Aging poses significant challenges to cardiovascular health necessitating novel therapeutic approaches. This study investigates the potential of the brown adipose tissue (BAT) derived lipokine 12,13-diHOME to mitigate age-induced impairments in cardiovascular function. Analysis of human and rodent plasma signaling lipids reveals a decline in 12,13-diHOME levels with age. Transplantation of BAT or sustained upregulation of 12,13-diHOME effectively preserved cardiac function in aged male and female mice. Bulk RNA-Seq of hearts from aged mice reveals significant increases in pathways involved in ER stress and fibrosis which were partially attenuated by BAT transplantation or sustained upregulation of 12,13-diHOME. Mechanistically, in vivo and in vitro models demonstrate that 12,13-diHOME alleviated ER stress through CaMKII inhibition, particularly in males. These findings underscore 12,13-diHOME as a promising candidate for combating age-related cardiovascular dysfunction, offering insights into potential therapeutic strategies for addressing cardiovascular diseases in aging populations.

Heart failure (HF) represents a major burden on the healthcare system, with patients with HF at increased risk for a host of comorbidities, including ventricular arrhythmias. Despite considerable advances in defining cell- and organ-level changes associated with HF, the precise mechanisms driving structural and electrical remodeling remain to be defined. We sought to elucidate the role of the two-pore K+ channel TREK-1 in cardiac remodeling in pressure overload-induced HF. Cardiac-specific TREK-1 conditional knockout (TREK1cKO) and floxed control mice were subjected to transaortic contraction (TAC) or sham procedure and evaluated for 6 wk by echocardiography and subsurface electrocardiograms. Ventricular myocytes were isolated for action potential, intracellular Ca2+, and contractility measurements. The expression/regulation of key cell signaling pathways was evaluated early in remodeling. TREK1cKO and control mice showed a significant decrease in cardiac systolic function with evidence of hypertrophy as early as 2 wk post-TAC compared with sham. However, TREK1cKO mice displayed a more severe decline in function with enhanced left ventricular chamber dilation (eccentric remodeling) compared with control 6 wk post-TAC. Similarly, TAC TREK1cKO mice demonstrated greater prolongation of the QT and QRS intervals compared with TAC control. TAC TREK1cKO ventricular myocytes exhibited greater action potential prolongation with paradoxical improvements in Ca2+ homeostasis and contractility compared with control. Two weeks post-TAC, TREK1cKO hearts exhibited elevation of STAT3 phosphorylation at Y705 compared with control. Our findings reveal a complex interaction between chronic stress, TREK-1, STAT3 regulation, and cardiac remodeling, with TREK-1 exerting both maladaptive and protective effects on overall cardiac function.NEW & NOTEWORTHY A major finding of this study is the involvement of the background K+ channel TREK-1 in modulating STAT3 activation, profibrotic gene expression, and fibrosis with implications for the cardiac remodeling response to chronic pressure overload.

