Pathophysiology Of Heart Failure With Preserved Ejection Fraction Research Articles

Exercise testing in heart failure with preserved ejection fraction: an appraisal through diagnosis, pathophysiology and therapy-A clinical consensus statement of the Heart Failure Association and European Association of Preventive Cardiology of the European Society of Cardiology.

Patients with heart failure with preserved ejection fraction (HFpEF) universally complain of exercise intolerance and dyspnoea as key clinical correlates. Cardiac as well as extracardiac components play a role for the limited exercise capacity, including an impaired cardiac and peripheral vascular reserve, a limitation in mechanical ventilation and/or gas exchange with reduced pulmonary vascular reserve, skeletal muscle dysfunction and iron deficiency/anaemia. Although most of these components can be differentiated and quantified through gas exchange analysis by cardiopulmonary exercise testing (CPET), the information provided by objective measures of exercise performance has not been systematically considered in the recent algorithms/scores for HFpEF diagnosis, by neither European nor US groups. The current clinical consensus statement by the Heart Failure Association (HFA) and European Association of Preventive Cardiology (EAPC) of the European Society of Cardiology (ESC) aims at outlining the role of exercise testing and its pathophysiological, clinical and prognostic insights, addressing the implications of a thorough functional evaluation from the diagnostic algorithm to the pathophysiology and treatment perspectives of HFpEF. Along with these goals, we provide a specific analysis of the evidence that CPET is the standard for assessing, quantifying, and differentiating the origin of dyspnoea and exercise impairment and even more so when combined with echocardiography and/or invasive haemodynamic evaluation. This will lead to improved quality of diagnosis when applying the proposed scores and may also help to implement the progressive characterization of the specific HFpEF phenotypes, a critical step toward the delivery of phenotype‐specific treatments.

Endothelial Dysfunction in Heart Failure With Preserved Ejection Fraction: What are the Experimental Proofs?

Heart failure with preserved ejection fraction (HFpEF) has been recognized as the greatest single unmet need in cardiovascular medicine. Indeed, the morbi-mortality of HFpEF is high and as the population ages and the comorbidities increase, so considerably does the prevalence of HFpEF. However, HFpEF pathophysiology is still poorly understood and therapeutic targets are missing. An unifying, but untested, theory of the pathophysiology of HFpEF, proposed in 2013, suggests that cardiovascular risk factors lead to a systemic inflammation, which triggers endothelial cells (EC) and coronary microvascular dysfunction. This cardiac small vessel disease is proposed to be responsible for cardiac wall stiffening and diastolic dysfunction. This paradigm is based on the fact that microvascular dysfunction is highly prevalent in HFpEF patients. More specifically, HFpEF patients have been shown to have decreased cardiac microvascular density, systemic endothelial dysfunction and a lower mean coronary flow reserve. Importantly, impaired coronary microvascular function has been associated with the severity of HF. This review discusses evidence supporting the causal role of endothelial dysfunction in the pathophysiology of HFpEF in human and experimental models.

Microvascular Dysfunction in Heart Failure with Preserved Ejection Fraction: Pathophysiology, Assessment, Prevalence and Prognosis.

Heart failure with preserved ejection fraction (HFpEF) currently accounts for approximately half of all new heart failure cases in the community. HFpEF is closely associated with chronic lifestyle-related diseases, such as obesity and type 2 diabetes, and clinical outcomes are worse in those with than without comorbidities. HFpEF is pathophysiologically distinct from heart failure with reduced ejection fraction, which may explain, in part, the disparity of treatment options available between the two heart failure phenotypes. The mechanisms underlying HFpEF are complex, with coronary microvascular dysfunction (MVD) being proposed as a potential key driver in its pathophysiology. In this review, the authors highlight the evidence implicating MVD in HFpEF pathophysiology, the diagnostic approaches for identifying MVD (both invasive and non-invasive) and the prevalence and prognostic significance of MVD.

