BACKGROUND AND AIMS:Ageing is accompanied by progressive microvascular dysfunction, a key determinant of organ performance and longevity. The molecular drivers of this process remain incompletely defined, and the mechanisms by which exercise counters vascular ageing are unclear. This study investigated whether exercise-regulated long noncoding RNAs (lncRNAs) contribute to microvascular ageing and age-related cardiac dysfunction. METHODS:RNA sequencing was performed in naturally aged mice with and without voluntary exercise. Functional studies of candidate lncRNAs were conducted using AAV-mediated overexpression, antisense oligonucleotides, and CRISPR-based knockdown, both in vivo and in endothelial cells (ECs). RESULTS:A novel set of lncRNAs altered in hearts from exercised aged mice was identified and termed Senescence Associated LncRNA Transcripts in Exercise (SALTes). Among these, SALTe1 is evolutionarily conserved and enriched in ECs. SALTe1 expression is elevated in hearts from aged mice and in patients with various types of heart failure but suppressed by exercise. In 20-month-old mice, SALTe1 inhibition, via antisense GapmeRs or EC-specific deletion, attenuated endothelial senescence, restored microvascular perfusion, and improved diastolic function. Mechanistic studies showed that SALTe1 acts, at least in part, through upregulation of PARP9. CONCLUSIONS:These findings establish SALTe1 as a pivotal regulator of endothelial senescence as well as microvascular and cardiac dysfunction in ageing. Targeted inhibition of SALTe1 recapitulates the vasculoprotective effects of exercise, highlighting a tractable antisense-based therapeutic strategy for combating age-related cardiac decline.

Adaptation to physiological stress is fundamental to health but varies widely among individuals. In humans, this heterogeneity is evident in markedly different gains in fitness in response to identical exercise training. The molecular determinants of this variable "trainability" remain poorly understood. Here we identify insulin-like growth factor binding protein-7 (IGFBP7), a senescence-associated secreted protein, as a circulating constraint on exercise adaptation. Plasma proteomics in older adults enrolled in a randomized exercise trial revealed that IGFBP7 levels inversely predicted fitness gains after one year of high-intensity interval training despite similar baseline fitness. In mice, genetic deletion of IGFBP7 markedly amplified training-induced gains in exercise capacity across distinct training protocols, whereas somatic overexpression abolished this advantage. In the UK Biobank, lower IGFBP7 levels were associated with reduced mortality and multiple incident age-related diseases, mirroring the breadth of ties between fitness and healthspan. Together, these findings identify circulating IGFBP7 as a molecular brake on physiological plasticity in response to exercise, linking training responsiveness, aging biology, and health outcomes.

Heart failure remains a major cause of morbidity and mortality that is associated with myocardial changes in metabolism, contractile function, and molecular remodeling. Cardiomyopathies comprise a diverse group of disorders that can be triggered by various external and internal stressors. This review aims to cover the underlying molecular mechanism driving heart failure progression, at the level of alternative splicing. Alternative splicing is a fundamental mechanism that expands transcriptomic diversity through the differential inclusion or exclusion of exons. This process enables a single gene to generate multiple mRNA isoforms, thereby fine-tuning gene function in a context-dependent manner. Splicing outcomes are determined by a highly coordinated regulatory network, including cis-acting splicing elements, transcriptional kinetics, and trans-regulatory RNA-binding proteins, which together form a dynamic “splicing code” that responds to physiological and pathological stresses. In the heart, alternative splicing regulates cardiac cell homeostasis and normal physiological function. Dysregulated alternative splicing has been increasingly recognized as a key contributor to cardiovascular diseases, particularly in the context of sarcomere gene isoform switching. However, emerging evidence suggests that cardiomyopathies arising from distinct etiologies including dilated, ischemic, and cardiometabolic disorder are associated with unique splicing programs. Here, we provide a comprehensive overview of the regulatory mechanisms governing alternative splicing in the heart, with a particular emphasis on disease-specific splicing events across different forms of cardiomyopathy. We further discuss recent advances in targeting aberrant splicing for therapies as well as novel splicing analysis platforms, highlighting the potential of RNA-based strategies to modulate splicing in heart failure.

