Function In Heart Failure With Preserved Ejection Fraction Research Articles

The value of speckle-tracking stratified strain combined with myocardial work measurement in evaluating left ventricular function in patients with heart failure with preserved ejection fraction.

Heart failure with preserved ejection fraction (HFpEF) is a highly prevalent progressive disease accompanied by poor quality of life, high utilization of medical resources, morbidity, and mortality. However, the role of left ventricular (LV) systolic dysfunction has yet to be well elaborated despite the preservation of the LV ejection fraction. This study aimed to explore the diagnostic value of speckle-tracking stratified strain combined with myocardial work (MW) measurement in evaluating LV systolic dysfunction in patients with HFpEF. A total of 125 study consecutive individuals, 64 HFpEF patients, and 61 controls were prospectively enrolled in the Fourth Affiliated Hospital of Harbin Medical University. In addition to the conventional echocardiographic parameters, LV stratified strain and MW parameters were statistically compared between the HFpEF and control groups. The global longitudinal strain (GLS) of the subendocardium, myocardium, and subepicardium (GLSendo, GLSmyo, and GLSepi); the transmural gradient (ΔGLS); the global myocardial work index (GWI), global myocardial work efficiency (GWE), global myocardial constructive work (GCW), and the global myocardial wasted work (GWW) were included. Area under the receiver operating characteristic curve analysis was used to evaluate the diagnostic performance of these univariate and multivariable logistic models in detecting impaired LV systolic function in HFpEF. Ten-fold cross-validation was used to evaluate the generalizability of the predictive model. Stratified strains values showed a gradient decline from GLSendo to GLSepi in both control and HFpEF patients. Compared with the control group, HFpEF patients had a significantly reduced GLSepi, GLSmyo, GLSendo, ΔGLS, GWI, GWE, and GCW and a significantly increased GWW (all P<0.001). In the derivation set, the optimal logistic model (combined stratified strain and MW variables) demonstrated the highest performance in predicting LV systolic function impairment in HFpEF patients. The best-performing model with a mean area under the curve (AUC) of 0.966 [95% confidence interval (CI): 0.88 to 1] accessed by 10-fold cross-validation. In the validation set, the AUC of the optimal logistic model was 0.933 (95% CI: 0.85 to 1), the sensitivity was 87%, and the specificity was 93%. Both speck-tracking stratified strain and MW measurement may sensitively detect impairment of LV myocardial function at an early stage for patients with HFpEF. Combining the two techniques may improve the quality of HFpEF diagnosis and may provide a reference value for the early diagnosis of HFpEF in the future.

Abstract 13403: Age-Related Echocardiographic Characteristics in Patients With Heart Failure With Preserved Ejection Fraction in PARAGON-HF

Introduction: Heart failure with preserved ejection fraction (HFpEF) may have different characteristics by age groups. Aim Compare clinical and echocardiographic characteristics in patients with HFpEF enrolled in the PARAGON-HF echocardiography substudy by age groups. Methods: Echocardiography was performed in 1097 patients in PARAGON-HF (Prospective Comparison of ARNI with ARB Global Outcomes in HF with Preserved Ejection Fraction), where patients with left ventricular ejection fraction (LVEF) &gt;=45% were enrolled. Clinical and echocardiographic characteristics were compared in patients who were &lt;65, 65-74, and &gt;75 years of age. Results: Younger patients were more likely to be male, obese, have prior myocardial infarction (MI) and diabetes, but less likely to have atrial fibrillation (AF, Table 1). Older patients had smaller left ventricular (LV) dimension indices, more likely to have concentric hypertrophy or remodeling, higher LVEF and better global longitudinal strain, and more likely to have left atrial enlargement and echocardiographic evidence of higher LV filling pressure (Table 1). Echocardiographic measures of pulmonary pressure and right ventricular function were similar across age groups. After adjusting for sex, race, region, history of MI, diabetes, AF, and body mass index, every 10 years of increase in age was associated with 5.1 mL/m 2 decrease in LV end-diastolic volume index (95% confidence interval [CI] 3.9 - 6.5, p &lt; 0.001), 0.4% increase in absolute global longitudinal strain (95% CI 0.1% - 0.7%, p = 0.017), and 1.07 increase in E/e’ septal ratio (95% CI 0.42 - 1.73, p = 0.001). Conclusions: Compared with younger patients, older patients with HFpEF were more likely to be female with AF, have better systolic function and higher LV filling pressure. These findings demonstrated the heterogeneity in cardiac structure and function in HFpEF by age and may have implications for treatment and future clinical trial recruitment.