Endothelial protection does not prevent diastolic dysfunction in high fat diet + L-NAME treated mice

Schiattarella et al. introduced a new mouse model mimicking heart failure with preserved ejection fraction (HFpEF). In this model, diastolic dysfunction is induced by a high fat diet (HFD) regimen with L-NAME treatment. Small vessel disease is currently proposed to be responsible for HFpEF. Moreover, blocking Cdon, a negative co-receptor of Hedgehog signalling pathway, in endothelial cells in mice promote endothelium integrity in inflammatory conditions. Consequently, CdonECKO mice represent a good model of endothelial protection. To determine whether prevent endothelial dysfunction prevent diastolic dysfunction. Ovariectomized CdonECKO female mice were fed with HFD from 8 weeks of age. L-NAME treatment was initiated 2 weeks later. Cardiac function was assessed via echocardiography and left ventricle (LV) catheterization at 20 weeks of age. Immediately after, mice were sacrificed for histological and gene expression analyses. Consistently with our previous results, CdonECKO mice treated with HFD and L-NAME display a decreased permeability, a decreased expression of ICAM1 and a decreased infiltration of CD45+ leukocytes compared to their controls. Capillary density and mural cell coverage were not modified. Despite their endothelial improvement, mice displayed increased end diastolic pressure with a preserved LV ejection fraction. Diastolic dysfunction was associated with cardiac hypertrophy and fibrosis as in their controls. Prevention of endothelial dysfunction observed in HFpEF mice models does not prevent diastolic dysfunction in HFD + L-NAME treated mice supporting that small vessel disease is not the only key factor in the pathophysiology of HFpEF.

MO461: A Novel Chronic Kidney Disease to HFpEF Connection: Inflammatory Signaling, Micro-RNAs, and NF-KB

Abstract BACKGROUND AND AIMS Chronic kidney disease (CKD) is an independent risk factor for heart failure with preserved ejection fraction (HFpEF), a progressive condition that affects ˃50% of patients in dialysis. We developed a swine model of CKD-HFpEF and showed that renal inflammatory signaling plays a key role in HFpEF pathophysiology via cardiac activation of nuclear factor-kappa B (NF-kB). However, the mechanisms of CKD-induced cardiac NF-κB activation remain unclear. We hypothesized that micro-RNA (miRNA)-mediated processes contribute to cardiac NF-kB activation in CKD-HFpEF. METHOD Using an in-silico approach (miRWalk3.0 and TargetScan 7.2), we identified all miRNAs capable of targeting the NFKB Inhibitor Alpha (NFKBIA) gene. We then identified those expressed in swine myocardium and measured their levels in normal and CKD pigs by qPCR. In a biomimetic heart culture system that mimics the cardiac CKD-HFpEF microenvironment, pig heart slices were exposed to plasma from normal or CKD pigs, and cardiac kinetics, NF-kB signaling, and miRNA expression levels were investigated in vitro. RESULTS We identified 5 miRNAs expressed in swine hearts capable of targeting NFKBIA, of which only miR-1271–3p showed higher expression in the myocardium of CKD-HFpEF pigs compared to normal pigs. miR-1271–3p upregulation was mirrored in pig heart slices exposed to plasma from CKD pigs, associated with blunted cardiac contraction/relaxation kinetics, downregulation of NFKBIA, and increased protein expression of NF-κB (Figure). CONCLUSION Our data support a novel pathophysiological mechanism for cardiac activation of NF-κB in CKD via post-transcriptional modulation of NFKBIA partly through miR-1271–3p. This miRNA might represent a novel therapeutic target to ameliorate the deleterious effects that renal inflammatory signaling in CKD imposes on the heart and may lead to HFpEF.

Heart failure with preserved ejection fraction (HFpEF) in type 2 diabetes mellitus: from pathophysiology to therapeutics.

Type 2 diabetes mellitus (T2DM or T2D) is a devastating metabolic abnormality featured by insulin resistance, hyperglycemia, and hyperlipidemia. T2D provokes unique metabolic changes and compromises cardiovascular geometry and function. Meanwhile, T2D increases the overall risk for heart failure (HF) and acts independent of classical risk factors including coronary artery disease, hypertension, and valvular heart diseases. The incidence of HF is extremely high in patients with T2D and is manifested as HF with preserved, reduced, and midrange ejection fraction (HFpEF, HFrEF, and HFmrEF, respectively), all of which significantly worsen the prognosis for T2D. HFpEF is seen in approximately half of the HF cases and is defined as a heterogenous syndrome with discrete phenotypes, particularly in close association with metabolic syndrome. Nonetheless, management of HFpEF in T2D remains unclear, largely due to the poorly defined pathophysiology behind HFpEF. Here, in this review, we will summarize findings from multiple preclinical and clinical studies as well as recent clinical trials, mainly focusing on the pathophysiology, potential mechanisms, and therapies of HFpEF in T2D.

