Dysfunction In Heart Failure With Preserved Ejection Fraction Research Articles

Connecting heart failure with preserved ejection fraction and renal dysfunction: the role of endothelial dysfunction and inflammation

Renal dysfunction in heart failure with preserved ejection fraction (HFpEF) is common and is associated with increased mortality. Impaired renal function is also a risk factor for developing HFpEF. A new paradigm for HFpEF, proposing a sequence of events leading to myocardial remodelling and dysfunction in HFpEF, was recently introduced, involving inflammatory, microvascular, and cardiac components. The kidney might play a key role in this systemic process. Renal impairment causes metabolic and systemic derangements in circulating factors, causing an activated systemic inflammatory state and endothelial dysfunction, which may lead to cardiomyocyte stiffening, hypertrophy, and interstitial fibrosis via cross-talk between the endothelium and cardiomyocyte compartments. Here, we review the role of endothelial dysfunction and inflammation to explain the link between renal dysfunction and HFpEF, which allows for identification of new early risk markers, prognostic factors, and unique targets for intervention.

Association of cystatin C with heart failure with preserved ejection fraction in elderly hypertensive patients: potential role of altered collagen metabolism.

Cystatin C has been shown to be associated with heart failure with preserved ejection fraction (HFPEF). In addition, myocardial fibrosis has been involved in diastolic dysfunction in HFPEF. Therefore, we hypothesized that increased cystatin C levels may be associated with altered collagen metabolism, contributing to diastolic dysfunction in patients with HFPEF. One hundred and forty-one elderly hypertensive patients with HFPEF were included. Cardiac morphology and function was assessed by echocardiography. Circulating levels of cystatin C, biomarkers of collagen type I synthesis (carboxy-terminal propeptide of procollagen type I) and degradation [matrix metalloproteinase-1 (MMP-1) and its inhibitor TIMP-1] and osteopontin were analyzed by ELISA. Twenty elderly sex-matched patients with no identifiable cardiac disease were used as controls. In-vitro studies were performed in human cardiac fibroblasts. Compared with controls, cystatin C was increased (P < 0.001) in patients with HFPEF, even in those with a normal estimated glomerular filtration rate (eGFR; P < 0.05). Cystatin C was directly correlated with the estimated pulmonary capillary wedge pressure (P < 0.01), TIMP-1 and osteopontin (P < 0.001) and inversely correlated with MMP-1:TIMP-1 (P < 0.01), but not with carboxy-terminal propeptide of procollagen type I or MMP-1 in all patients with HFPEF. These associations were independent of eGFR. In vitro, osteopontin (P < 0.01) and TIMP-1 (P < 0.001) increased in the supernatant of cardiac fibroblasts exposed to cystatin C. In patients with HFPEF of hypertensive origin, cystatin C is increased and associated with diastolic dysfunction and alterations in collagen metabolism independently of eGFR. An excess of cystatin C might contribute to diastolic dysfunction in HFPEF by facilitating myocardial fibrosis via accumulation of osteopontin and TIMP-1.

Abstract 10889: Treating Heart Failure With Preserved Ejection Fraction Through Troponin I Phospho-mimicry