Leucine Supplementation Improves Diastolic Function in HFpEF by HDAC4 Inhibition.

Heart failure with preserved ejection fraction (HFpEF) is a complex syndrome associated with a high morbidity and mortality rate. Leucine supplementation has been demonstrated to attenuate cardiac dysfunction in animal models of cachexia and heart failure with reduced ejection fraction (HFrEF). So far, no data exist on leucine supplementation on cardiac function in HFpEF. Thus, the current study aimed to investigate the effect of leucine supplementation on myocardial function and key signaling pathways in an established HFpEF rat model. Female ZSF1 rats were randomized into three groups: Control (untreated lean rats), HFpEF (untreated obese rats), and HFpEF_Leu (obese rats receiving standard chow enriched with 3% leucine). Leucine supplementation started at 20 weeks of age after an established HFpEF was confirmed in obese rats. In all animals, cardiac function was assessed by echocardiography at baseline and throughout the experiment. At the age of 32 weeks, hemodynamics were measured invasively, and myocardial tissue was collected for assessment of mitochondrial function and for histological and molecular analyses. Leucine had already improved diastolic function after 4 weeks of treatment. This was accompanied by improved hemodynamics and reduced stiffness, as well as by reduced left ventricular fibrosis and hypertrophy. Cardiac mitochondrial respiratory function was improved by leucine without alteration of the cardiac mitochondrial content. Lastly, leucine supplementation suppressed the expression and nuclear localization of HDAC4 and was associated with Protein kinase A activation. Our data show that leucine supplementation improves diastolic function and decreases remodeling processes in a rat model of HFpEF. Beneficial effects were associated with HDAC4/TGF-β1/Collagenase downregulation and indicate a potential use in the treatment of HFpEF.

Abstract P2094: The Regulatory Role Of Sirtuin 6 In Coronary Microcirculation In Hfpef

Coronary vasculature is essential to support the supply oxygen and nutrients to the heart and maintain the normal cardiac function. Obstruction of large vessels of coronaries (atherosclerosis) is well studied, but coronary microvascular dysfunction (CMD), which is associated with diabetic cardiomyopathy, Takotsubo cardiomyopathy, andheart failure with preserved ejection fraction (HFpEF), is understudied. CMD is characterized by impaired endothelial-dependent vasodilation, but detailed mechanisms have yet to be elucidated. Sirtuin 6 (Sirt6) has been implicated in obesity, insulin resistance, type 2 diabetes mellitus, and cardiovascular diseases. Sirt6 protects EC from premature senescence, oxidative stress, and atherosclerosis by sustaining high eNOS levels and preserving cell replication. A recent publication showed that overexpressed Sirt 6 in EC mitigated heart failure with preserved ejection fraction (HFpEF) in diabetes. We hypothesize Sirt 6 deficiency causes CMD in HFpEF How Sirt6 regulates coronary microvascular function remains to be determined. Inducible Sirt6 endothelial-specific knockout and wild-type (WT) mice were fed a chow or high fat and sugar (HFHS) diet. Coronary arterioles were isolated, and endothelial-dependent vasodilation (EDD) was assessed using myography (DMT). Echocardiography and treadmill exercise exertion tests were performed to evaluate cardiac function. Myocardial blood flow (MBF) was measured by doppler. Cardiac fibrosis was detected using trichrome staining, and molecular pathways were elucidated via gene and protein analysis. Our preliminary data show that the EDD of coronary arterioles of Sirt6 endothelial-specific knockout treated with HFHS was impaired, and the mediator of coronary vasodilation switched from NO to H 2 O 2 in the Sirt6 knockout mice. Compared to the WT mice, myocardial blood flow and cardiac function were changed in Sirt6 knockout mice. Our data suggest that Sirt6 regulated coronary microvascular function through endothelial cells, and ablation of Sirt6 in endothelial cells caused CMD and diastolic dysfunction, eventually HFpEF. Further genetic profiling will elucidate the pathways and mechanisms converging with Sirt6 to regulate microvascular function in HFpEF.

Linkage of Left Atrial Function to Heart Failure with Preserved Ejection Fraction.