BACKGROUND:Exercise improves functional outcomes in patients with diabetic cardiomyopathy (DiaCM). The molecular mechanism underlying cardiac benefits of exercise in DiaCM remains incompletely understood. N6-methyladenosine (m6A) is the most common form of messenger RNA modification in eukaryotes and has been implicated in cardiac development and disease. However, the role of m6A in DiaCM and in the mitigating effects of exercise on this disease are unclear. METHODS:Cardiomyocyte-specific N6-adenosine-methyltransferase-like 3 (METTL3, an m6A methyltransferase) knockout mice and their wild-type littermates were subjected to either chow diet or high-fat diet feeding and injection of streptozotocin to induce DiaCM, followed by an 8-week exercise training and assessment of cardiac function. Some of the mice were injected with adeno-associated viral vector encoding METTL3 to overexpress METTL3 in cardiomyocytes. Cardiac METTL3 expressions were assessed in patients with nonischemic primary dilated cardiomyopathies without or with diabetes. Potential METTL3 downstream effector YBX1 (Y-box binding protein 1) was identified through RNA sequencing. The functional role of YBX1 was examined through adeno-associated viral vector overexpression or knockdown in cardiomyocytes in DiaCM mice. RESULTS:We showed that cardiac METTL3 protein expression and m6A level were downregulated in patient with dilated cardiomyopathy and further downregulated in patients with dilated cardiomyopathy and diabetes. Consistently, cardiac METTL3 and m6A were downregulated in mouse with DiaCM, whereas they were upregulated by exercise. Cardiomyocyte-specific METTL3 knockout eliminated the cardiac benefits of exercise on DiaCM. Conversely, cardiomyocyte-specific METTL3 overexpression improved systolic and diastolic function in 2 DiaCM mouse models. We demonstrated that exercise enhanced cardiac METTL3 expression in DiaCM through signal transducer and activator of transcription 3. Moreover, METTL3 attenuated DiaCM through m6A-depdendent YBX1 upregulation and the subsequent activation of Nrf2. Cardiomyocyte-specific YBX1 overexpression promoted Nrf2 activation and attenuated oxidative stress, resulting in an improvement in cardiac function in DiaCM. In contrast, cardiomyocyte-specific YBX1 gene knockdown abolished the effect of METTL3 on cardiac improvement in mice with DiaCM. Further, pharmacological activation of METTL3 using a small molecule attenuated cardiac dysfunction in DiaCM. CONCLUSIONS:These studies reveal an essential role of METTL3 in the cardiac benefits of exercise and identify METTL3 and YBX1 as promising therapeutic targets for treating DiaCM.

Introduction: Exercise is an effective strategy for improving functional outcomes in patients with diabetic cardiomyopathy (DiaCM), yet the underlying molecular mechanisms are not fully understood. N-acetyltransferase (NAT10), the only known N4-acetylcytidine (ac4C) writer, has been linked to cardiac disease. However, the roles of NAT10 in the benefits of exercise in DiaCM are unknown. Hypothesis: NAT10 is necessary for cardiac benefits of exercise in DiaCM. Methods: NAT10 floxed mice were injected with AAV9 encoding cTnT-driven Cre recombinase to knockout (KO) NAT10 in cardiomyocytes (CMs). CM-specific NAT10 KO mice, NAT10 floxed mice, and their wild-type littermates were subjected to either chow diet or high-fat (HFD) diet feeding and injection of streptozotocin (STZ) to induce DiaCM, followed by an eight-week exercise training. Cardiac NAT10 expressions were assessed in patients with nonischemic primary dilated cardiomyopathies with diabetes (DM/DCM). Downstream effectors of NAT10 were identified through ac4C RNA immunoprecipitation-sequencing (RIP-seq). Results: HFD+STZ mice displayed increased E/e’, decreased fractional shortening (FS), reduced cardiac NAT10 and ac4C levels (p<0.05 for all). Exercise improved E/e’ (Sedentary: -37.01 ± 1.31 vs Exercise: -31.01 ± 1.21, p=0.02, n=6) and FS (Sedentary: 26.31% ± 1.49 vs Exercise: 32.24% ± 1.48, p=0.04, n=6) and increased cardiac NAT10 protein expression by ~two-fold (p<0.01, n=6) and ac4C level. These effects of exercise were canceled by CM-specific NAT10 KO (E/e’: Control: -22.42 ± 2.78 vs KO: -39.09 ± 2.50; FS: Control: 32.86% ± 0.93 vs KO: 25.99% ± 1.19, p<0.01 for all, n=6). Pathway analysis from RIP-seq revealed a significant enrichment of the ferroptosis pathway. In HFD+STZ mice, ac4C levels of key ferroptosis regulators FTH1, SLC7A11, and GPX4 were increased by exercise while reduced by CM-specific NAT10 KO (p<0.01 for all, n=4). Cardiac NAT10 and ac4C levels, and protein expressions of ferroptosis markers SLC7A11 and GPX4 were reduced in DM/DCM patients (vs. nonfailing controls, p<0.01 for all; n=12 in DM/DCM, n=8 in nonfailing). Conclusions: Exercise via NAT10 enhances ac4C deposition on ferroptosis regulators, reducing ferroptosis and improving cardiac function in DiaCM.