Background —Heart failure with preserved ejection fraction (HF-pEF), characterized by resistance to ventricular filling from impaired myofilament relaxation (lusitropy), is the most common variant of heart failure. In HF-pEF, blunting of the lusitropic effect of troponin I (TnI) Ser-23/24 phosphorylation through the β-receptor-cAMP- protein kinase A (PKA) pathway contributes to impaired diastolic relaxation. Methods and Results —To identify small molecule compounds capable of generating the lusitropic effect of PKA-dependent TnI phosphorylation, we developed a 2D in vitro screen, where dye-labeled thin filaments are titrated with Ca 2+ and myosin motors. Thin filament activation is monitored by a FRET assay with FRET donor on the mobile element of TnI and the FRET acceptor on the C-lobe of troponin C (TnC). We observed that full activation of the thin filament required myosin binding. The Ca 2+ -sensitizer bepridil acted as myosin, enhancing thin filament affinity for Ca 2+ and stabilizing the association of the mobile element of TnI with TnC. In the presence of saturating bepridil, adding myosin had no effect on activation, suggesting that bepridil and myosin activate the thin filament through a common mechanism. PKA-treatment decreased the sensitivity of the thin filament to Ca 2+ and to myosin motors, and it reduced the FRET efficiency in the absence of Ca 2+ , suggesting that TnI phosphorylation causes a structural transition in the C-lobe of TnC. Epigallocatechin-3-gallate, the most prevalent polyphenol in green tea, acted as Ser23/24 phospho-TnI, reducing thin filament affinity for Ca 2+ and reducing affinity of myosin for the thin filament under both relaxing and Ca 2+ -activated conditions, suggesting that epigallocatechin-3-gallate and Ser23/24 phospho-TnI relax the myofilament through a common mechanism. Conclusions —Our results suggest that bepridil and myosin activate the cardiac thin filament through a common mechanism while epigallocatechin-3-gallate and Ser23/24 phospho-TnI deactivate the thin filament through a common mechanism. “Myofilament relaxers,” small molecule compounds that mimic the effects of Ser23/24 phospho-TnI may be an effective strategy in correcting diastolic dysfunction in HF-pEF.

Myocardial hypertrophy and its role in heart failure with preserved ejection fraction.

Left ventricular hypertrophy (LVH) is the most common myocardial structural abnormality associated with heart failure with preserved ejection fraction (HFpEF). LVH is driven by neurohumoral activation, increased mechanical load, and cytokines associated with arterial hypertension, chronic kidney disease, diabetes, and other comorbidities. Here we discuss the experimental and clinical evidence that links LVH to diastolic dysfunction and qualifies LVH as one diagnostic marker for HFpEF. Mechanisms leading to diastolic dysfunction in LVH are incompletely understood, but may include extracellular matrix changes, vascular dysfunction, as well as altered cardiomyocyte mechano-elastical properties. Beating cardiomyocytes from HFpEF patients have not yet been studied, but we and others have shown increased Ca(2+) turnover and impaired relaxation in cardiomyocytes from hypertrophied hearts. Structural myocardial remodeling can lead to heterogeneity in regional myocardial contractile function, which contributes to diastolic dysfunction in HFpEF. In the clinical setting of patients with compound comorbidities, diastolic dysfunction may occur independently of LVH. This may be one explanation why current approaches to reduce LVH have not been effective to improve symptoms and prognosis in HFpEF. Exercise training, on the other hand, in clinical trials improved exercise tolerance and diastolic function, but did not reduce LVH. Thus current clinical evidence does not support regression of LVH as a surrogate marker for (short-term) improvement of HFpEF.

Cell- and molecular-level mechanisms contributing to diastolic dysfunction in HFpEF

Heart failure with preserved ejection fraction (HFpEF) is the default diagnosis for patients who have symptoms of heart failure, an ejection fraction >0.5, and evidence of diastolic dysfunction. The clinical condition, which was largely unrecognized 30 years ago, is now a major health problem and currently accounts for 50% of all patients with heart failure. Clinical studies show that patients with HFpEF exhibit increased passive stiffness of the ventricles and a slower rate of pressure decline during diastole. This review discusses some of the cell- and molecular-level mechanisms that contribute to these effects and focuses on data obtained using human samples. Collagen cross linking, modulation of protein kinase G-related pathways, Ca(2+) handling, and strain-dependent detachment of cross bridges are highlighted as potential factors that could be modulated to improve ventricular function in patients with HFpEF.

