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Highlights • The prevalence of heart failure with preserved ejection fraction among patients who present with symptoms of heart failure is approximately 50%. • Pharmacologic therapy has not conclusively shown benefits in morbidity and mortality in clinical trials. • Although it represents an active area of research, no device-based therapy has received regulatory approval for the treatment of heart failure with preserved ejection fraction. • Approaches such as atrial shunts, left ventricular expanders, mechanical circulatory support devices, and neurostimulators are at various stages of development., Central Illustration, Summary Characterized by a rapidly increasing prevalence, elevated mortality and rehospitalization rates, and inadequacy of pharmaceutical therapies, heart failure with preserved ejection fraction (HFpEF) has motivated the widespread development of device-based solutions. HFpEF is a multifactorial disease of various etiologies and phenotypes, distinguished by diminished ventricular compliance, diastolic dysfunction, and symptoms of heart failure despite a normal ejection performance; these symptoms include pulmonary hypertension, limited cardiac reserve, autonomic imbalance, and exercise intolerance. Several types of atrial shunts, left ventricular expanders, stimulation-based therapies, and mechanical circulatory support devices are currently under development aiming to target one or more of these symptoms by addressing the associated mechanical or hemodynamic hallmarks. Although the majority of these solutions have shown promising results in clinical or preclinical studies, no device-based therapy has yet been approved for the treatment of patients with HFpEF. The purpose of this review is to discuss the rationale behind each of these devices and the findings from the initial testing phases, as well as the limitations and challenges associated with their clinical translation.

Visual Abstract, Highlights • Early cardiac mitochondrial dysfunction is mediated by transcriptional down-regulation of the mitochondrial proteome. • Comprehensive metabolic remodeling is conserved throughout HFpEF progression and includes increased amino acid and lipid species, indicative of impaired oxidative metabolism. • Transcriptional and metabolic remodeling of skeletal muscle suggests cardiac signaling as a mediator of peripheral tissue maladaptation. • Unbiased systems-level analysis provides new mechanisms underlying HFpEF development., Summary In this study the authors used systems biology to define progressive changes in metabolism and transcription in a large animal model of heart failure with preserved ejection fraction (HFpEF). Transcriptomic analysis of cardiac tissue, 1-month post-banding, revealed loss of electron transport chain components, and this was supported by changes in metabolism and mitochondrial function, altogether signifying alterations in oxidative metabolism. Established HFpEF, 4 months post-banding, resulted in changes in intermediary metabolism with normalized mitochondrial function. Mitochondrial dysfunction and energetic deficiencies were noted in skeletal muscle at early and late phases of disease, suggesting cardiac-derived signaling contributes to peripheral tissue maladaptation in HFpEF. Collectively, these results provide insights into the cellular biology underlying HFpEF progression.

Cardiac amyloidosis has recently garnered substantial attention. Although the advent of noninvasive diagnostic algorithms revolutionized diagnosis, endomyocardial biopsy may still be considered in select cases to determine the amyloidosis subtype definitively. We report a case of a patients with a known mutation causing hereditary apolipoprotein A-I–associated cardiac amyloidosis. (Level of Difficulty: Advanced.), Central Illustration

Visual Abstract, Highlights • Heart failure patients demonstrate pulmonary hypertension during exertion that correlates with limitations in exercise capacity. • Titrated partial occlusion of the IVC through balloon inflation (mechanical preload control) during exercise significantly reduced PA pressure by 25% (from 68 ± 7 mm Hg to 51 ± 7 mm Hg) with no significant reduction in peak VO2 (from 16.4 ± 5.8 ml/kg/min to 16.2 ± 4.0 ml/kg/min) or cardiac output (14.4 ± 5.9 l/min to 12.8 ± 2.9 l/min). • Mechanical preload control trended toward longer exercise times and significantly reduced respiratory rate at matched exercise, suggesting that pulmonary pressures directly contribute to exercise limitations and hyperventilation in heart failure patients. • Mechanical preload control may serve as a novel research and treatment strategy for heart failure patients., Summary Exercise intolerance remains one of the major factors determining quality of life in heart failure patients. In 6 patients with heart failure with preserved ejection fraction (HFpEF) undergoing invasive cardiopulmonary exercise testing, balloon inflation within the inferior vena cava (IVC) was performed during exercise to reduce and maintain pulmonary arterial (PA) pressures. Partial IVC occlusion significantly reduced PA pressures without reducing cardiac output. Partial IVC occlusion significantly reduced respiratory rate at matched levels of exercise. These findings highlight the importance of pulmonary pressures in the pathophysiology of HFpEF and suggest that therapies targeting hemodynamics may improve symptoms and exercise capacity in these patients.

