Ambulatory Pulmonary Artery Pressures After Transcatheter Edge-to-Edge Repair of the Mitral Valve in Patients With Heart Failure and Mitral Regurgitation.

The objective of this study was to assess ambulatory hemodynamics after transcatheter edge-to-edge repair (TEER) of the mitral valve. Pulmonary artery pressure (PAP) measurements from implanted sensors were collected through a remote monitoring database and linked to Medicare fee-for-service claims data. Among patients with linked data, those undergoing TEER were included if the ambulatory PAP monitor was implanted ≥3 months before TEER and ≥3 months of PAP data after TEER were available. The primary end point was diastolic PAP (dPAP) at 3 months after TEER compared with baseline. A total of 50 patients undergoing TEER between July 2014 and March 2020 were included, with an average age of 75 ± 8 years and 70% were men. dPAP was significantly lower at 3 months after TEER than baseline, -1.8 ± 4.8 mm Hg, p = 0.010. The cumulative reduction in dPAP (area under the curve) was significantly lower at 3 months after TEER, 113 ± 267 mm Hg-days, p = 0.004. A reduction in dPAP at 3 months after TEER was independently associated with a significantly lower risk of heart failure hospitalization (p = 0.023). TEER of the mitral valve is associated with a clinically relevant and sustained reduction in dPAP.

Assessment of arrhythmia mechanism and burden of the infarcted ventricles following remuscularization with pluripotent stem cell-derived cardiomyocyte patches using patient-derived models.

AIMS: Direct remuscularization with pluripotent stem cell-derived cardiomyocytes (PSC-CMs) seeks to address the onset of heart failure post-myocardial infarction (MI) by treating the persistent muscle deficiency that underlies it. However, direct remuscularization with PSC-CMs could potentially be arrhythmogenic. We investigated two possible mechanisms of arrhythmogenesis-focal vs. re-entrant-arising from direct remuscularization with PSC-CM patches in two personalized, human ventricular computer models of post-MI. Moreover, we developed a principled approach for evaluating arrhythmogenicity of direct remuscularization that factors in the VT propensity of the patient-specific post-MI fibrotic substrate and use it to investigate different conditions of patch remuscularization. METHODS AND RESULTS: Two personalized, human ventricular models of post-MI (P1 and P2) were constructed from late gadolinium enhanced (LGE)-magnetic resonance images (MRIs). In each model, remuscularization with PSC-CM patches was simulated under different treatment conditions that included patch engraftment, patch myofibril orientation, remuscularization site, patch size (thickness and diameter), and patch maturation. To determine arrhythmogenicity of treatment conditions, VT burden of heart models was quantified prior to and after simulated remuscularization and compared. VT burden was quantified based on inducibility (i.e. weighted sum of pacing sites that induced) and severity (i.e. the number of distinct VT morphologies induced). Prior to remuscularization, VT burden was significant in P1 (0.275) and not in P2 (0.0, not VT inducible). We highlight that re-entrant VT mechanisms would dominate over focal mechanisms; spontaneous beats emerging from PSC-CM grafts were always a fraction of resting sinus rate. Moreover, incomplete patch engraftment can be particularly arrhythmogenic, giving rise to particularly aberrant electrical activation and conduction slowing across the PSC-CM patches along with elevated VT burden when compared with complete engraftment. Under conditions of complete patch engraftment, remuscularization was almost always arrhythmogenic in P2 but certain treatment conditions could be anti-arrhythmogenic in P1. Moreover, the remuscularization site was the most important factor affecting VT burden in both P1 and P2. Complete maturation of PSC-CM patches, both ionically and electrotonically, at the appropriate site could completely alleviate VT burden. CONCLUSION: We identified that re-entrant VT would be the primary VT mechanism in patch remuscularization. To evaluate the arrhythmogenicity of remuscularization, we developed a principled approach that factors in the propensity of the patient-specific fibrotic substrate for VT. We showed that arrhythmogenicity is sensitive to the patient-specific fibrotic substrate and remuscularization site. We demonstrate that targeted remuscularization can be safe in the appropriate individual and holds the potential to non-destructively eliminate VT post-MI in addition to addressing muscle deficiency underlying heart failure progression.

