardiomyopathy model prolonged ventricular ERP as measured by programmed electrical stimulation. This hypothesis-generating study warrants additional studies to further characterize the antiarrhythmic or proarrhythmic effects of this novel surgical therapy., Competing Interests: Competing interests: JWK, SG, and JJL have disclosed a financial interest in Avery Therapeutics, Inc. to the University of Arizona. In addition, the University of Arizona has a financial interest in Avery Therapeutics, Inc. These interests have been reviewed and are being managed by the University of Arizona in accordance with its policies on outside interests. All other authors have no relevant conflicts to disclose., (© American Federation for Medical Research 2021. No commercial re-use. See rights and permissions. Published by BMJ.)

Heart failure (HF) post-myocardial infarction (MI) presents with increased vulnerability to monomorphic ventricular tachycardia (mmVT). To appropriately evaluate new therapies for infarct-mediated reentrant arrhythmia in the preclinical setting, chronologic characterization of the preclinical animal model pathophysiology is critical. This study aimed to evaluate the rigor and reproducibility of mmVT incidence in a rodent model of HF. We hypothesize a progressive increase in the incidence of mmVT as the duration of HF increases. Adult male Sprague-Dawley rats underwent permanent left coronary artery ligation or SHAM surgery and were maintained for either 6 or 10 wk. At end point, SHAM and HF rats underwent echocardiographic and invasive hemodynamic evaluation. Finally, rats underwent electrophysiologic (EP) assessment to assess susceptibility to mmVT and define ventricular effective refractory period (ERP). In 6-wk HF rats ( n = 20), left ventricular (LV) ejection fraction (EF) decreased ( P < 0.05) and LV end-diastolic pressure (EDP) increased ( P < 0.05) compared with SHAM ( n = 10). Ten-week HF ( n = 12) revealed maintenance of LVEF and LVEDP ( P > 0.05), ( P > 0.05). Electrophysiology studies revealed an increase in incidence of mmVT between SHAM and 6-wk HF ( P = 0.0016) and ERP prolongation ( P = 0.0186). The incidence of mmVT and ventricular ERP did not differ between 6- and 10-wk HF ( P = 1.0000), ( P = 0.9831). Findings from this rodent model of HF suggest that once the ischemia-mediated infarct stabilizes, proarrhythmic deterioration ceases. Within the 6- and 10-wk period post-MI, no echocardiographic, invasive hemodynamic, or electrophysiologic changes were observed, suggesting stable HF. This is the necessary context for the evaluation of experimental therapies in rodent HF. NEW & NOTEWORTHY Rodent model of ischemic cardiomyopathy exhibits a plateau of inducible monomorphic ventricular tachycardia incidence between 6 and 10 wk postinfarction.

Background: To treat chronic heart failure (CHF), we developed a robust, easy to handle bioabsorbable tissue-engineered patch embedded with human neonatal fibroblasts and human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs). This patch was implanted on the epicardial surface of the heart covering the previously infarcted tissue., Methods: Sprague-Dawley rats (6-8 weeks old) underwent sham surgery (n = 12) or left coronary artery ligation (n = 45). CHF rats were randomized 3 weeks after ligation to CHF control with sham thoracotomy (n = 21), or a fibroblasts/hiPSC-CMs patch (n = 24) was implanted. All sham surgery rats also underwent a sham thoracotomy. At 3 weeks after randomization, hemodynamics, echocardiography, electrophysiologic, and cell survival studies were performed., Results: Patch-treated rats had decreased (P < .05) left ventricular-end diastolic pressure and the time constant of left ventricular relaxation (Tau), increased anterior wall thickness in diastole, and improved echocardiography-derived indices of diastolic function (E/e' [ratio of early peak flow velocity to early peak LV velocity] and e'/a' [ratio of early to late peak left ventricular velocity]). All rats remained in normal sinus rhythm, with no dysrhythmias. Rats treated with the patch showed improved electrical activity. Transplanted hiPSC-CMs were present at 7 days but not detected at 21 days after implantation. The patch increased (P < .05) gene expression of vascular endothelial growth factor, angiopoietin 1, gap junction α-1 protein (connexin 43), β-myosin heavy 7, and insulin growth factor-1 expression in the infarcted heart., Conclusions: Epicardial implantation of a fibroblasts/hiPSC-CMs patch electrically enhanced conduction, lowered left ventricular end-diastolic pressure, and improved diastolic function in rats with CHF. These changes were associated with increases in cytokine expression., (Copyright © 2019 The Society of Thoracic Surgeons. Published by Elsevier Inc. All rights reserved.)