Visual Abstract, Highlights • A large animal model that recapitulates the clinical heterogeneity of HFpEF has been developed. • Multiple comorbidities, including obesity, hypercholesterolemia, pre-diabetic phenotype, as well as pulmonary and systemic arterial hypertension, were induced in adult female Göttingen minipigs by mineralocorticoid excess and a diet high in cholesterol, fat, fructose, and salt. • Severity of each comorbidity was titrated, such that marked left ventricular and left atrial diastolic dysfunction, profound left ventricular concentric remodeling, impaired coronary vasorelaxation, and extensive multiorgan fibrosis were achieved over a relatively short time. • This novel heart failure model was generated in Göttingen minipigs to allow for translational studies of novel pharmacological agents and for human-sized device testing in adult-aged animals. • This novel “multihit” minipig heart failure model enabled investigations into the pathology of HFpEF without the confounding effects inherent with invasive surgical procedures or the administration of agents that induce hypertension and end-organ damage in an artificial manner., Summary A lack of preclinical large animal models of heart failure with preserved ejection fraction (HFpEF) that recapitulate this comorbid-laden syndrome has led to the inability to tease out mechanistic insights and to test novel therapeutic strategies. This study developed a large animal model that integrated multiple comorbid determinants of HFpEF in a miniswine breed that exhibited sensitivity to obesity, metabolic syndrome, and vascular disease with overt clinical signs of heart failure. The combination of a Western diet and 11-deoxycorticosterone acetate salt−induced hypertension in the Göttingen miniswine led to the development of a novel large animal model of HFpEF that exhibited multiorgan involvement and a full spectrum of comorbidities associated with human HFpEF.

Transseptal access for atrial fibrillation ablation can be challenging in the presence of iatrogenically modified interatrial septum. We report the first described transseptal left atrial access for atrial fibrillation ablation in the presence of an investigational interatrial shunt device, performed in a patient with heart failure with preserved ejection fraction. (Level of Difficulty: Intermediate.), Graphical abstract

Background\ud \ud Cardiac magnetic resonance imaging (MRI) is emerging as an important imaging tool in the assessment of heart failure with preserved ejection fraction (HFpEF). This systematic review and meta-analysis aim to synthesise and consolidate the current literature on cardiac MRI for prognostication of HFpEF.\ud \ud \ud Methods design\ud \ud Systematic review and meta-analysis. Data sources: Scopus (PubMed and Embase) for studies published between 2008 and 2019. Eligibility criteria for study selection were studies that evaluated the prognostic role of cardiac MRI in HFpEF. Random effects meta-analyses of the reported hazard ratios (HR) for clinical outcomes was performed.\ud \ud \ud Results\ud \ud Initial screening identified 97 studies. From these, only nine (9%) studies met all the criteria. The main cardiac MRI methods that demonstrated association to prognosis in HFpEF included late gadolinium enhancement (LGE) assessment of scar (n = 3), tissue characterisation with T1-mapping (n = 4), myocardial ischaemia (n = 1) and right ventricular dysfunction (RVSD) (n = 1). The pooled HR for all 9 studies was 1.52 (95% CI 1.05–1.99, P < 0.01). Sub-evaluation by cardiac MRI methods revealed varying HRs: LGE (net n = 402, HR = 1.6, 95% CI 0.42–2.78, P = 0.008); T1-mapping (n = 1623, HR = 1.25, 95% CI 0.891–1.60, P < 0.001); myocardial ischaemia or RVSD (n = 325, HR = 3.19, 95% CI 0.30–6.08, P = 0.03).\ud \ud \ud Conclusion\ud \ud This meta-analysis demonstrates that multiparametric cardiac MRI has value in prognostication of patients with HFpEF. HFpEF patients with a detectable scar on LGE, fibrosis on T1-mapping, myocardial ischaemia or RVSD appear to have a worse prognosis.\ud \ud \ud PROSPERO registration number\ud \ud CRD42020187228.

Coronary artery fistulas are rare coronary abnormalities. Most of these fistulas have a congenital origin, and only a few are acquired. We report the case of a patient with late-acquired multiple coronary fistulas secondary to a stab wound, diagnosed in the setting of ischemic heart failure secondary to coronary steal syndrome. (Level of Difficulty: Intermediate.).

Background Whether cardiovascular (CV) disease risk factors and biomarkers associate differentially with heart failure (HF) risk in men and women is unclear. Objectives The purpose of this study was to evaluate sex-specific associations of CV risk factors and biomarkers with incident HF. Methods The analysis was performed using data from 4 community-based cohorts with 12.5 years of follow-up. Participants (recruited between 1989 and 2002) were free of HF at baseline. Biomarker measurements included natriuretic peptides, cardiac troponins, plasminogen activator inhibitor-1, D-dimer, fibrinogen, C-reactive protein, sST2, galectin-3, cystatin-C, and urinary albumin-to-creatinine ratio. Results Among 22,756 participants (mean age 60 ± 13 years, 53% women), HF occurred in 2,095 participants (47% women). Age, smoking, type 2 diabetes mellitus, hypertension, body mass index, atrial fibrillation, myocardial infarction, left ventricular hypertrophy, and left bundle branch block were strongly associated with HF in both sexes (p, Central Illustration