Chronic Pressure Overload and Ovariectomy Alters the Regulation of Cardiac Fibrosis in a Chamber‐Specific Manner in Yucatan Mini‐Swine

Cardiac fibrosis, a hallmark feature of heart failure with preserved ejection fraction (HFpEF), is increased in postmenopausal women and may occur due to imbalances in the regulation of collagen metabolism. Our goal was to evaluate the effect of the loss of sex hormones via ovariectomy (OVX) on the development of aortic‐banding (AB) induced heart failure and cardiac fibrosis in 4 groups of female Yucatan mini‐swine: control (N=7); OVX (N=6); AB (N=7); and AB‐OVX (N=7). A 2x2 ANOVA (AB X OVX) was used to determine significance at the p < 0.05 and 0.10 levels. Biochemical evaluation of total collagen demonstrated an increase due to OVX (main effect) in the left ventricle (LV) independent of AB. In contrast, total collagen was increased due to AB (main effect) in the right ventricle (RV) independent of OVX. These results led to the hypothesis that collagen is differentially regulated in a chamber‐specific manner due to imbalances in its metabolism. Collagen I and III mRNA levels were evaluated using qRT‐PCR. Collagen I mRNA was increased by AB (main effect) in both the LV and the RV. Collagen III mRNA levels were not altered in the LV, but were decreased due to OVX (main effect) in the RV. Collagen I and III protein levels, evaluated via western blot, were not significantly different in the LV, demonstrating a disconnect whereby changes to collagen I mRNA did not directly translate to alterations in protein. In the RV, collagen I protein levels were increased due to AB (main effect), while collagen III protein levels were unaltered. Thus, in contrast to the LV, a direct relationship between mRNA and protein was observed in the RV for collagen I. Given alterations to mRNA did not always match changes in protein level, collagen degradation was evaluated. Collagen degradation is regulated by matrix metalloproteinases (MMPs), which degrade collagen, and tissue inhibitors of matrix metalloproteinases (TIMPs), which inhibit MMPs. MMP‐2 and ‐9 activity/abundance was evaluated with gelatin zymography, MMP‐14 activity was evaluated via a fluorogenic substrate assay, and TIMP2 protein was evaluated through western blot. In the LV, there was a significant interaction for MMP‐2 and MMP‐9 whereby activity/abundance due to AB was dependent upon the presence of sex hormones. This interaction was not observed in the RV. MMP‐14 activity was decreased due to AB (main effect) in the LV, but not altered in the RV. TIMP2 protein levels were decreased due to OVX (main effect) in the LV, with no differences observed in the RV. In conclusion, these results demonstrate chamber‐specific differences in the regulation of cardiac fibrosis including: 1) An imbalance in collagen metabolism in the LV consisting of collagen mRNA levels not directly translating to protein, with dysregulation of MMP/TIMP protein and activity levels resulting from both OVX and AB; and 2) in the RV, an increase in collagen I mRNA and protein due to AB with no alterations to bioregulators of collagen degradation. These findings demonstrate important differences in the regulation of fibrosis due to the loss of sex hormones and chronic pressure overload between the LV and RV that may be critical to understanding the pathophysiology of HFpEF in postmenopausal women.

Reactive Oxygen Species Induced Pathways in Heart Failure Pathogenesis and Potential Therapeutic Strategies.