BACKGROUND:Cardiac hypertrophy, defined as a stress-induced increase in heart mass/size, is a major risk factor for adverse cardiovascular events, including heart failure and arrhythmia. Within this general definition, the orientation of cell and organ growth varies considerably depending on stress type and duration, with important implications for cardiac function, yet little is known regarding the mechanisms that regulate hypertrophic orientation. Here, we evaluated the role of the cytoskeletal protein βIV-spectrin and associated prohypertrophic STAT3 (signal transducer and activator of transcription 3) to direct the orientation of hypertrophic growth. METHODS:Transgenic mouse models with altered STAT3 signaling through modified interaction with its scaffolding partner βIV-spectrin, or phospho-regulation of STAT3 directly, were evaluated at baseline, and after transaortic constriction, or aortocaval fistula. Unbiased screening of gene expression from these structurally divergent states was evaluated for pathways responsible for directing myocyte length/width. These pathways were tested in vitro using primary mouse myocytes and in vivo to tune growth patterns for therapeutic intervention. RESULTS:Loss of βIV-spectrin or direct STAT3 activation promoted a preferential increase in myocyte length over width, resulting in dilation of the left ventricular chamber (eccentric hypertrophy) and decreased systolic function. Conversely, preservation of βIV-spectrin favored an increase in myocyte width without left ventricular dilation (concentric hypertrophy) and preserved systolic function in response to transaortic constriction or aortocaval fistula. Differential expression of genes associated with microtubules, including the trafficking kinesin motor, KIF20A (kinesin family member 20A), were identified in concentric versus eccentric hypertrophic states. In vitro assays revealed a relationship between βIV-spectrin/STAT3 signaling, KIF20A expression, microtubule density, and spatial distribution of mRNA for the sarcomeric gene actc1. Finally, intervention with pharmacological STAT3 inhibition after chronic 6-week transaortic constriction successfully recovered concentric growth with improved systolic function. CONCLUSIONS:These data identify a novel and pivotal role for βIV-spectrin/STAT3 to modify microtubule properties and sarcomeric transcript distribution to direct myocyte geometry in response to chronic stress. These studies further illustrate the unique separation of hypertrophic growth and orientation as distinct pathways in cardiac remodeling.

Diastolic dysfunction and delayed ventricular repolarization are typically observed in the elderly, but whether these defects are intimately associated with the progressive manifestation of the aging myopathy remains to be determined. In this regard, aging in experimental animals is coupled with increased late Na+ current (I-Na,I-L) in cardiomyocytes, raising the possibility that I-Na,I-L conditions the modality of electrical recovery and myocardial relaxation of the aged heart. For this purpose, aging male and female wild-type (WT) C57Bl/6 mice were studied together with genetically engineered mice with phosphomimetic (gain of function, GoF) or ablated (loss of function, LoF) mutations of the sodium channel Nav1.5 at Ser571 associated with, respectively, increased and stabilized I-Na,I-L. At similar to 18 mo of age, WT mice developed prolonged duration of the QT interval of the electrocardiogram and impaired diastolic left ventricular (LV) filling, defects that were reversed by I-Na,I-L inhibition. Prolonged repolarization and impaired LV filling occurred prematurely in adult (similar to 5 mo) GoF mutant mice, whereas these alterations were largely attenuated in aging LoF mutant animals. Ca2+ transient decay and kinetics of myocyte shortening/relengthening were delayed in aged (similar to 24 mo) WT myocytes, with respect to adult cells. In contrast, delayed Ca2+ transients and contractile dynamics occurred at adult stage in GoF myocytes and further deteriorated in old age. Conversely, myocyte mechanics were minimally affected in aging LoF cells. Collectively, these results document that Nav1.5 phosphorylation at Ser571 and the late Na+ current modulate the modality of myocyte relaxation, constituting the mechanism linking delayed ventricular repolarization and diastolic dysfunction. NEW & NOTEWORTHY We have investigated the impact of the late Na current (I-Na,I-L) on cardiac and myocyte function with aging by using genetically engineered animals with enhanced or stabilized I-Na,I-L, due to phosphomimetic or phosphoablated mutations of Nav1.5. Our findings support the notion that phosphorylation of Nav1.5 at Ser571 prolongs myocardial repolarization and impairs diastolic function, contributing to the manifestations of the aging myopathy.