Visual Abstract, Highlights • Cardiac energy deprivation due to mitochondrial dysfunction is characteristic of heart failure. • Mitochondrial dysfunction contributes to worsening of the heart failure state. • Pharmacologic targeting of mitochondria in heart failure is an unmet need. • Mitochondrial dysfunction in heart failure can be reversed with novel experimental drugs., Summary The burden of heart failure (HF) in terms of health care expenditures, hospitalizations, and mortality is substantial and growing. The failing heart has been described as “energy-deprived” and mitochondrial dysfunction is a driving force associated with this energy supply-demand imbalance. Existing HF therapies provide symptomatic and longevity benefit by reducing cardiac workload through heart rate reduction and reduction of preload and afterload but do not address the underlying causes of abnormal myocardial energetic nor directly target mitochondrial abnormalities. Numerous studies in animal models of HF as well as myocardial tissue from explanted failed human hearts have shown that the failing heart manifests abnormalities of mitochondrial structure, dynamics, and function that lead to a marked increase in the formation of damaging reactive oxygen species and a marked reduction in on demand adenosine triphosphate synthesis. Correcting mitochondrial dysfunction therefore offers considerable potential as a new therapeutic approach to improve overall cardiac function, quality of life, and survival for patients with HF.

Visual Abstract, Highlights • The lean diabetic SKO mouse represents a novel and validated murine model of HFpEF. • The SKO HFpEF mouse model recapitulates the cardiac structure and function abnormalities in lean diabetic HFpEF patients in Asia. • Altered cellular titin phosphorylation and increased extracellular interstitial fibrosis associated with neutrophil extracellular traps contribute to the left ventricular stiffness. • Metabolic disturbances arising from insulin resistance and diabetes in the absence of hypertension or obesity may lead to HFpEF., Summary The lean diabetic patients with heart failure with preserved ejection fraction (HFpEF) in Asia suffer from adverse clinical outcomes and poor life quality. The suitable animal models are urgently needed for mechanistic study and therapeutic innovations. Our study reports that lipodystrophic mice with seipin depletion are lean, diabetic, and recapitulate major manifestations of clinical HFpEF, thereby clarifying that lean diabetes per se may produce HFpEF characteristics. We further demonstrate that increased cardiac titin phosphorylation and reactive interstitial fibrosis associated with neutrophil extracellular traps lead to left ventricular stiffness and suggest that both pathways may be potential therapeutic targets in Asian HFpEF patients.

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Summary Background Although cardiovascular comorbidities seem to be strongly associated with worse outcomes in patients with coronavirus disease 2019 (COVID-19), data regarding patients with preexisting heart failure are limited. Aims To investigate the incidence, characteristics and clinical outcomes of patients with COVID-19 with a history of heart failure with preserved or reduced ejection fraction. Methods We performed an observational multicentre study including all patients hospitalized for COVID-19 across 24 centres in France from 26 February to 20 April 2020. The primary endpoint was a composite of in-hospital death or need for orotracheal intubation. Results Overall, 2809 patients (mean age 66.4 ± 16.9 years) were included. Three hundred and seventeen patients (11.2%) had a history of heart failure; among them, 49.2% had heart failure with reduced ejection fraction and 50.8% had heart failure with preserved ejection fraction. COVID-19 severity at admission, defined by a quick sequential organ failure assessment score > 1, was similar in patients with versus without a history of heart failure. Before and after adjustment for age, male sex, cardiovascular comorbidities and quick sequential organ failure assessment score, history of heart failure was associated with the primary endpoint (hazard ratio [HR]: 1.41, 95% confidence interval [CI]: 1.06–1.90; P = 0.02). This result seemed to be mainly driven by a history of heart failure with preserved ejection fraction (HR: 1.61, 95% CI: 1.13–2.27; P = 0.01) rather than heart failure with reduced ejection fraction (HR: 1.19, 95% CI: 0.79–1.81; P = 0.41). Conclusions History of heart failure in patients with COVID-19 was associated with a higher risk of in-hospital death or orotracheal intubation. These findings suggest that patients with a history of heart failure, particularly heart failure with preserved ejection fraction, should be considered at high risk of clinical deterioration.

Visual Abstract, Highlights • With aging, phosphorylated-mimetic cMyBP-C mice exhibited better survival, better preservation of systolic and diastolic functions, and unchanging wall thickness compared with control mice. • Aged wild-type equivalent mice exhibited decreasing cMyBP-C phosphorylation (S273 and S282) along with worsening cardiac function and hypertrophy similarly to what was observed in hypophosphorylated cMyBP-C mice. • Intact papillary muscle experiments suggest that cMyBP-C phosphorylation increased cross-bridge detachment rates as the underlying mechanism. • Phosphorylating cMyBP-C is therefore a novel mechanism that can prevent aging-related development of cardiac dysfunction., Summary Cardiac myosin binding protein-C (cMyBP-C) phosphorylation prevents aging-related cardiac dysfunction. We tested this hypothesis by aging genetic mouse models of hypophosphorylated cMyBP-C, wild-type equivalent, and phosphorylated-mimetic cMyBP-C for 18 to 20 months. Phosphorylated-mimetic cMyBP-C mice exhibited better survival, better preservation of systolic and diastolic functions, and unchanging wall thickness. Wild-type equivalent mice showed decreasing cMyBP-C phosphorylation along with worsening cardiac function and hypertrophy approaching those found in hypophosphorylated cMyBP-C mice. Intact papillary muscle experiments suggested that cMyBP-C phosphorylation increased cross-bridge detachment rates as the underlying mechanism. Thus, phosphorylating cMyBP-C is a novel mechanism with potential to treat aging-related cardiac dysfunction.