Although radiofrequency ablation has revolutionized the management of tachyarrhythmias, the rate of arrhythmia recurrence is a large drawback. Successful substrate identification is paramount to abolishing arrhythmia, and bipolar voltage electrogram's narrow field of view can be further reduced for increased sensitivity. In this report, we perform cardiac mapping with monophasic action potential (MAP) amplitude. We hypothesize that MAP amplitude (MAPA) will provide more accurate infarct sizes than other mapping modalities via increased sensitivity to distinguish healthy myocardium from scar tissue. Using the left coronary artery ligation Sprague-Dawley rat model of ischemic heart failure, we investigate the accuracy of in vivo ventricular epicardial maps derived from MAPA, MAP duration to 90% repolarization (MAPD 90 ), unipolar voltage amplitude (UVA), and bipolar voltage amplitude (BVA) compared with gold standard histopathological measurement of infarct size. Numerical analysis reveals discrimination of healthy myocardium versus scar tissue using MAPD 90 ( P = 0.0158) and UVA ( P < 0.001, n = 21). MAPA and BVA decreased between healthy and border tissue ( P = 0.0218 and 0.0015, respectively) and border and scar tissue ( P = 0.0037 and 0.0094, respectively). Contrary to our hypothesis, BVA mapping performed most accurately regarding quantifying infarct size. MAPA mapping may have high spatial resolution for myocardial tissue characterization but was quantitatively less accurate than other mapping methods at determining infarct size. BVA mapping's superior utility has been reinforced, supporting its use in translational research and clinical electrophysiology laboratories. MAPA may hold potential value for precisely distinguishing healthy myocardium, border zone, and scar tissue in diseases of disseminated fibrosis such as atrial fibrillation. NEW & NOTEWORTHY Monophasic action potential mapping in a clinically relevant model of heart failure with potential implications for atrial fibrillation management.

This review will outline cell-based therapy for heart failure focusing on tissue engineering to deliver cells to the damaged heart. We will present an overview of the central approaches focusing on pluripotent stem cell-derived cells, mechanisms of action, autologous vs . allogeneic cell approaches, immunologic modulation, and safety considerations. We will outline the progress that has been made to-date and define the areas that still need to be investigated in order to advance the field., Competing Interests: Conflicts of interest Drs. Lancaster, Koevary, Goldman and Ms. Daugherty have a financial interest in Avery Therapeutics, a biotechnology company that is commercializing platform technologies to deliver cell-based therapies for clinical use. The other authors (Chinyere IR, Fox KA) report no conflicts.

Background: Gap junction remodeling is well established as a consistent feature of human heart disease involving spontaneous ventricular arrhythmia. The mechanisms responsible for gap junction remodeling that include alterations in the distribution of, and protein expression within, gap junctions are still debated. Studies reveal that multiple transcriptional and posttranscriptional regulatory pathways are triggered in response to cardiac disease, such as those involving RNA-binding proteins. The expression levels of FXR1 (fragile X mental retardation autosomal homolog 1), an RNA-binding protein, are critical to maintain proper cardiac muscle function; however, the connection between FXR1 and disease is not clear., Methods: To identify the mechanisms regulating gap junction remodeling in cardiac disease, we sought to identify the functional properties of FXR1 expression, direct targets of FXR1 in human left ventricle dilated cardiomyopathy (DCM) biopsy samples and mouse models of DCM through BioID proximity assay and RNA immunoprecipitation, how FXR1 regulates its targets through RNA stability and luciferase assays, and functional consequences of altering the levels of this important RNA-binding protein through the analysis of cardiac-specific FXR1 knockout mice and mice injected with 3xMyc-FXR1 adeno-associated virus., Results: FXR1 expression is significantly increased in tissue samples from human and mouse models of DCM via Western blot analysis. FXR1 associates with intercalated discs, and integral gap junction proteins Cx43 (connexin 43), Cx45 (connexin 45), and ZO-1 (zonula occludens-1) were identified as novel mRNA targets of FXR1 by using a BioID proximity assay and RNA immunoprecipitation. Our findings show that FXR1 is a multifunctional protein involved in translational regulation and stabilization of its mRNA targets in heart muscle. In addition, introduction of 3xMyc-FXR1 via adeno-associated virus into mice leads to the redistribution of gap junctions and promotes ventricular tachycardia, showing the functional significance of FXR1 upregulation observed in DCM., Conclusions: In DCM, increased FXR1 expression appears to play an important role in disease progression by regulating gap junction remodeling. Together this study provides a novel function of FXR1, namely, that it directly regulates major gap junction components, contributing to proper cell-cell communication in the heart., (© 2017 American Heart Association, Inc.)

A chronic heart failure (CHF) rat underwent epicardial programmed electrical stimulation (PES). Ventricular tachycardia (VT) developed during PES. Mechanical alternans was noted despite fixed tachycardia cycle length. Anti-tachycardia pacing attempts initiated a second VT that generated pulse intermittently and then degenerated into pulseless VT with electrical alternans.To our knowledge electrical and mechanical alternans have not been recorded in animal models of CHF during VT. The distinct events of mechanical alternans and electrical alternans may be indicative of progressively worsened calcium handling in the compromised cardiomyocytes.Although ion channel differences between rodents and humans exist, this work attempts to demonstrate this rat model's usefulness in understanding cardiac electrophysiology in CHF., (Copyright © 2017 Elsevier Inc. All rights reserved.)