In heart failure with preserved ejection fraction (HFpEF), left atrial enlargement is a surrogate marker reflecting chronic left ventricular diastolic dysfunction. As a result, the left atrial volume is often evaluated in daily clinical practice to determine the presence of left ventricular diastolic dysfunction. However, recent studies have shown that left atrial dysfunction is an important factor contributing to the pathogenesis of HFpEF, and it is expected to become one of the therapeutic targets of HFpEF, rather than just a surrogate marker. Echocardiography plays a central role in the identification of left atrial dysfunction and remodeling in HFpEF. In this review, we describe an approach to the evaluation of left atrial function in HFpEF using echocardiography.

Sildenafil and Kidney Function in Heart Failure with Preserved Ejection Fraction.

Chronic kidney disease (CKD) worsens the prognosis for people with heart failure with preserved ejection fraction (HFpEF). In the RELAX trial, sildenafil decreased estimated glomerular filtration rate (eGFR) compared to placebo despite favorable kidney effects in preclinical models. Since acute eGFR decline precedes long-term kidney benefits for select medications, we assessed the influence of sildenafil on acute and chronic eGFR slopes. The RELAX trial randomized 216 participants to placebo or sildenafil and assessed 24-week changes in cardiopulmonary exercise testing, cardiovascular imaging, and laboratory data. We applied linear mixed modeling to calculate the total, acute (0-12 weeks), and chronic (3-24 weeks) eGFR slopes by treatment. Using regression modeling, we assessed respective associations between eGFR slope and baseline data and clinical endpoints. We repeated the analyses using a binary outcome based on a substantial (≥20%) decline in eGFR. The mean baseline eGFR was 60.8 ml/min/1.73 m2, and the mean eGFR slope during follow-up was -3.21 ml/min/1.73 m2/year. Sildenafil did not alter total eGFR slope compared to placebo (difference +0.47 ml/min/1.73 m2/year, 95% CI -6.63 - 7.57 ml/min/1.73 m2/year). Sildenafil users tended to experience a more negative acute eGFR slope (difference -3.15 ml/min/1.73 m2/year) and more positive chronic slope (+2.06 ml/min/1.73 m2/year) compared to placebo, but neither difference reached statistical significance. Baseline NT-proBNP and loop diuretic use were associated with worse eGFR trajectory regardless of treatment. Substantial eGFR decline was associated with increase in endothelin-1 and a greater risk of hospitalization or death (HR 2.34, 95% CI 1.21-4.53, p=0.01). Sildenafil induced an acute effect on eGFR without change in the overall eGFR slope after 24 weeks in a HFpEF cohort, suggesting lack of long-term risk related to early reduction in eGFR after initiating treatment. Long-term studies are needed to determine the effect of sildenafil on kidney function in HFpEF.

Increased Soluble Epoxide Hydrolase Activity Positively Correlates with Mortality in Heart Failure Patients with Preserved Ejection Fraction: Evidence from Metabolomics.

The online version contains supplementary material available at 10.1007/s43657-022-00069-8.

Effect of Ivabradine on Left Ventricular Diastolic Function of Patients With Preserved Ejection Fraction - Results of the IVA-PEF Study.

Background: The association between heart rate (HR) reductions caused by ivabradine and left ventricular (LV) diastolic function in heart failure with preserved ejection fraction (HFpEF) remains uncertain because of off-label use. Thus, the present study investigated the effect of HR reductions by ivabradine on LV diastolic function in HFpEF patients.Methods and Results: This study enrolled 16 HFpEF patients with HR ≥75 beats/min. After 3 months administration of ivabradine, no significant changes were observed in mitral inflow E and mitral e’ annular velocities, B-type natriuretic peptide, or left atrial volume index, but there were significant improvements in global longitudinal strain.Conclusions: Ivabradine did not improve LV diastolic function for HFpEF patients with HR ≥75 beats/min. Because this may be due to some study limitations, further studies should be conducted.

Unmasking systolic impairment in HFpEF by cardiovascular magnetic resonance derived hemodynamic force assessment: insights from the HFpEF stress trial