Visual Abstract, Highlights • CMECs exert a direct positive effect on cardiomyocyte contraction and relaxation, which is mainly mediated by endothelial-derived NO. • Pro-inflammatory stimulation of CMECs by pre-incubation with TNF-α or interleukin-1β abrogates the positive regulatory function of these cells on cardiomyocyte contractile property. • Mechanistically, pro-inflammatory activation of CMECs leads to mitochondrial and cytoplasmic ROS accumulation that results in the scavenging of NO. • Empagliflozin directly restores the beneficial effect of CMECs on cardiomyocyte contraction and relaxation by reducing TNF-α-induced mitochondrial and cytoplasmic ROS accumulation, which leads to reinstatement of CMEC-derived NO delivery., Summary The positive findings of the EMPA-REG OUTCOME trial (Randomized, Placebo-Controlled Cardiovascular Outcome Trial of Empagliflozin) on heart failure (HF) outcome in patients with type 2 diabetes mellitus suggest a direct effect of empagliflozin on the heart. These patients frequently have HF with preserved ejection fraction (HFpEF), in which a metabolic risk-related pro-inflammatory state induces cardiac microvascular endothelial cell (CMEC) dysfunction with subsequent cardiomyocyte (CM) contractility impairment. This study showed that CMECs confer a direct positive effect on contraction and relaxation of CMs, an effect that requires nitric oxide, is diminished after CMEC stimulation with tumor necrosis factor-α, and is restored by empagliflozin. Our findings on the effect of empagliflozin on CMEC-mediated preservation of CM function suggests that empagliflozin can be used to treat the cardiac mechanical implications of microvascular dysfunction in HFpEF.

Visual Abstract, Highlights • This study evaluated the impact of the sodium-glucose−linked co-transporter-2 inhibitor, empagliflozin, on cardiac function and structure in a nondiabetic model of heart failure with preserved ejection fraction in the deoxycorticosterone acetate salt-sensitive rat. • Deoxycorticosterone acetate rats developed hypertension, left ventricular hypertrophy, and diastolic dysfunction as measured by the time constant of relaxation, Tau. • Empagliflozin therapy, which did not significantly reduce blood pressure, increased hematocrit, reduced left ventricular and cardiomyocyte hypertrophy, and reduced wall stress, which led to improved diastolic function (shortening of Tau). • Empagliflozin treatment did not modify molecular markers of metabolism or hypertrophy, nor did it significantly affect key proteins involved in myocardial calcium handling. • This study concluded that the sodium-glucose−linked co-transporter-2 inhibitor, empagliflozin, in a nondiabetic model of heart failure with preserved ejection fraction improved cardiac diastolic function and reduced wall stress primary through a reduction in cardiac preload, and also altered hemodynamics., Summary Recent studies send an unambiguous signal that the class of agents known as sodium-glucose–linked co-transporter-2 inhibitors (SGLT2i) prevent heart failure hospitalization in patients with type 2 diabetes. However, the mechanisms remain unclear. Herein the authors utilize a rodent model of heart failure with preserved ejection fraction (HFpEF), and demonstrate that treatment with the SGLT2i empagliflozin, reduces left ventricular mass, improving both wall stress and diastolic function. These findings extend the observation that the main mechanism of action of empagliflozin involves improved hemodynamics (i.e., reduction in preload and afterload) and provide a rationale for upcoming trials in patients with HFpEF irrespective of glycemic status.

Background Spontaneous pneumomediastinum (SPM) is a rare condition defined by the presence of air in the mediastinum in the absence of traumatic or iatrogenic injury. Although the imaging findings and complications of SARS-CoV-2 infection have been reported many times, there are few reports of the prevalence and outcomes of patients with SPM. Purpose In this paper, we aimed to illustrate the different manifestations, management, and outcome of three cases of SPM in COVID-19 patients and provide an extensive review available literature. Materials and Methods Detailed report of patients' demographics, clinical presentation, management, and outcome of three cases of COVID-19 induced SPM seen in our institution was provided. Additionally, literature search was employed through March 2021 using Pubmed and Google scholar databases where a total of 22 articles consisting of 35 patients were included. Results Statistical analysis of the reviewed articles showed that SPM in COVID-19 occurs in patients with a mean age of 55.6 ± 16.7 years. Furthermore, 80% of the 35 patients are males and almost 60% have comorbidities. Intriguingly, SPM in COVID-19 is associated with a 28.5% mortality rate. These findings are consistent with our case series and are different from previous reports of SPM in non-COVID-19 cases where it most commonly occurs in younger individuals and has a self-limiting course with a good outcome. Conclusion Therefore, SPM in COVID-19 patients occurs in older patients and is potentially associated with a higher mortality rate. Further studies are necessary to assess its role as a prognostic marker of poor outcome.