With respect to structural and functional cardiac disorders, heart failure (HF) is divided into HF with reduced ejection fraction (HFrEF) and HF with preserved ejection fraction (HFpEF). Oxidative stress contributes to the development of both HFrEF and HFpEF. Identification of a broad spectrum of reactive oxygen species (ROS)-induced pathways in preclinical models has provided new insights about the importance of ROS in HFrEF and HFpEF development. While current treatment strategies mostly concern neuroendocrine inhibition, recent data on ROS-induced metabolic pathways in cardiomyocytes may offer additional treatment strategies and targets for both of the HF forms. The purpose of this article is to summarize the results achieved in the fields of: (1) ROS importance in HFrEF and HFpEF pathophysiology, and (2) treatments for inhibiting ROS-induced pathways in HFrEF and HFpEF patients. ROS-producing pathways in cardiomyocytes, ROS-activated pathways in different HF forms, and treatment options to inhibit their action are also discussed.

Immunometabolic Mechanisms of Heart Failure with Preserved Ejection Fraction.

Heart failure with preserved ejection fraction (HFpEF) is increasing in prevalence worldwide, already accounting for at least half of all heart failure (HF). As most patients with HFpEF are obese with metabolic syndrome, metabolic stress has been implicated in syndrome pathogenesis. Recently, compelling evidence for bidirectional crosstalk between metabolic stress and chronic inflammation has emerged, and alterations in systemic and cardiac immune responses are held to participate in HFpEF pathophysiology. Indeed, based on both preclinical and clinical evidence, comorbidity-driven systemic inflammation, coupled with metabolic stress, have been implicated together in HFpEF pathogenesis. As metabolic alterations impact immune function(s) in HFpEF, major changes in immune cell metabolism are also recognized in HFpEF and in HFpEF-predisposing conditions. Both arms of immunity - innate and adaptive - are implicated in the cardiomyocyte response in HFpEF. Indeed, we submit that crosstalk among adipose tissue, the immune system, and the heart represents a critical component of HFpEF pathobiology. Here, we review recent evidence in support of immunometabolic mechanisms as drivers of HFpEF pathogenesis, discuss pivotal biological mechanisms underlying the syndrome, and highlight questions requiring additional inquiry.

Age and Sex Differences in Heart Failure With Preserved Ejection Fraction.

Heart failure with preserved ejection fraction (HFpEF) is a multi-organ disorder that represents about 50% of total heart failure (HF) cases and is the most common form of HF in the elderly. Because of its increasing prevalence caused by the aging population, high mortality and morbidity, and very limited therapeutic options, HFpEF is considered as one of the greatest unmet medical needs in cardiovascular medicine. Despite its complex pathophysiology, numerous preclinical models have been established in rodents and in large animals to study HFpEF pathophysiology. Although age and sex differences are well described in HFpEF population, there are knowledge gaps in sex- and age-specific differences in established preclinical models. In this review, we summarize various strategies that have been used to develop HFpEF models and discuss the knowledge gaps in sex and age differences in HFpEF.

The Role of Systemic Microvascular Dysfunction in Heart Failure with Preserved Ejection Fraction.

Heart failure with preserved ejection fraction (HFpEF) is a condition with increasing incidence, leading to a health care problem of epidemic proportions for which no curative treatments exist. Consequently, an urge exists to better understand the pathophysiology of HFpEF. Accumulating evidence suggests a key pathophysiological role for coronary microvascular dysfunction (MVD), with an underlying mechanism of low-grade pro-inflammatory state caused by systemic comorbidities. The systemic entity of comorbidities and inflammation in HFpEF imply that patients develop HFpEF due to systemic mechanisms causing coronary MVD, or systemic MVD. The absence or presence of peripheral MVD in HFpEF would reflect HFpEF being predominantly a cardiac or a systemic disease. Here, we will review the current state of the art of cardiac and systemic microvascular dysfunction in HFpEF (Graphical ), resulting in future perspectives on new diagnostic modalities and therapeutic strategies.

Characterization of Cardiac Sympathetic Nervous System and Inflammatory Activation in HFpEF Patients

We have shown that systemic and cardiac sympathetic activation is present in heart failure with preserved ejection fraction (HFpEF) patients. Conversely, whereas systemic inflammatory activation was also detected in HFpEF, we did not detect local myocardial release of inflammatory cytokines. Activation of the sympathetic system correlated with both hemodynamic and demographic factors that characteristically cluster together in HFpEF. Together these data suggest that there may be a role for antiadrenergic therapies in certain HFpEF patients. The study does not implicate locally derived cytokines in the myocardial biology of HFpEF, although systemic sources may contribute to the global pathophysiology of HFpEF.