Computational modeling of aberrant electrical activity following remuscularization with intramyocardially injected pluripotent stem cell-derived cardiomyocytes.

Acute engraftment arrhythmias (EAs) remain a serious complication of remuscularization therapy. Preliminary evidence suggests that a focal source underlies these EAs stemming from the automaticity of immature pluripotent stem cell-derived cardiomyocytes (PSC-CMs) in nascent myocardial grafts. How these EAs arise though during early engraftment remains unclear. In a series of in silico experiments, we probed the origin of EAs-exploring aspects of altered impulse formation and altered impulse propagation within nascent PSC-CM grafts and at the host-graft interface. To account for poor gap junctional coupling during early PSC-CM engraftment, the voltage dependence of gap junctions and the possibility of ephaptic coupling were incorporated. Inspired by cardiac development, we also studied the contributions of another feature of immature PSC-CMs, circumferential sodium channel (NaCh) distribution in PSC-CMs. Ectopic propagations emerged from nascent grafts of immature PSC-CMs at a rate of <96 bpm. Source-sink effects dictated this rate and contributed to intermittent capture between host and graft. Moreover, ectopic beats emerged from dynamically changing sites along the host-graft interface. The latter arose in part because circumferential NaCh distribution in PSC-CMs contributed to preferential conduction slowing and block of electrical impulses from host to graft myocardium. We conclude that additional mechanisms, in addition to focal ones, contribute to EAs and recognize that their relative contributions are dynamic across the engraftment process.

Mechanisms of Sinoatrial Node Dysfunction in Heart Failure With Preserved Ejection Fraction.

BACKGROUND: The ability to increase heart rate during exercise and other stressors is a key homeostatic feature of the sinoatrial node (SAN). When the physiological heart rate response is blunted, chronotropic incompetence limits exercise capacity, a common problem in patients with heart failure with preserved ejection fraction (HFpEF). Despite its clinical relevance, the mechanisms of chronotropic incompetence remain unknown. METHODS: Dahl salt-sensitive rats fed a high-salt diet and C57Bl6 mice fed a high-fat diet and an inhibitor of constitutive nitric oxide synthase (Nω-nitro-L-arginine methyl ester [L-NAME]; 2-hit) were used as models of HFpEF. Myocardial infarction was created to induce HF with reduced ejection fraction. Rats and mice fed with a normal diet or those that had a sham surgery served as respective controls. A comprehensive characterization of SAN function and chronotropic response was conducted by in vivo, ex vivo, and single-cell electrophysiologic studies. RNA sequencing of SAN was performed to identify transcriptomic changes. Computational modeling of biophysically-detailed human HFpEF SAN was created. RESULTS: Rats with phenotypically-verified HFpEF exhibited limited chronotropic response associated with intrinsic SAN dysfunction, including impaired ß-adrenergic responsiveness and an alternating leading pacemaker within the SAN. Prolonged SAN recovery time and reduced SAN sensitivity to isoproterenol were confirmed in the 2-hit mouse model. Adenosine challenge unmasked conduction blocks within the SAN, which were associated with structural remodeling. Chronotropic incompetence and SAN dysfunction were also found in rats with HF with reduced ejection fraction. Single-cell studies and transcriptomic profiling revealed HFpEF-related alterations in both the "membrane clock" (ion channels) and the "Ca2+ clock" (spontaneous Ca2+ release events). The physiologic impairments were reproduced in silico by empirically-constrained quantitative modeling of human SAN function. CONCLUSIONS: Chronotropic incompetence and SAN dysfunction were seen in both models of HF. We identified that intrinsic abnormalities of SAN structure and function underlie the chronotropic response in HFpEF.

A comprehensive, multiscale framework for evaluation of arrhythmias arising from cell therapy in the whole post-myocardial infarcted heart.