The conserved C-terminal end segment of troponin I (TnI) plays a critical role in regulating muscle relaxation. This function is retained in the isolated C-terminal 27 amino acid peptide (residues 184-210) of human cardiac TnI (HcTnI-C27): When added to skinned muscle fibers, HcTnI-C27 reduces the Ca2+-sensitivity of activated myofibrils and facilitates relaxation without decreasing the maximum force production. However, the underlying mechanism of HcTnI-C27 function is unknown. We studied the conformational preferences of HcTnI-C27 and a myopathic mutant, Arg192His, (HcTnI-C27-H). Both peptides were mainly disordered in aqueous solution with a nascent helix involving residues from Trp191 to Ile195, as shown by NMR analysis and molecular dynamics simulations. The population of nascent helix was smaller in HcTnI-C27-H than in HcTnI-C27, as shown by circular dichroism (CD) titrations. Fluorescence and isothermal titration calorimetry (ITC) showed that both peptides bound tropomyosin (alpha Tm), with a detectably higher affinity (similar to 10 mu M) of HcTnI-C27 than that of HcTnI-C27-H (similar to 15 mu M), consistent with an impaired Ca2+-desensitization effect of the mutant peptide on skinned muscle strips. Upon binding to aTm, HcTnI-C27 acquired a weakly stable helix-like conformation involving residues near Trp191, as shown by transferred nuclear Overhauser effect spectroscopy and hydrogen/deuterium exchange experiments. With the potent Ca2+-desensitization effect of HcTnI-C27 on skinned cardiac muscle from a mouse model of hypertrophic cardiomyopathy, the data support that the C-terminal end domain of TnI can function as an isolated peptide with the intrinsic capacity of binding tropomyosin, providing a promising therapeutic approach to selectively improve diastolic function of the heart.

Visual Abstract, Highlights • DM is a significant risk factor for major adverse cardiovascular events in patients with HFpEF. • Patients with diabetes with HFpEF have a distinct proteome compared with patients without diabetes with HFpEF. • Proteomics analysis identified higher levels of alpha-1-microglobulin/bikunin precursor protein in patients with diabetes with HFpEF and lower levels of CILP2 and Apo M. • Lower Apo M levels mediate most of the association between diabetes and major adverse cardiovascular events in HFpEF., Summary Diabetes mellitus (DM) is associated with a higher risk of heart failure hospitalization and mortality in patients with heart failure with preserved ejection fraction (HFpEF). Using SomaScan assays and proteomics analysis of plasma from participants in the TOPCAT (Treatment of Preserved Cardiac Function Heart Failure with an Aldosterone Antagonist) trial and the Penn Heart Failure Study, this study identified 10 proteins with significantly different expression in patients with HFpEF and DM. Of these, apolipoprotein M was found to mediate 72% (95% CI: 36% to 100%; p

Background Whereas heart failure with reduced ejection fraction (HFrEF) is associated with ventricular dilation and markedly reduced systolic function, heart failure with preserved ejection fraction (HFpEF) patients exhibit concentric hypertrophy and diastolic dysfunction. Impaired cardiomyocyte Ca2+ homeostasis in HFrEF has been linked to disruption of membrane invaginations called t-tubules, but it is unknown if such changes occur in HFpEF. Objectives This study examined whether distinct cardiomyocyte phenotypes underlie the heart failure entities of HFrEF and HFpEF. Methods T-tubule structure was investigated in left ventricular biopsies obtained from HFrEF and HFpEF patients, whereas cardiomyocyte Ca2+ homeostasis was studied in rat models of these conditions. Results HFpEF patients exhibited increased t-tubule density in comparison with control subjects. Super-resolution imaging revealed that higher t-tubule density resulted from both tubule dilation and proliferation. In contrast, t-tubule density was reduced in patients with HFrEF. Augmented collagen deposition within t-tubules was observed in HFrEF but not HFpEF hearts. A causative link between mechanical stress and t-tubule disruption was supported by markedly elevated ventricular wall stress in HFrEF patients. In HFrEF rats, t-tubule loss was linked to impaired systolic Ca2+ homeostasis, although diastolic Ca2+ removal was also reduced. In contrast, Ca2+ transient magnitude and release kinetics were largely maintained in HFpEF rats. However, diastolic Ca2+ impairments, including reduced sarco/endoplasmic reticulum Ca2+-ATPase activity, were specifically observed in diabetic HFpEF but not in ischemic or hypertensive models. Conclusions Although t-tubule disruption and impaired cardiomyocyte Ca2+ release are hallmarks of HFrEF, such changes are not prominent in HFpEF. Impaired diastolic Ca2+ homeostasis occurs in both conditions, but in HFpEF, this mechanism for diastolic dysfunction is etiology-dependent., Central Illustration