Emerging Horizons in Heart Failure with Preserved Ejection Fraction: The Role of SGLT2 Inhibitors.

Heart failure with preserved ejection fraction (HFpEF) is a condition with increasing disease burden. Prevalence of HFpEF is increasing, reflecting an increasingly elderly and comorbid population, as well as reinforcing the need for more treatments for this disease. The pathophysiology of HFpEF is complex. Some inflammatory processes seen in HFpEF are shared with diabetes mellitus (DM) and there is an association seen between the two conditions. It is therefore no wonder that treatments for diabetes may have some effect on heart failure outcomes. Current treatment strategies in HFpEF are limited, with treatments focusing on symptom control rather than morbidity or mortality benefit. However, there are now promising results from the EMPEROR-Preserved study that show significantly reduced cardiovascular death or hospitalisation for heart failure (HHF) in patients taking empagliflozin, compared to those taking placebo. These results indicate a promising future for sodium-glucose co-transporter 2 (SGLT2) inhibitors in HFpEF. The ongoing DELIVER trial (investigating the use of dapagliflozin in HFpEF) is awaited but could provide further evidence of support for SGLT2 inhibitors in HFpEF. With hospital admissions for HFpEF increasing in the UK, the economic impact of treatments that reduce HHF is vast. The European Society of Cardiology (ESC) recently added SGLT2 inhibitors to their guidelines for treatment of heart failure with reduced ejection fraction (HFrEF) following DAPA-HF and EMPEROR-Reduced trials and we suggest that similar changes be made to guidelines to support the use of SGLT2 inhibitors in the management of HFpEF in upcoming months.

The interleukin-1 receptor type I promotes the development of aging-associated cardiomyopathy in mice

BackgroundAging is associated with metabolic and structural changes causing heart failure with preserved ejection fraction (HFpEF). Interleukin-1 (IL-1) is a pro-inflammatory cytokine involved in aging-related inflammation. ObjectiveWe sought to determine whether IL-1 mediates aging-related changes in the heart, as seen in HFpEF. MethodsWe studied age-matched young (4-month-old), middle-aged (14-month-old), and old (23-month-old) wild-type (WT) C57BL/6J and IL-1 receptor type I deficient (IL1RI-KO) male mice. Echocardiography was used to evaluate left ventricular (LV) dimensions and systolic/diastolic function, and a pressure transducer was used to measure the LV end-diastolic pressure. Picrosirius red stain was used to assess for myocardial interstitial fibrosis (MIF) at pathology. ResultsWT and IL-1RIKO mice showed a normal cardiac phenotype at young age, without any differences between the two groups. With aging, the WT mice developed LV concentric hypertrophy (as measured by a significant increase in LV mass [+42%, P < 0.01] and relative wall thickness [+34%, P < 0.01]), whereas the aging IL-1RI-KO mice did not. With aging, the WT mice also developed diastolic dysfunction (as measured by a significant increase in isovolumetric relaxation time [+148%, P < 0.01] and a significantly higher LV end-diastolic pressure [+174%, P < 0.01]), whereas the aging IL1RI-KO did not. Aged WT mice showed a significant increase in MIF (+124%, P < 0.01) at cardiac pathology, whereas the aging IL-1RI-KO did not. ConclusionsGenetically-modified mice lacking the IL-1RI receptor, not responsive to IL-1, are protected from aging-related LV hypertrophy, fibrosis, and diastolic dysfunction. These data support a central role of IL-1 in the pathophysiology of aging-related HFpEF.

All-Cause Mortality as an End Point for Heart Failure With Preserved Ejection Fraction: Underperformance or Overambitious?

All-Cause Mortality as an End Point for Heart Failure With Preserved Ejection Fraction: Underperformance or Overambitious?