Postoperative delirium is a type of acute cognitive dysfunction characterized by inattention, disorganized thinking, and altered levels of consciousness that commonly develops after major surgery. Efforts to reduce the incidence of delirium have focused primarily on optimizing perioperative care, however the development of prophylactic interventions have been hindered by a limited understanding of the underlying mechanisms involved in delirium. In this secondary analysis of the Minimizing ICU Neurological Dysfunction with Dexmedetomidine-induced Sleep (MINDDS) trial, a nested case-control study (n = 51) was conducted using total RNA-sequencing analysis of whole-blood to investigate genes associated with delirium risk and development. Transcriptomic analysis revealed significantly lower expression of a key complement pathway inhibitor, C4BPA, in participants who experienced postoperative delirium. This finding was confirmed by quantitative PCR in the MINDDS cohort (n = 319) in adjusted logistic models. Furthermore, complement inhibitor CD55 was also found to be under-expressed in participants who developed delirium. Dexmedetomidine treatment modified associations between C4BPA and CD55 expression and the incidence of postoperative delirium by decreasing incidence in participants with low C4BPA and CD55 expression. This study revealed key complement regulators as risk biomarkers of postoperative delirium. Importantly, our findings suggest postoperative delirium risk is modifiable. Unlike previous research that has mainly focused on proteomics, this study underscores the effectiveness of whole-blood transcriptomics in identifying biomarkers and underlying biological mechanisms of postoperative delirium.

Introduction: Physical exercise induces physiological cardiac growth and protects the heart against pathological stresses. However, the molecular mechanisms underlying these cardiac benefits of exercise remain incompletely understood. Signal Transducer and Activator of Transcription 3 (STAT3) is a transcription factor that plays a critical role in the heart’s response to cellular injury. However, its role in exercise-induced cardiac benefits is largely unknown. Hypothesis: STAT3 is essential for exercise-induced physiological cardiac growth. Methods: STAT3 floxed mice were crossed with aMHC-Cre mice to generate cardiomyocyte (CM)-specific STAT3 knockout (KO) mice. Eight-week-old CM-specific STAT3 KO mice and STAT3 floxed mice either underwent eight weeks of voluntary wheel running (Run) or were kept sedentary (Sed). Cardiac RNA-sequencing was performed to identify potential mechanisms by which CM STAT3 regulates the cardiac response to exercise. Results: No differences were observed in cardiac size and function at baseline between floxed and KO mice. At the end of 8 weeks, floxed and KO mice ran similar daily distances (5.68±0.21 in floxed vs 5.59±0.23 km/day in KO, p=0.65, n=6/group). In floxed mice, running increased the heart weight to tibial length ratio (HW/TL, 6.15±0.18 in Sed vs 7.41±0.52 in Run, p<0.01, n=6/group) and CM size without affecting fractional shortening (FS), consistent with physiological remodeling. In KO mice, running also increased HW/TL (6.57±0.22 in Sed vs 7.82±0.35 in Run, p<0.01, n=6/group) and CM size but reduced FS (39.78±0.31 in Sed vs 25.82±0.42% in Run, p<0.01, n=6/group) and increased LV size (LVIDs: 3.41±0.27 in Sed vs 4.03±0.43 mm in Run, p<0.05, n=6/group) while reducing wall thickness, suggesting a maladaptive cardiac remodeling response to running in KO animals. RNA sequencing analysis revealed that in floxed mice, running upregulated expression of pathways associated with glycogenolysis and beta-oxidation of very long-chain fatty acids. In contrast, hearts from running KO mice had downregulation in gene expression in these pathways. Conclusions: STAT3 is essential for exercise-induced mitochondrial energy metabolism, CM hypertrophy, and adaptive remodeling. STAT3 deficiency leads to maladaptive cardiac remodeling under physiological stress.