Abstract Background The diagnosis of heart failure with preserved ejection fraction (HFpEF) remains challenging. Exercise-stress testing is recommended in case of uncertainty; however, this approach is time-consuming and costly. Since preserved EF does not represent normal systolic function, we evaluated cardiovascular magnetic resonance (CMR) comprehensive cardiac hemodynamic forces (HDF) analyses for an in-depth characterisation of cardiac function at rest. Methods The HFpEF Stress Trial (DZHK-17) prospectively recruited 75 patients with exertional dyspnea, preserved EF (≥50%) and signs of diastolic dysfunction (E/e' ≥8) on echocardiography. Patients underwent right heart catheterisation, echocardiography and CMR. 68 patients entered the final study cohort (HFpEF n=34 and non-cardiac dyspnea n=34 according to pulmonary capillary wedge pressure (PCWP)). HDF assessment included left ventricular (LV) longitudinal, systolic peak and impulse, systolic/diastolic transition, E-wave deceleration as well as A-wave acceleration forces. Two patients were lost to 24 months follow-up evaluating cardiovascular mortality and hospitalisation (CVH). Results HDF assessment revealed impairment of LV longitudinal force in HFpEF (15.8 vs. 18.3, p=0.035) attributable to impairment of systolic peak (38.6 vs 51.6, p=0.003) and impulse (20.8 vs. 24.5, p=0.009) forces as well as late diastolic filling (−3.8 vs −5.4, p=0.029). Impairment of early diastolic filling could be observed in HFpEF patients identified at rest only but not stress (7.7 vs. 9.9, p=0.004). Impaired systolic peak was associated to CVH (HR 0.95, p=0.016) and superior for CVH prediction compared to LV global longitudinal strain (AUC 0.76 vs. 0.61, p=0.048). Conclusions Assessment of HDF reveals impairment of LV systolic and diastolic function in HFpEF. The value of systolic HDF assessment exceeded that of conventional deformation imaging for CVH prediction. Funding Acknowledgement Type of funding sources: Public grant(s) – National budget only. Main funding source(s): German Centre for Cardiovascular Research

Right atrial function in HFpEF in sinus rhythm vs. atrial fibrillation

Abstract Aims We sought to study the prognostic impact of right atrial (RA) size and function in patients with heart failure with preserved ejection fraction (HFpEF) in sinus rhythm (SR) vs. atrial fibrillation (AF). Methods and results Consecutive HFpEF patients were enrolled and indexed RA volumes and emptying fractions (RA-EF) were assessed by cardiac magnetic resonance imaging (CMR). For patients in SR during CMR feature tracking of the RA wall was performed (Figure 1). In addition, all patients underwent right and left heart catheterization, 6 min walk test, and N-terminal prohormone of brain natriuretic peptide (NT-proBNP) evaluation. We prospectively followed patients and used Cox regression models to determine the association of RA size and function with a composite endpoint of heart failure hospitalization and cardiovascular death. A total of 188 patients (71% female patients, 70±8 years old) were included of whom 96 (51%) were in SR. Eighty-five patients reached the combined endpoint during a follow-up of 72 (33–101) months. After multivariate cox regression analysis adjusted for age, NT-proBNP level, right ventricular ejection fraction and HF functional class, impaired RA strain (Figure 1A) (HR 0.959; 95% CI [0.924–0.996], P=0.024), RA conduit strain (Figure 1A) (HR 0.944; 95% CI [0.898–0.993], P=0.027) and RA conduit strain rate (Figure 1B) (HR 0.990; 95% CI [0.883–0.998], P=0.013) were significantly associated with adverse outcome for patients in SR (Table 1). In persistent AF, no RA imaging parameter was related to outcome after multivariate regression analysis. Conclusions In HFpEF patients in SR, CMR parameters of impaired RA conduit function show the best association with adverse cardiovascular outcome. In persistent AF, RA parameters lose their prognostic ability. Funding Acknowledgement Type of funding sources: None.

Cryoballoon-ablation of atrial fibrillation in patients with heart failure and preserved ejection fraction