Background Patients with pre-existing heart failure (HF) are likely at higher risk for adverse outcomes in coronavirus disease-2019 (COVID-19), but data on this population are sparse. Objectives This study described the clinical profile and associated outcomes among patients with HF hospitalized with COVID-19. Methods This study conducted a retrospective analysis of 6,439 patients admitted for COVID-19 at 1 of 5 Mount Sinai Health System hospitals in New York City between February 27 and June 26, 2020. Clinical characteristics and outcomes (length of stay, need for intensive care unit, mechanical ventilation, and in-hospital mortality) were captured from electronic health records. For patients identified as having a history of HF by International Classification of Diseases-9th and/or 10th Revisions codes, manual chart abstraction informed etiology, functional class, and left ventricular ejection fraction (LVEF). Results Mean age was 63.5 years, and 45% were women. Compared with patients without HF, those with previous HF experienced longer length of stay (8 days vs. 6 days; p, Central Illustration

The obesity paradox, which suggests a survival advantage for the obese in heart failure (HF) has sparked debate in the medical community. Studies demonstrate a survival advantage in obese patients with HF, including those with advanced HF requiring continuous inotropic support for palliation or disease modifying therapy with a left ventricular assist device (LVAD) or heart transplantation (HT). Importantly, the obesity paradox is affected by the level of cardiorespiratory fitness (CRF). It is now recommended that HF patients with body mass index ≥35 kg/m2 achieve at least 5–10% weight loss, in order to improve symptoms and cardiac function, though more robust data are urgently needed. CRF may be the single best predictor of overall health and small improvements in fitness levels may lead to improved outcomes in HF. In addition to implications of obesity in chronic HF, we also discuss management of obese patients with advanced HF and their implications for therapies such as LVAD implantation and HT., Key points • Heart failure patients with a body mass index ≥35 kg/m2 should achieve at least 5–10% weight loss. • The obesity paradox has been demonstrated in patients with heart failure across the continuum of disease including those receiving palliative inotropic therapy, left ventricular assist device implantation and heart transplantation. • Bariatric surgery performed concomitantly with left ventricular assist device implantation may be a promising means of achieving bridge to transplant, however more data is needed.

COVID-19 is a global pandemic caused by SARS-CoV-2. Infection is associated with significant morbidity and mortality. Individuals with pre-existing cardiovascular disease or evidence of myocardial injury are at risk for severe disease and death. Little is understood about the mechanisms of myocardial injury or life-threatening cardiovascular sequelae., Graphical abstract

The progression of cardiovascular research is often impeded by the lack of reliable disease models that fully recapitulate the pathogenesis in humans. These limitations apply to both in vitro models such as cell-based cultures and in vivo animal models which invariably are limited to simulate the complexity of cardiovascular disease in humans. Implementing human heart tissue in cardiovascular research complements our research strategy using preclinical models. We established the Human Explanted Heart Program (HELP) which integrates clinical, tissue and molecular phenotyping thereby providing a comprehensive evaluation into human heart disease. Our collection and storage of biospecimens allow them to retain key pathogenic findings while providing novel insights into human heart failure. The use of human non-failing control explanted hearts provides a valuable comparison group for the diseased explanted hearts. Using HELP we have been able to create a tissue repository which have been used for genetic, molecular, cellular, and histological studies. This review describes the process of collection and use of explanted human heart specimens encompassing a spectrum of pediatric and adult heart diseases, while highlighting the role of these invaluable specimens in translational research. Furthermore, we highlight the efficient procurement and bio-preservation approaches ensuring analytical quality of heart specimens acquired in the context of heart donation and transplantation., Graphical abstract Illustration of the Human Explanted Heart Program (HELP) pathway as an integrative program that brings together clinicians and researchers aiming to unravel the underpinnings of cardiovascular disease and discover novel therapeutics. Our biobank contains tissue collections covering all sections of the explanted heart. A comprehensive review of the research participant clinical profile is also integrated into the analysis while complementary academic partnerships enabled us to broaden and diversify our approach to human heart disease.Unlabelled Image, Highlights • HELP - the largest research-integrated human heart transplant platform in Canada • Sizable specimen inventory of HELP enables research on a spectrum of heart diseases. • Systematic review of the methodology for HELP biobank management • Detailed evaluation on use of human hearts in translational cardiovascular medicine

Visual Abstract, Highlights • A large animal model of progressive PO was created that evolved into phenotypic features of HFpEF. • The progression from PO to the HFpEF pathophysiology was accompanied by specific shifts in the collagen matrix microstructure over and above collagen content (i.e., fibrosis). • Using early changes in regional myocardial stiffness measurements by speckle tracking methodology predicted the extent and magnitude of the HFpEF phenotype at later timepoints., Summary This study assessed the regional changes in myocardial geometry, microstructure, mechanical behavior, and properties that occur in response to progressive left ventricular pressure overload (LVPO) in a large animal model. Using an index of local biomechanical function at early onset of LVPO allowed for prediction of the magnitude of left ventricular chamber stiffness (Kc) and left atrial area at LVPO late timepoints. Our study found that LV myocardial collagen content alone was insufficient to identify mechanisms for LV myocardial stiffness with progression to heart failure with preserved ejection fraction (HFpEF). Serial assessment of regional biomechanical function might hold value in monitoring the natural history and progression of HFpEF, which would allow evaluation of novel therapeutic approaches.