BACKGROUND:Preeclampsia is a hypertensive disorder of pregnancy characterized by systemic endothelial dysfunction. The pathophysiology of preeclampsia remains incompletely understood. This study used human venous endothelial cell (EC) transcriptional profiling to investigate potential novel mechanisms underlying EC dysfunction in preeclampsia.METHODS:Venous ECs were isolated from postpartum patients with severe preeclampsia and those with normotensive pregnancy using a J wire-based technique in the antecubital vein followed by CD144 (vascular endothelial cadherin) magnetic bead isolation. Venous EC transcriptomes were compared between preeclamptic and normotensive individuals. Differentially expressed genes were carried forward for genetic validation using expression quantitative trait loci from the Genotype-Tissue Expression project as exposures for vascular-specific Mendelian randomization. Functional validation of the top candidate was performed in human umbilical vein ECs using gain- and loss-of-function genetic approaches.RESULTS:Seventeen individuals with preeclampsia and 7 normotensive controls were included. Pairwise analysis yielded 14 protein-coding genes nominally differentially expressed in participants with preeclampsia. Mendelian randomization revealed a significant association between higher genetically predicted METAP1 (methionyl aminopeptidase 1) expression in aortic and tibial arterial tissues and greater risk of preeclampsia. METAP1 overexpression in human umbilical vein ECs decreased angiogenesis, with a 66% decrease in tube formation (P=7.9x10-3) and 72% decrease in cell proliferation (P=2.9x10-2). Furthermore, METAP1 overexpression decreased VEGFA expression and increased expression of multiple preeclampsia-related genes, for example, FLT1, INHBA, and IL1B. Conversely, METAP1 knockdown produced opposite effects on tube formation, cell proliferation, and inflammation-related gene expression.CONCLUSIONS:In a cohort of early postpartum individuals, we observed greater METAP1 expression in venous ECs of women with preeclampsia versus normotensive delivery. Mendelian randomization supported a causal relationship between greater vascular METAP1 expression and higher preeclampsia risk, and functional experiments demonstrated antiangiogenic and proinflammatory effects of METAP1 in human ECs consistent with alterations observed in preeclampsia. Ex vivo EC transcriptomics can identify novel mechanisms underlying preeclampsia pathophysiology, with implications for prevention and treatment.

Exercise exerts myriad cardiovascular benefits and protects against most forms of cardiovascular disease. While extensive epidemiological evidence supports the clinical benefits of exercise, our understanding of the molecular underpinnings of its benefits in the heart remains incomplete. Pinpointing these mechanisms is essential to identifying molecular targets modulated by exercise for therapeutic gain. In this review, we discuss the cellular and molecular mechanisms through which exercise benefits the heart, with a focus on the cardiomyocyte. We highlight cardiomyocyte-secreted mediators of intercell communication, intracellular signaling pathways, transcriptional regulation, and posttranscriptional mechanisms through noncoding RNAs that have been implicated in the cardiac exercise response. We emphasize pathways and mediators regulated by exercise training that may provide therapeutic targets in heart failure.