Abstract 420: Characterization of Dahl Salt-Sensitive Rat Model for Heart Failure with Preserved Ejection Fraction Research: Defining Diagnostic Criteria

Heart failure with preserved ejection fraction (HFpEF) is a condition that accounts for approximately 50 % of heart failure cases with the prevalence increased with advancing age. As of now, no effective treatment is available for HFpEF, which calls for continued efforts towards novel therapies. Dahl salt-sensitive (Dahl SS) rats have recently been reported as an experimental model of HFpEF, although a specific diagnostic criteria for HFpEF is still unclear in rodents. We aimed to provide clear criteria to identify HFpEF in Dahl SS rats. After a follow-up of 28 weeks, adult female Dahl SS rats receiving high salt (HS, 8 % NaCl) diet developed chronic hypertension (209 ± 80 vs. 147 ± 55 mm Hg; P &lt;0.05 vs. low salt-fed control group (LS, 0.3 % NaCl) with consistent left ventricle (LV) remodeling compared to LS rats (LV hypertrophy index: 2.62 ± 0.07 vs. 1.79 ± 0.03 mg/mm, and cardiomyocyte cross-sectional area: 497 ± 38.9 vs. 290 ± 8.15 μm 2 , respectively; P &lt; 0.05) and EF &gt; 50 % (67.7 ± 1.5 %). Evidence that HS rats have developed HFpEF was observed only in rats with left atrial dimension (LAD)/body weight (BW), E/A, and E/E’ ratios above the 75 th percentile of the LS group (17.50 mm/kg, 1.53, and 14.25, respectively). In addition, HS rats diagnosed with HFpEF had increased LV end-diastolic pressure and plasma NT-proBNP compared to LS rats (12.8 ± 3.4 vs. 5.8 ± 0.8 mm Hg, and 78.7 ± 18.0 vs. 17.7 ± 3.5 pg/mL, respectively; P &lt; 0.05), while no significant changes in LAD/BW, E/A, E/E’, and plasma NT-proBNP were demonstrated in HS rats not matching the suggested criteria for HFpEF. Distance run was not different between HS and LS groups. Survival rate was 39.9 % in HS compared to 94.7 % in LS rats ( P = 0.0001), with stroke as the main cause of death (69.6 % incidence in HS rats). These results provide the first clear criteria for diagnosis of HFpEF in Dahl SS rats. Our findings have important implications for future preclinical studies aiming to develop novel therapeutic strategies targeting diastolic dysfunction in HFpEF.

Imaging in Heart Failure with Preserved Ejection Fraction

Heart failure (HF) with preserved ejection fraction (HFpEF) is becoming the predominant form of HF. Understanding cardiac structure and function in this syndrome is highly relevant for diagnosis, prognosis, pathophysiology, and management. However, identifying cardiac dysfunction in HFpEF can be challenging and requires an integrated assessment of cardiac structure, systolic and diastolic function, and hemodynamics. Comprehensive transthoracic echocardiography is the noninvasive imaging test of choice for evaluating patients with HF. Importantly, cardiac dysfunction may not be present at rest in HFpEF but may be unmasked with exercise or pharmacologic stress testing. Imaging in HFpEF is reviewed.

Inhibition of the NA+/CA2+ Exchanger (Ncx) Improves Cardiomyocyte Contractile Dysfunction in a Rat Model with Compensated Renal Failure and Heart Failure with Preserved Ejection Fraction

