Julie R. McMullen

Heart failure with reduced ejection fraction (HFrEF) and heart failure with preserved ejection fraction (HFpEF) are subtypes of heart failure with overlapping clinical features but have some distinct functional characteristics and cellular and molecular mechanisms. Exercise training is an accessible, non-pharmacological therapy recommended for the management of HFrEF and is increasingly showing promise for treating HFpEF. This review summarises the underlying pathophysiology of HFrEF and HFpEF and the evidence from clinical and preclinical studies showing that exercise training can improve cardiac function. The authors also summarise the underlying cellular and molecular mechanisms between HFrEF and HFpEF, with respect to cardiac remodelling, fibrosis, mitochondrial adaptations and metabolism, inflammation and inter-organ crosstalk, and provide evidence that exercise training elicits protective adaptations in HFrEF and HFpEF through some different signalling pathways targeted by exercise. Finally, the authors discuss the use of exercise training as a therapeutic intervention for HFrEF and HFpEF through personalised training by phenotype and in combination with emerging pharmacological treatments.

Background: Heart failure (HF) with preserved ejection fraction (HFpEF) is a heterogeneous condition that accounts for more than half of all HF cases. It is a major cause of morbidity and mortality worldwide; however, preclinical models often do not capture the heterogeneity and sex-specific and cardiometabolic features observed in patients. We hypothesised that biological sex and the degree of nitric oxide synthase (NOS) inhibition would influence development of HFpEF-like versus HFrEF-like phenotypes. Methods and Results: Male and female C57BL/6J mice (>24 weeks) were exposed to a high-fat diet (HFD) combined with low-dose (0.3 g/L; female only) or high-dose (0.5 g/L; male and female) NOS inhibition using N(ω)-nitro-L-arginine methyl ester (L-NAME) for 15 weeks. Female mice receiving low-dose L-NAME+HFD developed a HFpEF-like phenotype characterised by impaired diastolic function, exercise intolerance and preserved systolic function. Increasing NOS inhibition did not worsen diastolic dysfunction but induced inflammatory and stress-associated transcriptional pathways in female hearts. In contrast, male mice administered high-dose L-NAME+HFD developed hypertension, elevated ventricular pressures and impaired systolic function, consistent with a HFrEF-like phenotype. Despite different cardiac phenotypes, circulating lipidomic profiling revealed broadly conserved sphingolipid and phospholipid remodelling, with sex-specific regulation of phosphatidylinositol and lysophosphatidylcholine species. Transcriptomic analyses identified shared regulation of extracellular matrix, calcium-handling and metabolic pathways, whereas greater NOS inhibition was associated with transcriptional signatures related to inflammatory signalling, cellular stress responses and mitochondrial homeostasis. Conclusions: Cardiometabolic stress does not produce a uniform HF phenotype. Instead, biological sex and the degree of NOS inhibition direct distinct functional and molecular remodelling trajectories, identifying HFpEF-like dysfunction as one of several potential cardiac responses to cardiometabolic injury in male and female mice.

The development of new cancer therapies with greater efficacy has reduced mortality for many cancers, as well as improving survivorship. However, for some cancer treatments, this has uncovered unintended cardiotoxicity during or after treatment, and cardiovascular disease has emerged as a leading cause of mortality in some cancer survivors. This may occur because many of the same growth factor signaling pathways that lead to tumor growth are also critical for maintaining normal heart function. A class IA phosphoinositide 3-kinase, PI3K(p110 α ), is a critical regulator of normal heart biology, function and exercise-induced cardiac protection, but is also mutated/increased in some cancer types. In this review, we discuss the dual role of PI3K(p110 α ) signaling in cancer and the heart. The paradox being, that inhibiting PI3K(p110 α ) in a setting of some cancer types would be beneficial for halting/slowing tumor progression but could also damage heart muscle cells. Exercise and PI3K(p110 α ) has beneficial effects on heart function via cardiac excitation and contraction, mitochondrial adaptations, cellular stress responses to promote survival, preventing cell death and cardiac fibrosis. We contrast this to the chemotherapy, doxorubicin, which is crucial for the treatment of many cancers but negatively impacts many of the beneficial effects of exercise and PI3K(p110 α ). Doxorubicin's clinical efficacy is limited by dose-dependent cardiotoxicity including cardiomyopathy, atrial fibrillation, and heart failure. A summary of reported cardiovascular effects in clinical trials using PI3K inhibitors is also provided. Finally, we discuss some of the current and emerging approaches to mitigate cancer therapy-induced cardiotoxicity including pharmacological interventions, gene therapy and dietary approaches based on preclinical studies. Advances in the field are likely to come from continued refinement of cardiotoxicity models, the investigation of targeting molecular pathways and targets with relevant primary endpoints for both cancer and heart function, and collaborative research with discovery/preclinical scientists and clinicians.

