Heart failure (HF) with preserved ejection fraction (HFpEF) is currently the predominant form of HF with a dramatic increase in risk with age. Low‐grade inflammation, as occurs with aging (termed “inflammaging”), is a common feature of HFpEF pathology. Suppression of proinflammatory pathways has been associated with attenuated HFpEF disease severity and better outcomes. From this perspective, inflammasome signaling plays a central role in mediating chronic inflammation and cardiovascular disease progression. However, the causal link between the inflammasome‐immune signaling axis on the age‐dependent progression of HFpEF remains conjectural. In this review, we summarize the current understanding of the role of inflammatory pathways in age‐dependent cardiac function decline. We will also evaluate recent advances and evidence regarding the inflammatory pathway in the pathophysiology of HFpEF, with special attention to inflammasome signaling.

Arrhythmogenic cardiomyopathy (ACM) is characterized by progressive loss of cardiomyocytes, and fibrofatty tissue replacement. Extracellular vesicles (EVs) secreted by cardiosphere-derived cells, immortalized, and engineered to express high levels of β-catenin, exert anti-inflammatory, and anti-fibrotic effects. The aim of the current study was to assess efficacy of EVs in an ACM murine model. Four-week-old homozygous knock-in mutant desmoglein-2 (Dsg2^mt/mt) were randomized to receive weekly EVs or vehicle for 4 weeks. After 4 weeks, DSG2^mt/mt mice receiving EVs showed improved biventricular function (left, P < 0.0001; right, P = 0.0037) and less left ventricular dilation (P < 0.0179). Electrocardiography revealed abbreviated QRS duration (P = 0.0003) and QTc interval (P = 0.0006) in EV-treated DSG2^mt/mt mice. Further electrophysiology testing in the EV group showed decreased burden (P = 0.0042) and inducibility of ventricular arrhythmias (P = 0.0037). Optical mapping demonstrated accelerated repolarization (P = 0.0290) and faster conduction (P = 0.0274) in Dsg2^mt/mt mice receiving EVs. DSG2^mt/mt hearts exhibited reduced fibrosis, less cell death, and preserved connexin 43 expression after EV treatment. Hearts of Dsg2^mt/mt mice expressed markedly increased levels of inflammatory cytokines that were, in part, attenuated by EV therapy. The pan-inflammatory transcription factor nuclear factor-κB (NF-κB), the inflammasome sensor NLRP3, and the macrophage marker CD68 were all reduced in EV-treated animals. Blocking EV hsa-miR-4488 in vitro and in vivo reactivates NF-κB and blunts the beneficial effects of EVs. Extracellular vesicle treatment improved cardiac function, reduced cardiac inflammation, and suppressed arrhythmogenesis in ACM. Further studies are needed prior to translating the present findings to human forms of this heterogenous disease. Salutary effects of extracellular vesicles (EVs) in arrhythmogenic cardiomyopathy resulting in improved ejection fraction (EF) and decreased ventricular arrhythmias (VAs). CM, Cardiomyocyte; IC, Intercalated disc; CV, Conduction velocity; APD, Action potential duration; LV/RV, Left Ventricle/Right Ventricle; Cx-43, Connexin-43.

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 β-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 “Ca ²⁺ clock” (spontaneous Ca ²⁺ 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.