Background: Heart failure with preserved ejection fraction (HFPEF) and renal impairment are often associated but the underlying pathomechanisms are largely unknown. We investigated tissue fibrosis and cardiomyocyte contractile function in a rat model with HFPEF and compensated renal failure.Methods: Seventy young male Wistar rats were subjected to subtotal nephrectomy (NXT) or sham operation (SOP). Blood/urine samples, echocardiography, pressure-volume loops were performed after 8 and 24 weeks. Left ventricular (LV) hypertrophy, fibrosis (picosirius-red-staining) and NCX protein expression (Western blot) were determined after sacrification. Cardiomyocyte function (Ca2+ transients, cell shortening) was quantified in isolated cardiomyocytes without and with the NCX inhibitor SEA0400 (300nM).Results: NXT rats showed stable renal impairment with preserved urine excretion and elevated arterial pressure (148±8 and 154±7 vs. 105±3 and 109±2 mmHg, p<0.01) at 8 and 24 weeks, respectively. LV in NXT were significantly hypertrophied at 8 and 24 weeks, but LV systolic function (EF, dP/dt) were preserved. LVEDP, LA size and lung weight were significantly increased indicating HFPEF with pulmonary congestion. Fibrosis was increased in LV from NXT. LV cardiomyocytes showed significantly prolonged time for early (50%) relaxation and decay of the Ca2+ transient. Time constant of the caffeine-induced Ca2+ transient (TAU) was significantly prolonged indicating reduced NCX forward mode activity, while NCX protein expression was upregulated. Acute treatment with SEA0400 (300nM) significantly accelerated early relaxation in cardiomyocytes from NXT (8 weeks).Conclusion: In this model of compensated renal failure and HFPEF cardiomyocyte relaxation was prolonged already at an early stage. Our results suggest increased NCX activity may contribute to contractile dysfunction, likely through reverse mode Ca2+ influx. NCX represents a potential target to treat cardiomyocyte dysfunction in HFPEF.

Diagnosing heart failure with preserved ejection fraction

Heart failure with preserved ejection fraction (HFPEF) is a common syndrome, accounting for about 50% of all patients with heart failure (HF). Morbidity and mortality are similar to patients with HF with reduced ejection fraction (HFREF), yet no effective treatment has been identified in randomized clinical trials. This article provides an overview of the available literature regarding diagnosing established HFPEF and potential new therapeutic targets for the early diagnosis of HFPEF. Vascular dysfunction, ventricular-arterial coupling, oxidative stress, extracellular matrix regulation, chronotropic incompetence, pulmonary hypertension, exercise testing and biomarkers were taken into consideration next to conventional measurements of diastolic dysfunction. Measuring diastolic dysfunction in HFPEF is considered important in many patients. Nevertheless, today we know that other causes besides diastolic dysfunction are also involved in the pathophysiology of many HFPEF patients and need to be investigated in order to make a correct diagnosis. Therefore, further research is required to allow better and more specific diagnostic and treatment options to reduce the morbidity and mortality for this ever-expanding HF population.

Circulation : Clinical Summaries

<i>Circulation</i> : Clinical Summaries

Diagnosis of heart failure with preserved ejection fraction: which parameters and diagnostic strategies are more valuable?

There are no unified criteria for diagnosing heart failure with preserved ejection fraction (HFpEF). The aim of this study was to evaluate the present main diagnostic criteria and to discover which parameters and strategies are more valuable. Echocardiographic data and plasma N-terminal pro-brain natriuretic peptide levels were assessed in a derivation cohort (n= 236) and a validation cohort (n= 98). Both cohorts included normal controls, patients with hypertensive heart disease without heart failure and patients with HFpEF. In the derivation cohort, the ratio of early mitral inflow velocity to tissue Doppler velocity at lateral mitral annulus (lateral E/e'≥12), left atrial volume index (LAVI≥34 mL/m(2)), and the difference between duration of reversed pulmonary vein atrial systole flow and duration of mitral A wave flow (Ard-Ad>30 ms) had the greatest diagnostic value among all the single parameters. A brief strategy that consisted of either: (i) lateral E/e'≥12; or (ii) 12>lateral E/e'≥8, with either LAVI≥34 mL/m(2) or Ard-Ad>30 ms, provided good diagnostic accuracy for identifying diastolic dysfunction in HFpEF, with a sensitivity of 77% and specificity of 81%. These observations were confirmed in the validation cohort. Echocardiographic parameters including lateral E/e', LAVI, and Ard-Ad have the greatest value in diagnosing HFpEF. A brief strategy that included these three parameters had great diagnostic value and would be simple to use in clinic practice.