Introduction: Obesity is a risk factor for atrial fibrillation (AF) and its incidence that has tripled over the past 30 years. Obesity is associated with dramatic changes in atrial structure and electrophysiology through unclear mechanisms. The linoleic acid metabolite 12,13-dihydroxy-9Z-octadecenoic acid (12,13-diHOME) is a signaling lipid released by brown adipose tissue that acts in an endocrine manner on myriad tissues including the heart. 12,13-diHOME enhances cardiac myocyte Ca 2+ cycling and overall function, though the precise mechanisms are undetermined. This study tested the hypothesis that 12,13-diHOME inhibits the pro-arrhythmic molecule Ca 2+ /calmodulin-dependent kinase II (CaMKII). We propose that obesity-induced loss of 12,13-diHOME promotes CaMKII dysfunction, in vitro ectopy and atrial arrhythmia (AA). Methods: Adult male and female mice were fed either high fat diet (HFD, 60% kcal from fat) or normal chow (NFD) (21% kcal from fat) for 8-16 weeks. Atrial myocytes were isolated for action potential (AP) measurements using whole-cell patch clamp ±12,13-diHOME (5 μM). To test the effect of 12,13-diHOME on AA inducibility, a second cohort of mice was fed HFD and subjected to weekly tissue nanotransfection for non-viral delivery of either Ephx1/2 (HFD-TNT), enzymes responsible for production of 12,13-diHOME, or empty plasmid (HFD-con). Following treatment, mice underwent intracardiac pacing studies to determine AA inducibility. The ability of 12,13-diHOME to directly interact with and inhibit CaMKII was tested using purified components with in vitro radioassay and microscale thermophoresis. Results: HFD induced atrial myocyte AP duration prolongation and a higher incidence of spontaneous depolarization compared to NFD, both of which were reversed by 12,13-diHOME (figure). HFD-TNT exhibited decreased phospho-CaMKII compared to HFD-con mice. In parallel, HFD-TNT trended toward reduced inducibility of AA (0/7 mice inducible, 0%) compared to TNT-CON mice (5/7, 58%) (p=0.07). Radioassay revealed that 12,13-diHOME inhibits CaMKII; thermophoresis demonstrated direct binding with K 1/2 = 19 mM. Conclusion: HFD induces dysregulation in 12,13-diHOME and CaMKII signaling together with defects in atrial myocyte excitability and AA in mice. Non-viral overexpression of 12,13-diHOME shows promise in normalizing CaMKII activity and reducing AA burden. 12,13-diHOME represents a novel avenue for direct regulation of CaMKII signaling and downstream pathology in the heart.

INTRODUCTION:Atrial fibrillation (AF) is the most common arrhythmia. Catheter ablation is a successful rhythm control strategy in paroxysmal AF, but it has demonstrated dramatically lower AF-free survival rates in patients with persistent AF. In recent years, myriad novel rhythm control strategies have been developed, each with the promise of improved persistent AF ablation success. AREAS COVERED:This review discusses multiple novel techniques and approaches to persistent AF. Authors identified relevant papers by searching PubMed and Google Scholar databases and considered all papers identified, regardless of publication date. It begins by discussing recent advances in electrogram analysis that yielded improved AF-free survival following persistent AF catheter ablation. Next, it discusses several trials revealing the shortcomings of MRI in guiding persistent AF ablation. Finally, it discusses one nascent technique (Vein of Marshall ablation) and technology (AI-assisted electrogram analysis) who have shown promise in improving persistent AF ablation. EXPERT OPINION:In the authors' expert opinions, upcoming persistent AF ablations will utilize a stepwise approach of (1) ensuring PV isolation, (2) Vein of Marshall ablation and (3) AI-assisted ablation to optimize future persistent AF ablation outcomes. This approach systematically addresses arrhythmogenic sources beyond the pulmonary veins, the historical treatment target.