Direct remuscularization approaches to cell-based heart repair seek to restore ventricular contractility following myocardial infarction (MI) by introducing new cardiomyocytes (CMs) to replace lost or injured ones. However, despite promising improvements in cardiac function, high incidences of ventricular arrhythmias have been observed in animal models of MI injected with pluripotent stem cell-derived cardiomyocytes (PSC-CMs). The mechanisms of arrhythmogenesis remain unclear. Here, we present a comprehensive framework for computational modeling of direct remuscularization approaches to cell therapy. Our multiscale 3D whole-heart modeling framework integrates realistic representations of cell delivery and transdifferentiation therapy modalities as well as representation of spatial distributions of engrafted cells, enabling simulation of clinical therapy and the prediction of emergent electrophysiological behavior and arrhythmogenensis. We employ this framework to explore how varying parameters of cell delivery and transdifferentiation could result in three mechanisms of arrhythmogenesis: focal ectopy, heart block, and reentry.

Cardiac regeneration following cryoinjury in the adult zebrafish targets a maturation-specific biomechanical remodeling program.

Cardiac regeneration post-injury is a tantalizing feature of many lower vertebrates such as fishes and urodeles, but absent in adult humans. Restoration of pumping function is a key endpoint of cardiac regeneration, but very little is known about the biomechanical remodeling process. Here, we quantify and compare the evolution of cellular composition and mechanical stiffness of the zebrafish ventricular myocardium during maturation and following cryoinjury during regeneration to better understand the dynamics of biomechanical remodeling during these two processes. With increasing age, normal myocardial trabecular density and cardiomyocyte fraction increased, while non-myocyte cell fractions decreased. Cell density remained constant during maturation. Cardiomyocyte sarcomeres shortened to a minimum reached at 7.5 months of age, but lengthened with additional age. Concomitantly, ventricular wall stiffness increased up until 7.5 months before plateauing with additional age. Endothelial, myofibroblast/smooth muscle, and cardiomyocyte cell fractions were disrupted following cryoinjury, but were progressively restored to age-specific natural norms by 35 days post infarct (DPI). Infarcted myocardium stiffened immediately following cryoinjury and was a 100-fold greater than non-infarcted tissue by 3 DPI. By 14 DPI, stiffness of the infarcted myocardium had fallen below that of 0 DPI and had completely normalized by 35 DPI. Interestingly, cardiomyocyte sarcomere length increased until 14 DPI, but subsequently shortened to lengths below age-specific natural norms, indicating recovery from a volume overloaded condition. These observations are consistent with the view that regenerating myocardium requires biomechanical stimulation (e.g. strain) to rescue from a volume overloaded condition. Intriguingly, the biomechanical progression of the infarcted adult myocardial wall mirrors that of normal remodeling during aging. The biomechanical progression of the infarcted myocardium targets the values of age-specific norms despite a large divergence in initial conditions. These findings identify a novel biomechanical control of heart regeneration that may orchestrate cellular and tissue level remodeling responses.

Early somatic mosaicism is a rare cause of long-QT syndrome.

Somatic mosaicism, the occurrence and propagation of genetic variation in cell lineages after fertilization, is increasingly recognized to play a causal role in a variety of human diseases. We investigated the case of life-threatening arrhythmia in a 10-day-old infant with long QT syndrome (LQTS). Rapid genome sequencing suggested a variant in the sodium channel NaV1.5 encoded by SCN5A, NM_000335:c.5284G > T predicting p.(V1762L), but read depth was insufficient to be diagnostic. Exome sequencing of the trio confirmed read ratios inconsistent with Mendelian inheritance only in the proband. Genotyping of single circulating leukocytes demonstrated the mutation in the genomes of 8% of patient cells, and RNA sequencing of cardiac tissue from the infant confirmed the expression of the mutant allele at mosaic ratios. Heterologous expression of the mutant channel revealed significantly delayed sodium current with a dominant negative effect. To investigate the mechanism by which mosaicism might cause arrhythmia, we built a finite element simulation model incorporating Purkinje fiber activation. This model confirmed the pathogenic consequences of cardiac cellular mosaicism and, under the presenting conditions of this case, recapitulated 2:1 AV block and arrhythmia. To investigate the extent to which mosaicism might explain undiagnosed arrhythmia, we studied 7,500 affected probands undergoing commercial gene-panel testing. Four individuals with pathogenic variants arising from early somatic mutation events were found. Here we establish cardiac mosaicism as a causal mechanism for LQTS and present methods by which the general phenomenon, likely to be relevant for all genetic diseases, can be detected through single-cell analysis and next-generation sequencing.