Graphical abstract, The coronavirus disease 2019 (COVID-19), elicited by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection, is a pandemic public health emergency of global concern. Other than the profound severe pulmonary damage, SARS-CoV-2 infection also leads to a series of cardiovascular abnormalities, including myocardial injury, myocarditis and pericarditis, arrhythmia and cardiac arrest, cardiomyopathy, heart failure, cardiogenic shock, and coagulation abnormalities. Meanwhile, COVID-19 patients with preexisting cardiovascular diseases are often at a much higher risk of increased morbidity and mortality. Up–to-date, a number of mechanisms have been postulated for COVID-19-associated cardiovascular damage including SARS-CoV-2 receptor angiotensin-converting enzyme 2 (ACE2) activation, cytokine storm, hypoxemia, stress and cardiotoxicity of antiviral drugs. In this context, special attention should be given towards COVID-19 patients with concurrent cardiovascular diseases, and special cardiovascular attention is warranted for treatment of COVID-19.

Itraconazole is well known for carrying a black-box warning for new or worsening congestive heart failure. Single cases of other cardiac- and fluid-related disturbances have been reported periodically since its issuance. We describe a large cohort of patients on itraconazole experiencing a breadth of cardiac- and fluid-related toxicities, ranging from new-onset hypertension to cardiac arrest. A retrospective, single-center, large case series at a large tertiary medical center was conducted. Patients with itraconazole and cardiac toxicity—including hypertension, cardiomyopathy, reduced ejection fraction, and edema—in medical record between January 1, 1999, and May 21, 2019, were identified and assigned a Naranjo score; 31 patients were included with a Naranjo score of 5 or higher. There were slightly more male subjects than female subjects, average age was 66, and all subjects were Caucasian. Median time until presentation of adverse effects was 4 weeks (range: 0.3 to 104 weeks). Most common symptom was edema (74% of patients), followed by heart failure without and with preserved ejection fraction (19.4% and 22.6% of patients, respectively). Worsening or new hypertension was also common (25.8% of patients). Rarer were pulmonary edema, pericardial effusion, and cardiac arrest that occurred in 1 patient. In most cases, clinicians stopped itraconazole (74%) or decreased itraconazole dose (19%), resulting in improvement or resolution of symptoms. In 4 cases, the adverse effect did not resolve. Itraconazole can cause a range of possible serious cardiac and fluid-associated adverse events. Dose decrease or cessation usually resulted in symptomatic improvement or reversal.

Visual Abstract, Highlights • ΔAVo2 during exercise is a complex metric that incorporates into its calculation skeletal muscle blood flow and DmO2 across the skeletal muscle capillary membrane. • Although ΔAVo2 was reduced in patients with HFpEF during both systemic and local (forearm) exercise, there was no difference in forearm DmO2 among subjects with HFpEF, those with hypertension, and healthy control subjects; therefore, abnormalities in forearm DmO2 cannot explain the reduced forearm ΔAVo2 seen in subjects with HFpEF. • Local forearm exercise performance predicted about one-third of the variability in systemic aerobic capacity, demonstrating that peripheral factors are important in determining whole-body exercise tolerance. • Degree of adiposity strongly correlated with ΔAVo2 during both local and whole-body exercise, suggesting that adipose tissue may play an active role in limiting exercise capacity in subjects with HFpEF., Summary The aim of this study was to determine the arteriovenous oxygen content difference (ΔAVo2) in adult subjects with and without heart failure with preserved ejection fraction (HFpEF) during systemic and forearm exercise. Subjects with HFpEF had reduced ΔAVo2. Forearm diffusional conductance for oxygen, a lumped conductance parameter that incorporates all impediments to the movement of oxygen from red blood cells in skeletal muscle capillaries into the mitochondria within myocytes, was estimated. Forearm diffusional conductance for oxygen was not different among adults with HFpEF, those with hypertension, and healthy control subjects; therefore, diffusional conductance cannot explain the reduced forearm ΔAVo2. Instead, adiposity was strongly associated with ΔAVo2, suggesting an active role for adipose tissue in reducing exercise capacity in patients with HFpEF.

Background Sodium–glucose cotransporter 2 (SGLT2) inhibitors reduce the composite of heart failure (HF) hospitalizations or cardiovascular mortality among patients with HF. However, the efficacy of SGLT2 inhibitors in secondary endpoints of randomized trials and in subgroups of HF patients is not well known. Methods We performed a systematic review and meta-analysis of placebo-controlled, randomized trials of SGLT2 inhibitors in patients with HF. PubMed, Embase, and Cochrane databases were searched for trials published up to January 21, 2021. Data were extracted from published reports and quality assessment was performed per Cochrane recommendations. Hazard ratios (HRs) with 95% CI were pooled across trials. The primary endpoints of interest were all-cause and cardiovascular mortality. Results Out of 3969 database results, 15 randomized trials and 20,241 patients were included; 10,594 (52·3%) received SGLT2 inhibitors. All-cause mortality (HR 0·86; 95% CI 0·79–0·94; p = 0·0007; I2=0%) and cardiovascular mortality (HR 0·86; 95% CI 0·78–0·96; p = 0·006; I2=0%) were significantly lower in patients treated with SGLT2 inhibitors compared with placebo. The composite of cardiovascular mortality, HF hospitalizations, or urgent visits for HF was significantly reduced with SGLT2 inhibitors in all the following subgroups: male, female, age < 65, age ≥ 65, race – Black and White, estimated glomerular filtration rate (eGFR)