Background: Cardiac hypertrophy is a major risk factor for adverse cardiovascular events including heart failure and arrhythmia. However, the precise orientation of cell and organ growth varies considerably depending on stress type and duration with important implications for cardiac function. Despite this, little is known regarding the mechanisms that regulate hypertrophic orientation. Here we evaluate the role of the cytoskeletal protein β IV -spectrin and signal transducer and activator of transcription (STAT3) in directing the orientation of pressure overload-induced hypertrophy. Methods: Transgenic mouse models with altered STAT3 signaling through modified interaction with its scaffolding partner β IV -spectrin, or phospho-regulation of STAT3 directly, were evaluated at baseline and transaortic constriction (TAC) for its role in promoting concentric versus eccentric morphologies and resulting impact on systolic function. Unbiased screening of gene expression from these structurally divergent states were evaluated for pathways responsible for directing myocyte length/width. These pathways were tested in vitro using primary mouse myocytes and in vivo to tune growth patterns for therapeutic intervention. Results: Loss of β IV -spectrin or direct STAT3 activation promoted a preferential increase in myocyte length over width, resulting in dilation of the left ventricular (LV) chamber (eccentric hypertrophy) and decreased systolic function. Conversely, preservation of β IV -spectrin favored an increase in myocyte width without LV dilation (concentric hypertrophy) and preserved systolic function in response to TAC. Differential expression of genes associated with microtubule dynamics were identified in concentric vs. eccentric hypertrophic states. In vitro assays revealed a relationship between β IV -spectrin/STAT3 signaling and microtubule stability which impacted spatial distribution of mRNA for the sarcomeric gene actc1 . Finally, intervention with pharmacologic STAT3 inhibition following chronic 6-week TAC successfully recovered concentric growth with improved systolic function. Conclusions: These data identify a novel and pivotal role for β IV -spectrin/STAT3 to modify microtubule dynamics and sarcomeric transcript distribution to direct myocyte geometry and therapeutically serve in the prevention or recovery from HF. These mechanisms further illustrate the unique separation of hypertrophic drivers from growth orientation as distinct pathways in cardiac remodeling.

Localized reentrant drivers have been suggested to maintain persistent atrial fibrillation (perAF). However, their existence, electrophysiological mechanisms, and structural substrates in-vivo are controversial.

Importance Ibrutinib has been associated with serious cardiotoxic arrhythmias. In preclinical models, these events are paralleled or proceeded by diffuse myocardial injury (inflammation and fibrosis). Yet whether this is seen in patients or has implications for future cardiotoxic risk is unknown. Objective To assess the incidence and outcomes of myocardial injury among patients with ibrutinib-related cardiotoxicity. Design, Setting, and Participants This cohort study included consecutive patients treated with ibrutinib from 2012 to 2019, phenotyped using cardiovascular magnetic resonance (CMR) from a large US Comprehensive Cancer Center registry. Exposures Ibrutinib treatment for cancer control. Main Outcomes and Measures The primary outcome was the presence of late gadolinium enhancement (LGE) fibrosis. The secondary outcome was the occurrence of major adverse cardiac events (MACE), defined as atrial fibrillation, heart failure, symptomatic ventricular arrhythmias, and sudden death of probable or definite ibrutinib association after CMR. We also assessed parametric-mapping subclinical fibrosis (native-T1, extracellular volume fraction) and inflammation/edema (max-T2) measures. Cardiovascular magnetic resonance measures were compared with those obtained in similar consecutive patients with cancer without ibrutinib treatment (pretreatment controls). Observed measures were also compared with similar-aged broad population rates (general-population controls) and a broader pool of cardiovascular disease (CVD) risk-matched cancer controls. Multivariable regression was used to assess the association between CMR measures and MACE. Results Overall, 49 patients treated with ibrutinib were identified, including 33 imaged after treatment initiation (mean [SD] age, 65 [10] years, 9 [27%] with hypertension, and 23 [69.7%] with index-arrhythmias); median duration of ibrutinib-use was 14 months. The mean (SD) pretreatment native T1 was 977.0 (73.0) ms, max-T2 56.5 (4.0) ms, and 4 (13.3%) had LGE. Posttreatment initiation, mean (SD) native T1 was 1033.7 (48.2) ms, max-T2 61.5 (4.8) ms, and 17 (54.8%) had LGE (P < .001, P = .01, and P < .001, respectively, pre- vs post-ibrutinib treatment). Native T12SDs was elevated in 9 (28.6%), and max-T22SDs in 21 (63.0%), respectively. Cardiovascular magnetic resonance measures were highest in those with suspected toxic effects (P = .01 and P = .01, respectively). There was no association between traditional CVD-risk or cancer-treatment status and abnormal CMR measures. Among those without traditional CVD, 16 (58.6%) had LGE vs 38 (13.3%) in matched-controls (relative-risk, 4.8; P < .001). Over a median follow-up of 19 months, 13 (39.4%) experienced MACE. In multivariable models inclusive of traditional CVD risk factors, LGE (hazard ratio [HR], 4.9; P = .04), and native-T12SDs (HR, 3.3; P = .05) associated with higher risks of MACE. Conclusions and Relevance In this cohort study, myocardial injury was common in ibrutinib users, and its presence was associated with higher cardiotoxic risk.