Introduction: Heart failure with preserved ejection fraction (HFpEF) is the most common form of HF. Despite the best available therapies, prognosis remains poor for many patients with HFpEF. N6-methyladenosine (m6A) is the most common form of mRNA modification in eukaryotes and has been implicated in cardiac disease. However, whether m6A plays a role in HFpEF is unknown. Methods: Cardiomyocyte (CM)-specific methyltransferase like 3 (METTL3) knockout (KO) was achieved by injecting AAV9 encoding cTnT-driven Cre into METTL3 floxed mice. CM-specific METTL3 overexpression (OE) was achieved by injecting AAV9 encoding cTnT-driven METTL3 into wild-type (WT) mice. HFpEF mouse models were induced by (1) high-fat diet (HFD) and Nω-nitrol-arginine methyl ester for 15 weeks (HFD+L-NAME); or (2) HFD and transverse aortic constriction-induced moderate pressure overload for 15 weeks (HFD+mTAC). Cardiac METTL3 expression was assessed in patients with HFpEF. Results: METTL3 was the most downregulated m6A writer, at both the mRNA (by ~70%, p<0.001, n=12) and protein (by ~80%, p<0.001, n=12) levels, in hearts of HFpEF patients compared to matched controls. In HFD+L-NAME mice, cardiac METTL3 protein expression was reduced by ~70% (p<0.001, n=8), and associated with cardiac diastolic dysfunction, decreased contractile reserves, and increased fibrosis. These HFpEF phenotypes were further exacerbated in HFD+L-NAME mice with CM-specific METTL3 KO (E/e’: WT: -32.82±2.31 vs KO: -41.27±2.49, p=0.03, n=6). Conversely, CM-specific METTL3 OE improved cardiac diastolic function, increased contractile reserves, and reduced fibrosis in both HFD+L-NAME (E/e’: Control: -34.13±1.62 vs OE: -28.40±1.78, p=0.04, n=6) and HFD+mTAC mice (E/e’: Control: -33.80±1.92 vs OE: -28.34±0.94, p=0.02, n=6). Mechanistically, METTL3 functioned by increasing m6A deposition on Ankrd1 (a cardiac stress-response protein) and promoting its degradation, thereby reducing subsequent cardiac inflammation. Conclusions: CM METTL3 deficiency is part of the causal pathobiology of HFpEF and its CM-specific induction is sufficient to improve cardiac diastolic function and cardiac remodeling in HFpEF. These findings identify METTL3 as a promising therapeutic target for HFpEF.

Cardiac ageing is an intricate and multifaceted process with considerable impact on public health, especially given the global demographic shift towards aged populations. This review discusses structural, cellular, and functional changes associated with cardiac ageing and heart failure with preserved ejection fraction (HFpEF). Key molecular mediators are considered within the framework of the established hallmarks of ageing, with particular attention to promising therapeutic candidates. We further delineate the differential impacts of ageing on cardiac structure and function in men and women, addressing hormonal and chromosomal influences. The protective and mitigating effects of exercise in cardiac ageing and HFpEF in particular are discussed, as an inspiration for the identification of pathways that mitigate biological ageing. We also emphasize how much remains to be learned and the importance of these efforts in enhancing the cardiac health of ageing populations worldwide.

The lymphatic vasculature plays essential roles in fluid balance, immunity, and lipid transport. Chronic, low-grade inflammation in peripheral tissues develops when lymphatic structure or function is impaired, as observed during aging. While aging has been associated with a broad range of heart pathophysiology, its effect on cardiac lymphatic vasculature has not been characterized. Here, we analyzed cardiac lymphatics in aged 20-month-old mice versus young 2-month-old mice. Aged hearts showed reduced lymphatic vascular density, more dilated vessels, and increased inflammation and fibrosis in peri-lymphatic zones. As exercise has shown benefits in several different models of age-related heart disease, we further investigated the effects of aerobic training on cardiac lymphatics. Eight weeks of voluntary wheel running attenuated age-associated adverse remodeling of the cardiac lymphatics, including reversing their dilation, increasing lymph vessel density and branching, and reducing perilymphatic inflammation and fibrosis. Intravital lymphangiography demonstrated improved cardiac lymphatic flow after exercise training. Our findings illustrate that aging leads to cardiac lymphatic dysfunction, and that exercise can improve lymphatic health in aged animals.

Heart failure with preserved ejection fraction (HFpEF) represents a growing global public health challenge, now accounting for approximately half of all heart failure cases and often linked to a systemic pathophysiological process in older adults with multiple comorbidities. Despite increasing recognition of the vascular contributions to HFpEF, the precise molecular mechanisms, particularly the role of noncoding Ribonucleic Acids (ncRNAs) in mediating vascular aging and subsequent cardiac dysfunction, remain incompletely understood. This review provides a comprehensive overview of the mechanistic link between vascular aging and HFpEF, with a specific focus on the pivotal roles of ncRNAs in this complex interplay. We delineate the classification of vascular aging, its cellular hallmarks, including endothelial senescence, vascular smooth muscle cell phenotypic switching, and extracellular matrix remodeling, and its systemic implications, such as inflammaging, oxidative stress, and reduced nitric oxide bioavailability. We then detail how these vascular alterations, including increased ventricular afterload and impaired myocardial perfusion due to coronary microvascular dysfunction, contribute to HFpEF pathophysiology. The review extensively discusses recent findings on how diverse classes of ncRNAs, notably microRNAs, long noncoding RNAs, and circular RNAs, along with emerging evidence for PIWI-interacting RNAs, small nuclear RNAs, small nucleolar RNAs, and tRNA-derived small RNAs, regulate these vascular aging processes and serve as molecular bridges connecting vascular dysfunction to heart failure. In conclusion, understanding the regulatory landscape of ncRNAs in vascular aging may reveal novel biomarkers and therapeutic avenues, offering new strategies for precision medicine in HFpEF.