Abstract 13055: Endotrophin is Significantly Associated With Risk of Mortality in HFpEF Patients Irrespective of Underlying Atrial Fibrillation

Introduction: The global burden of heart failure with preserved ejection fraction (HFpEF) is increasing. HFpEF is projected to become the dominant type of HF, and atrial fibrillation (AF) is known to contribute to pathogenesis by aggravating fibrosis. Endotrophin is a bioactive molecule released from collagen type VI during its maturation, and it is a marker of fibroblast activity. The aim of this post-hoc analysis was to confirm the previously observed prognostic potential of endotrophin (measured by PRO-C6) for adverse outcome in HFpEF and to investigate the potential influence in risk stratification by AF. Methods: 166 patients with hypertensive HFpEF were included for analysis. 48.2% were NYHA Class II, 49.4% NYHA Class III and 1.2% NYHA Class IV. 50.6% of patients had a previous history of AF. Cardiac function was assessed by echocardiography and standard clinical measures. Circulating endotrophin was quantified at baseline in serum by means of an enzyme-linked immunosorbent assay, PRO-C6. Results: PRO-C6 levels increased significantly with disease severity in HFpEF patients (NYHA Class III vs II, p=0.0003), and in HFpEF patients with AF (p=0.023). PRO-C6 was able to discriminate between patients at risk of all-cause mortality (AUC=0.73, p&lt;0.001), but no improvement in this association was observed when factoring in AF (AUC=0.72, p=0.001). When looking at patients stratified in PRO-C6 tertiles, patients in the upper tertile had a significantly higher risk of mortality (p&lt;0.0001, hazard ratios 3 vs 1=4.1, 3 vs 2=3.5, respectively) and HF hospitalization (p&lt;0.0001, hazard ratio 3 vs 1=4.4, 3 vs 2=1.6, respectively) compared to tertiles 1 and 2. Conclusions: In this population of hypertensive HFpEF patients, circulating endotrophin, measured by PRO-C6, was increased with increasing disease severity, and associated with a higher risk of adverse outcome in HFpEF, regardless of underlying AF. The data presented here suggest a potential role of endotrophin in HFpEF pathophysiology, associated to disease progression in HFpEF patients with or without AF. These data confirm previous observations, and strengthen the usefulness of endotrophin, measured by the PRO-C6 biomarker, as a prognostic tool aiding in assessment of HFpEF patients.

Abstract 13208: Deletion of the Type I Interleukin-1 Receptor Prevents the Development of Cardiomyopathy Associated With Aging in Mice

Background: Aging is associated with metabolic and structural changes causing heart failure with preserved ejection fraction (HFpEF). Interleukin-1 (IL-1) is a pro-inflammatory cytokine involved in aging-related inflammation. We sought to determine whether IL-1 mediates aging-related changes in the heart as seen in HFpEF. Hypothesis: We hypothesize that mice with genetic deletion of IL-1RI, not responsive to IL-1β, would be protected from age-associated cardiac dysfunction. Methods: We studied age-matched young (4-month-old), middle-aged (14-month-old) and old (23-month-old) wild-type (WT) C57BL/6J and IL-1 receptor type I deficient (IL1RI-KO) male mice. Echocardiography was used to left ventricular (LV) dimensions and systolic/diastolic function, and a pressure-transducer was used to measure the LV end-diastolic pressure. Picrosirius red stain was used to assess for myocardial interstitial fibrosis (MIF) at pathology. Results: WT and IL-1RIKO mice showed a normal cardiac phenotype at young age, without any differences in between the two groups. With aging, the WT mice developed LV concentric hypertrophy (as measured by a significant increase in LV mass [+42%, P&lt;0.01] and relative wall thickness [+34%, P&lt;0.01]), whereas the aging IL-1RI-KO mice did not (Figure 1a,b). With aging the WT mice also developed diastolic dysfunction (as measured by a significant increase in isovolumetric relaxation time [+148%, P&lt;0.01] and a significantly higher LV end diastolic pressure [+174%, P&lt;0.01]), whereas the aging IL1RI-KO did not (Figure 1c,d). With aging WT mice showed a significant increase in MIF (+124%, P&lt;0.01) at cardiac pathology, whereas the aging IL-1RI-KO did not (Figure 1e). Conclusions: Genetically-modified mice lacking the IL-1RI receptor, not responsive to IL-1, are protected from aging-related LV hypertrophy, fibrosis and diastolic dysfunction. These data support a central role of IL-1 in the pathophysiology of aging-related HFpEF.