Introduction: Acalabrutinib and zanubrutinib are next generation Bruton’s tyrosine kinase inhibitors (BTKIs) associated with dramatic efficacy against B cell malignancies. In early trials, these BTKIs show less cardiac activity than ibrutinib. Yet, whether this is seen in longer term follow up is unknown. Methods: Leveraging the US Food and Drug Administration’s Adverse Events Reporting System (FAERS), we identified the relative incidence and predictive factors for atrial fibrillation (AF) after BTKI initiation from 2015-2022. Secondary outcomes were the reporting odds ratios (ROR) of major adverse cardiovascular adverse events (AEs), defined as AF, non-AF atrial arrhythmias, heart failure, conduction blocks, and ventricular arrythymias. In addition, using a registry cohort of 838 hematologic malignancy patients treated with ibrutinib or acalabrutinib from 2012-2020, we assessed the comparative incidence of new AF. Observed incident AF rates were compared with Framingham heart predicted rates, and absolute excess risks of AF were estimated. Multivariable logistic-regression models were used to identify factors associated with AF, other cardiac AEs, and mortality. Results: Among 21,435 events reported to FAERS during BTKI use, 3,453 were cardiovascular AEs. AF was the most reported AE (ROR 8.8, 95% CI, 8.3-9.4; Figure A ). The likelihood (ROR) of cardiac AE reporting in next generation BTKI treated patients was >3.0 ( P <0.05; Figure A ) for AF events. Furthermore, in acalabrutinib treated registry patients, 9.7% developed incident AF over a median follow up of 42 months. In those without prior ibrutinib use, the weighted average incidence was 281 per 10,000 person years compared to the Framingham predicted rate of 103 per 10,000 person years (RR 2.73, P <0.001; AER 178; Figure B ). Conclusions: These data suggest residual AF risk with next generation BTKIs.

Background Carfilzomib and other proteasome inhibitors (PIs) have revolutionized treatment of multiple myeloma (MM). PIs have proven to be highly effective, but are associated with significant cardiovascular adverse events (AEs). No prior study has compared the cardiotoxicity of carfilzomib against other PI’s and all other classes of medications. Objectives The purpose of this study is to characterize the cardiotoxicity of carfilzomib with respect to other PIs and all classes of medications using the US Food and Drug Administration Adverse Events Reporting System (FAERS) database and to define the observed cardiotoxicity profile. Methods The FAERS database was queried between years 2017 and 2020 to identify AEs associated with PIs. Data extracted included concomitant medications used, type and severity of AEs and patient characteristics including age, sex, and time from medication initiation to adverse event. Cardiotoxicities assessed included acute myocardial infarction, heart failure, and supraventricular tachycardia. The reporting odds ratio (ROR) and information component assessed the strength of association between PIs and cardiotoxicity. Results Over the study period, 21,026 adverse events were reported in patients taking carfilzomib among 55,195 total adverse events in patients taking PI’s were identified from 6,548,048 total events reported in the FAERS database. The most common AE associated with carfilzomib was development of heart failure (1116 adverse events); disproportionality analysis revealed a stronger association with hypertension and QT prolongation with carfilzomib than other PI’s. Conclusions While they have demonstrated efficacy and revolutionized treatment of MM, carfilzomib and other PI’s are associated with cardiotoxicities.