Advances in mass spectrometry have seen the identification of hundreds of new lipid species, some of which have been found to be associated with adverse cardiac remodeling. Key among these are GM3 gangliosides, which have been associated with metabolic disease, and more recently, adverse cardiac remodeling. Whether GM3s have a direct pathophysiological effect in the heart remains unclear. The present study investigated the effects of cardiomyocyte-specific knockout of GM3 synthase (GM3S, enzyme responsible for the synthesis of GM3) in the heart under basal settings and in response to ischemia-reperfusion (I/R) injury. A new cardiomyocyte-specific GM3S knockout (KO) model was generated, with knockout confirmed via lipidomic profiling. Under basal conditions, male GM3SKO mice exhibited reduced heart weight to tibia length (HW/TL) ratios with no evidence of pathological remodeling, while female mice showed no significant morphological differences. Male GM3SKO mice subjected to 1 hour ischemia and 4 weeks reperfusion demonstrated reduced HW/TL ratio compared to control mice subjected to I/R. However, no significant differences were observed in cardiac function, heart failure and fibrotic markers. Lipidomic profiling (49 classes, ∼850 species) revealed significant accumulation of dihexosylceramide, a metabolic precursor of GM3 in the male heart under basal and post-I/R conditions. In male GM3SKO I/R hearts, GM3 reduction was associated with decreases in odd- and branch-chained phospholipids, together with distinct changes in circulating ether lipid species. Collectively, cardiomyocyte-specific GM3 depletion contributed to sphingolipid remodeling but did not confer protection against I/R-mediated injury. These findings suggest that elevated GM3 levels observed in settings of cardiac pathology are not cardiomyocyte driven, highlighting the importance of understanding cell-type specific contributions to adverse cardiac remodeling.

BACKGROUND: Cardiac fibrosis is a major cause of cardiac dysfunction and is associated with virtually all forms of heart disease. Recently, single-cell genomic approaches have revealed in unprecedented resolution the orchestrated cellular responses driving cardiac fibrosis. Yet, the fibrosis-inducing phenotypes that emerge in the heart after nonischemic cardiac stress and the transcriptional circuits that govern fibrogenic cellular phenotypes are not well understood. METHODS: Applying a single-cell paired-multiomic approach—by which both transcriptomic and epigenetic information is captured from individual cells—we reveal key transcription factors, in mouse and human hearts, associated with fibrosis development after nonischemic cardiac insults. Using high-throughput bulk transcriptomic and proteomic analyses, microscopy, and functional in vitro assays, we validate the distinct roles of new and established transcription factors in cardiac fibrosis. RESULTS: Analysis of mouse hearts undergoing reverse remodeling after angiotensin II stimulation, where cardiac fibrosis dissipates, we find these factors are reversibly activated. Further, silencing transcription factors—including those we have identified that are previously unlinked to cardiac fibrosis, such as CREB3L2 (CAMP Responsive Element Binding Protein 3 Like 2), BNC2 (Basonuclin Zinc Finger Protein 2), and NFAT5 (Nuclear Factor of Activated T Cells 5)—modulates induction of extracellular matrix gene expression by human cardiac fibroblasts. Detailed analysis of CREB3L2 showed that it regulates cardiac fibrosis by modulating extracellular matrix synthesis through a dual mechanism—involving its N-terminal transactivation domain and a paracrine-acting C-terminal fragment—which is triggered after endoplasmic reticular stress. CONCLUSIONS: This study identifies critical transcription factors regulating cardiac fibrosis and offers promising new targets to ameliorate the development of fibrosis in the context of stressors that cause cardiac dysfunction.

CD14 is a widely validated marker for monocyte/macrophage activity as well as an inflammatory biomarker and upstream regulator of macrophage activity. We herein test the hypothesis that interventional CD14 blockade with a murine analogue of atibuclimab, an anti-CD14 antibody, which has recently been reported to have a favorable safety profile, prevents secondary immunological exacerbation of cardiac injury in a translational mouse model of reperfused ST-elevation myocardial infarction (STEMI) with key clinical features. We report multiomic mechanistic and translation-informing evidence that CD14 blockade downregulated macrophagic pro-inflammatory and tissue remodeling processes without suppression of monocyte-macrophage infiltration or repair, and prevented the post-acute progression of LV dysfunction, dilatation, and haemodynamic decompensation. These data provide the first evidence to support a clinically practicable targeted immunomodulatory strategy of CD14 blockade initiated at reperfusion for the prevention of chronic immunological progression towards ischemic heart failure using multiple clinical modalities. These findings also provide new insights into the pleiotropic roles of CD14 in ischemic heart failure following ischemia injury-reperfusion.

Cardiovascular disease affects millions of people worldwide and often presents with other conditions including metabolic, renal and neurological disorders. A variety of secreted factors from multiple organs/tissues (proteins, nucleic acids and lipids) have been implicated in facilitating organ cross‐talk that may contribute to the development of multimorbidity. Secreted proteins have received the most attention, with the greatest body of research related to factors released from adipose tissue (adipokines), followed by skeletal muscle (myokines). To date, there have been fewer studies on proteins released from the heart (cardiokines) implicated with organ cross‐talk. Early evidence for the secretion of cardiac‐specific factors facilitating organ cross‐talk came in the form of natriuretic peptides which are secreted via the classical endoplasmic reticulum–Golgi pathway. More recently, studies in cardiomyocyte‐specific genetic mouse models have revealed cardiac‐initiated organ cross‐talk. Cardiomyocyte‐specific modulation of microRNAs (miR‐208a and miR‐23‐27‐24 cluster) and proteins such as the mediator complex subunit 13 (MED13), G‐protein‐coupled receptor kinase 2 (GRK2), mutant α‐myosin heavy‐chain (αMHC), ubiquitin‐like modifier‐activating enzyme (ATG7), oestrogen receptor alpha (ERα) and fibroblast growth factor 21 (FGF21) have resulted in metabolic and renal phenotypes. These studies have implicated a variety of factors which can be secreted via the classical pathway or via non‐classical mechanisms including the release of extracellular vesicles. Cross‐talk between the heart and the brain has also been described (e.g. via miR‐1 and an emerging concept, interoception: detection of internal neural signals). Here we summarize these studies taking into consideration that factors may be secreted in both settings of health and in disease. image