Introduction: Atrial fibrillation (AF) is a leading cause of stroke and heart failure. Recent genome-wide association studies have implicated ACVR2A , the gene encoding the Activin type IIA receptor (ActRIIA) in AF pathogenesis. The role of ActRIIA signaling in AF and its potential as a therapeutic target are unknown. Hypothesis: ActRIIA signaling is causal in AF pathophysiology. Methods: Causality was assessed using gain- and loss-of-function approaches in mice and cardiomyocytes (CM). ActRII signaling was increased in C57BL/6 mice using an activinA adenovirus (Ad.ActA) or recombinant ActA protein (R.ActA). ActRII was inhibited with CM-specific ActRIIA or ActRIIB knockout (KO) mice or an ActRIIA-Fc ligand trap in three murine AF models induced by high-fat diet (HFD), transverse aortic constriction (TAC), or aging. AF inducibility and electrical remodeling were assessed by invasive electrophysiology and optical mapping. Cardiac RNAseq was used to identify mechanisms, which were validated in CM and mice. Results: Ad.ActA and R.ActA increased circulating ActA, cardiac ActRII signaling, and AF inducibility (0%[Ad.GFP] vs 75%[Ad.ActA], p=0.06, n=4; 33%[PBS] vs 100%[R.ActA], p=0.001, n=9), and decreased atrial conduction velocity (0.6±0.02[Ad.GFP] vs 0.4±0.05m/s[Ad.ActA], p=0.001, n=3). Conversely, decreased trends of AF inducibility occurred in CM-ActRIIA-KO mice subjected to HFD (71%control] vs 48%[KO], p=0.09, n=21) or TAC (69%[control] vs 33%[KO], p=0.08, n=12), but not in CM-ActRIIB-KO mice. ActRIIA-Fc decreased AF inducibility in 22-month-old mice (85%[PBS] vs 0%[ActRIIA-Fc], p=0.01, n=5). RNAseq identified gap junctions as one of the most downregulated pathways in Ad.ActA mice (NES= -2.8, FDR< 0.001). In both mice and CM, R.ActA decreased CX43 protein expression by ~25% (p<0.05), which was associated with increased expression of the E3 ubiquitin ligase Smurf1 (mice: 1.3 fold, p=0.09; CM: 1.9 fold, p=0.02). In CM, ActRIIA, but not ActRIIB, knockdown (KD) decreased Smurf1 (-3-fold, p<0.001) and increased CX43 (1.8-fold, p=0.02). Lastly, both genetic and pharmacologic (A01) inhibition of Smurf1 increased CX43 in CM by 1.2-fold (p=0.06[KD], p=0.04[A01]). Conclusion: Increased ActA/ActRII signaling is causal in AF pathogenesis. This effect is mediated through ActRIIA, but not ActRIIB, suggesting ActRIIA specificity in AF, and its potential as a therapeutic target.

Cardiac complications, including myocardial injury and dysfunction, are common in severe viral respiratory infections (VRI) and are associated with increased mortality 1-3 . The pathophysiology of VRI-induced myocardial injury is multifactorial, but frequently involves structural damage to the heart's microvascular network that leads to subsequent myocardial ischemia and dysfunction 4-6 . Currently, there are no targeted therapies available to prevent or attenuate VRI-associated myocardial injury. Moreover, the molecular mechanisms driving the cardiac microvascular pathology in severe VRI are largely unclear. In this study, we identify increased endothelial cell (EC) activin type IIA receptor (ActRIIA) signaling as a key mediator of cardiac microvascular injury and pathologic remodeling in severe VRI. We show that genetic deletion of EC ActRIIA is sufficient to mitigate EC death and myocardial capillary loss in a murine model of severe influenza infection, which results in improved myocardial perfusion, cardiac function, and survival. We then provide proof-of-concept evidence for two novel pharmacological approaches to target EC ActRIIA pathophysiology in the treatment of VRI-induced cardiac dysfunction.