Objectives: We assessed left ventricular (LV) function and central hemodynamic effects in patients with a heart rate (HR) at rest of ≥70 beats per minute (bpm) and chronic coronary syndrome (CCS) after long-term treatment with ivabradine compared to placebo by cardiac magnetic resonance (CMR) imaging. Methods and results: In a randomized, double-blinded, prospective cross-over design, 23 patients (18 male, 5 female) were treated with ivabradine (7.5 mg bid) or placebo for 6 months. CMR imaging was performed at baseline and after 6 and 12 months to determine LV functional parameters.Mean resting HR on treatment with ivabradine was 58 ± 8.2 bpm and 70.2 ± 8.3 bpm during placebo (p

Visual Abstract, Highlights • The effects of UFA on CRF in patients with HFpEF are unknown. • In obese HFpEF patients, UFA consumption analyzed with a validated 24-h dietary recall was positively associated with improved body composition, cardiac diastolic function and greater CRF, measured as peak VO2 at maximal cardiopulmonary exercise testing. Conversely, sugars consumption was associated with worse CRF. • In mice, an isocaloric high-fat diet, high in UFA and low in saturated fat prevented cardiac diastolic dysfunction measured with echocardiography and body weight gain in a model of cardiac dysfunction and obesity induced by Western diet, despite similar total caloric intake. • A high-UFA diet is associated with preservation of CRF in patients with HFpEF and cardiac function in the mouse., Summary Heart failure with preserved ejection fraction (HFpEF) is associated with obesity and, indirectly, with unhealthy diet. The role of dietary components in HFpEF is, however, largely unknown. In this study, the authors showed that in obese HFpEF patients, consumption of unsaturated fatty acids (UFA), was associated with better cardiorespiratory fitness, and UFA consumption correlated with better diastolic function and with greater fat-free mass. Similarly, mice fed with a high-fat diet rich in UFA and low in sugars had preserved myocardial function and reduced weight gain. Randomized clinical trials increasing dietary UFA consumption and reducing sugar consumption are warranted to confirm and expand our findings.

Visual Abstract, Highlights • A transient elevation in preload produces mechanical stretch-induced myocyte injury and measurable cardiac troponin I release that is associated with reversible contractile dysfunction and myocyte apoptosis. • Using a porcine model of intermittent pressure overload, this study demonstrates that repetitive exposure to cyclical elevations in preload elicits significant myocyte loss, yet left ventricular systolic function is preserved and chamber dilatation is absent. • Instead, myocardial remodeling characterized by myocyte hypertrophy and interstitial fibrosis produces a reduction in left ventricular diastolic compliance that protects the heart from subsequent stretch-induced myocyte injury. • These results support a novel paradigm that links cardiac adaptations to repetitive stretch-induced injury with the pathogenesis of myocardial stiffening and may explain how reductions in left ventricular diastolic compliance can occur in the absence of sustained hypertension or anatomic hypertrophy., Summary Swine subjected to 2 weeks of repetitive pressure overload (RPO) exhibited significant myocyte loss, but left ventricular (LV) systolic function was preserved, and chamber dilatation did not occur. Instead, myocardial remodeling characterized by myocyte hypertrophy and interstitial fibrosis led to a marked reduction in LV diastolic compliance, which protected the heart from stretch-induced myocyte injury and preserved LV ejection fraction without anatomic LV hypertrophy. These results support a novel paradigm that links cardiac adaptations to RPO with the pathogenesis of reduced LV diastolic compliance and may explain how LV stiffening can occur in the absence of sustained hypertension or anatomic hypertrophy.

Visual Abstract, Highlights • The combination of a Western-diet and aortic banding results in a cardio-metabolic heart failure phenotype in Ossabaw swine. • Ossabaw swine with cardio-metabolic heart failure display cardiac dysfunction at the whole heart and cellular levels. • The left ventricle transcriptome showed gene signatures consistent with pro-inflammatory heart failure. • Cardio-metabolic heart failure was coupled with microvascular dysfunction in the heart, skeletal muscle, and brain. • Ossabaw swine with cardio-metabolic heart failure are sedentary and obese with liver dysfunction., Summary The development of new treatments for heart failure lack animal models that encompass the increasingly heterogeneous disease profile of this patient population. This report provides evidence supporting the hypothesis that Western Diet−fed, aortic-banded Ossabaw swine display an integrated physiological, morphological, and genetic phenotype evocative of cardio-metabolic heart failure. This new preclinical animal model displays a distinctive constellation of findings that are conceivably useful to extending the understanding of how pre-existing cardio-metabolic syndrome can contribute to developing HF.