Abstract 11432: The Impact of Regional Adipose Tissue Deposition on Physical Activity in Heart Failure with Preserved Ejection Fraction

Introduction: Obesity is common in heart failure with preserved ejection fraction (HFpEF) and is directly linked with lower levels of physical activity (PA). Visceral adiposity (VAT) is more common in HFpEF than controls and may play a role in its pathogenesis, characterized by impaired exercise capacity (peak VO 2 ). The direct relationship between VAT and PA in HFpEF is unknown. Hypothesis: Compared to controls, HFpEF patients will have excess regional adiposity (VAT, subcutaneous (SAT), and intramuscular (IMAT)), and these fat depots will be associated with lower levels of chronic physical activity. Methods: HFpEF patients (n=51; age 70±9) and non-HFpEF controls (n=49; age 65±5) prospectively underwent body composition measurement by dual-energy x-ray absorptiometry and magnetic resonance imaging. Peak VO 2 was measured by standard cardiopulmonary exercise testing. PA was monitored continuously via accelerometry over two weeks. Data were binned in arbitrary accelerometry units, averaged and stored in 30-second epochs (counts per epoch, CPE). Models were adjusted for age, sex, and ideal body weight. Results: HFpEF were less active overall (3.15±0.80 vs 3.59±0.73 CPE), had less moderate intensity PA (10.13±0.04 vs 10.15±0.03 CPE), and less morning (3.83±1.15 vs 4.24±1.09 CPE) and afternoon (3.84± 1.20 vs 4.53± 0.97 CPE) (p&lt;0.05 for all) PA. Patients with HFpEF spent a greater proportion of time sedentary (0.71±0.08 vs 0.67±0.08 CPE) and less time in moderate (0.04±0.03 vs 0.06±0.03 CPE) and vigorous (0.02±0.01 vs 0.03±0.03 CPE) PA (p&lt;0.01 for all). Chronic PA was significantly associated with regional fat depots (VAT β= -0.003, 95% CI: -0.004-0.001; SAT β= -0.003, 95%CI: -0.004-0.001; IMAT β=-0.02, 95% CI: -0.04—0.01) as a combined cohort (p&lt;0.01 for all). Muscle quality (β=0.28, 95%CI: 0.15-0.40), peak VO 2 (β=0.08, 95% CI: 0.03-0.13), and peak watts (β=0.01, 95% CI: -0.004-0.02) were associated with PA in HFpEF only (p≤0.01 for all). Conclusions: The amount and pattern of PA differs between HFpEF and controls, as do relationships between regional fat depots and PA, and the relationship of PA and peak VO 2 . Further investigation is needed to better understand the temporality and mechanisms related to the pathophysiology and severity of HFpEF.

Role of Diabetes Mellitus in Heart Failure With Preserved Ejection Fraction: A Review Article.

The pathophysiology of heart failure with preserved ejection fraction (HFpEF) is complex and poorly understood. There is a high prevalence of Diabetes Mellitus (DM) in patients with HFpEF, and the presence of DM has been shown to increase mortality of patients with HFpEF by 30%-50% even after adjustment for age, gender, hospital factors, and other patient characteristics. Since the prevalence of both entities is increasing worldwide, there is a need to explore their intricate relationship in order to elucidate potential management strategies to reduce the morbidity and mortality associated with this duo. In this review article, we explore the role of DM in the pathophysiology of HFpEF, ethnic and gender differences, and some therapeutic strategies in the management of patients with HFpEF and DM.

Potential Mechanisms of SGLT2 Inhibitors for the Treatment of Heart Failure With Preserved Ejection Fraction.

Heart failure with preserved ejection fraction (HFpEF) is an unsolved and growing concern in cardiovascular medicine. While no treatment options that improve prognosis in HFpEF patients has been established so far, SGLT2 inhibitors (SGLT2i) are currently being investigated for the treatment of HFpEF patients. SGLT2i have already been shown to mitigate comorbidities associated with HFpEF such as type 2 diabetes and chronic renal disease, however, more recently there has been evidence that they may also directly improve diastolic function. In this article, we discuss some potential beneficial mechanisms of SGLT2i in the pathophysiology of HFpEF with focus on contractile function.