OBJECTIVES The aim of this study was to assess temporal changes and clinical implications of peridevice leak (PDL) after left atrial appendage closure. BACKGROUND Endocardial left atrial appendage closure devices are alternatives to long-term oral anticoagulation (OAC) for patients with atrial fibrillation. PDL >5 mm may prohibit discontinuation of OAC. METHODS Patients included in the study had: 1) successful Watchman device implantation without immediate PDL; 2) new PDL identified at 45 to 90 days using transesophageal echocardiography; 3) eligibility for OAC; and 4) 1 follow-up transesophageal echocardiographic study for PDL surveillance. Relevant clinical and imaging data were collected by chart review. The combined primary outcome included failure to stop OAC after 45 to 90 days, transient ischemic attack or stroke, device-related thrombi, and need for PDL closure. RESULTS Relevant data were reviewed for 1,039 successful Watchman device implantations. One hundred eight patients (10.5%) met the inclusion criteria. The average PDL at 45 to 90 days was 3.2 +/- 1.6 mm. On the basis of a median PDL of 3 mm, patients were separated into #3 mm (n = 73) and >3 mm (n = 35) groups. In the #3 mm group, PDL regressed significantly (2.2 +/- 0.8 mm vs 1.6 +/- 1.4 mm; P = 0.002) after 275 +/- 125 days. In the >3 mm group, there was no significant change in PDL (4.9 +/- 1.4 mm vs 4.0 +/- 3.0 mm; P = 0.12) after 208 +/- 137 days. The primary outcome occurred more frequently (69% vs 34%; P = 0.002) in the >3 mm group. The incidence of transient ischemic attack or stroke in patients with PDL was significantly higher compared with patients without PDL, irrespective of PDL size. CONCLUSIONS New PDL detected by transesophageal echocardiography at 45 to 90 days occurred in a significant percentage of patients and was associated with worse clinical outcomes. PDL #3 mm tended to regress over time. (J Am Coll Cardiol EP 2022;8:15-25) (c) 2022 by the American College of Cardiology Foundation.

Introduction: Persistent (per) AF may be maintained by localized extra-PV drivers (DRs). Regional fibrosis can serve as a substrate for AF DRs, but its visualization by delayed enhancement (DE)-MRI lacks proper validation for driver substrates. The objective of this study is to evaluate if histology-validated normalized (HVN) DE-MRI thresholds can define arrhythmogenic fibrotic content in multielectrode mapping (MEM)-defined DRs from perAF patients’ (Pts) DE-MRI. Methods: PerAF Pts (n=14, 71% male; 63±10 y/o) had DE-MRI at 3T (0.63x0.63x0.63mm 3 , 0.2mmol/kg Gd) before their perAF ablation procedure. Chamber-specific DE-MRI intensity was normalized to the healthy atria (mean lowest 5% intensity, 0 AU) and mitral (LA) or tricuspid (RA) valve (100 AU). 3 control and 5 perAF canines had DE-MRI and regional histology to validate DE-MRI fibrotic thresholds for the LA and RA, which were defined as standard deviations (SD) above 40% of the mean healthy atrial tissue intensity (LA: 3.7 SD, RA: 2.7 SD). Fibrosis-enhancement of segmented MEM-defined DRs (LA: n=25, RA: n=11) were analyzed using conventional, non-normalized 3 SD and HVN thresholds and compared to 5 random regions (non-DRs) within the same anatomical region(s). Results: Only our HVN approach could reveal arrhythmogenic fibrotic substrates in LA DR regions, but not the conventional approach. Both approaches could not provide significant differences for RA DR vs non-DR fibrosis regions. The cut-off of 33.6% of LA DE-MRI fibrotic enhancement using the HVN approach allowed to distinguish LA DR vs. non-DR regions with 56% sensitivity and 70% specificity. At 12 months follow-up, 10 Pts remained free of AF. Conclusion: MEM-defined DRs within fibrotic regions, identified by HVN DE-MRI, may represent efficient targets for ablation of LA arrhythmogenic perAF substrates. Integration of MEM and MRI may lead to improved targeted ablation and long-term AF freedom.