Abstract Funding Acknowledgements Type of funding sources: Public Institution(s). Main funding source(s): Deutsches Zentrum für Herz-Kreislauf-Forschung (DZHK) Background Co-existence of atrial fibrillation (AF) and heart failure with preserved ejection fraction (HFpEF) is common and severely affects morbidity and prognosis. Purpose This study evaluates outcome after cryoballoon-ablation for AF in HFpEF compared to patients without heart failure employing multiple diagnostic modalities. Methods A total of 102 patients scheduled for cryoablation of AF with LVEF≥50% were prospectively enrolled. Baseline evaluation included echocardiography, stress echocardiography, six-minute-walk-test, biomarker measurements and quality of life assessment (SF-36). HFpEF was diagnosed according to current guidelines and confirmed applying the HFA-PEFF-Score. Procedural parameters as well as clinical, functional and echocardiographic endpoints at follow-up ≥12 months after AF-ablation were compared between patients with and without HFpEF. Results Patients with HFpEF (n=24) were older (median: 73.5 years [Q25: 66.5 years; Q75: 75.8 years] vs. 64.5 years [Q25: 55.0 years; Q75: 71.3 years], P&amp;lt;0.001) and more often female (83.3% vs. 28.2%). They were characterized by more pronounced AF-related symptoms (median EHRA-score: 3.0 [Q25:3.0; Q75:3.0] vs. 2.0 [Q25: 2.0; Q75: 3.0], P&amp;lt;0.001), reduced distance in six-minute-walk-test (median 487.5m [Q25: 378.1m; Q75: 517.8m] vs. 539.0m [Q25: 489.3m; Q75:589.1 m], P&amp;lt;0.001), and higher mean left atrial (LA)-pressure measured at the needle tip at transseptal puncture (14.0mmHg [Q25: 10.3mmHg; Q75: 21.5mmHg] vs. 10.0 mmHg [Q25: 8.0mmHg; Q75: 13.3mmHg], P=0.008). Procedural parameters were comparable between the two subgroups. Rates of AF-recurrence, repeat AF-ablation and AF-related re-hospitalization were increased in HFpEF (Figure 1A-C), which was confirmed after adjusting for intergroup differences in sex and age distribution by multiple regression analysis. There was no improvement of heart failure-related symptoms and persistent elevation of cardiac biomarkers, even in HFpEF-patients with successful restoration of sinus rhythm at follow-up (Figure 2A-C). Echocardiographic follow-up showed progression of adverse LA-remodeling (LA-volume index at baseline: 35.8ml/m2 [Q25: 32.2ml/m2; Q75: 41.9ml/m2] vs. 12-month follow-up: 40.5ml/m2 [Q25: 36.0ml/m2; Q75: 51.4ml/m2], P=0.017) and no improvement in diastolic function in HFpEF (E/e’ at baseline: 9.7 [Q25: 7.8; Q75: 12.1] vs 12-month follow-up: 10.2 [Q25: 8.4; Q75: 11.8], P=0.874), in particular in patients with HFpEF and AF-recurrence. Quality of life improved in patients without HFpEF in both physical and mental summary scales, however, no beneficial effect was seen in HFpEF. Conclusion Patients with HFpEF constitute a distinct subgroup with an elevated risk for arrhythmia recurrence after cryoablation of AF. Functional hallmarks and heart-failure related symptoms of HFpEF persisted in our cohort, irrespective of rhythm-status at follow-up. Future research is needed to optimize tailored treatment strategies in HFpEF.

Cystatin C Predicts Adverse Outcomes In Heart Failure With Preserved Ejection Fraction

<h3>Background</h3> Serum creatinine (Cr) is used to estimate glomerular filtration rate (GFR). Cr levels vary with lean muscle mass and diet, confounding measurement of renal function. Cystatin C (CysC) is an alternative marker used to estimate GFR which is not subject to these sources of variability. In conditions where frailty and low muscle mass are common, such as heart failure with preserved ejection fraction (HFpEF), Cr may overestimate GFR, leading to under detection of renal disease. Chronic kidney disease (CKD) is a common co-morbidity in HFpEF and portends worse prognosis; however, there are currently minimal data on CysC in HFpEF. <h3>Methods</h3> Patients enrolled in the Johns Hopkins HFpEF Program from July 2014 to March 2020 were included for study. Patients underwent a comprehensive clinical evaluation and echocardiography. Estimated GFR was calculated using the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equations for Cr (CKD-EPIcr) and CysC (CKD-EPIcys). Distributions of GFR were compared with a Wilcoxon matched-pairs test. Trends in clinical and echocardiographic variables with CysC were assessed using multivariate linear regression. Cox proportional hazard models examined the association of CysC with the combined outcome of heart failure hospitalization and all-cause mortality. <h3>Results</h3> The study cohort included 190 patients. The average age was 64 years; 65% of patients were female and 59% were black. Median follow-up was 28 months. The median estimated GFR by CKD-EPIcr and CKD-EPIcys were 54.0 mL/min/1.73m² and 46.7 mL/min/1.73m², respectively (<b>Figure A and C;</b> z=3.81, p<0.001). As compared to CKD-EPIcr, CKD-EPIcys reclassified 74 patients (39% of cohort) to a higher stage of CKD (<b>Figure B and D</b>). CysC was significantly associated with greater left ventricular mass index (β =7.16 [0.23-14.01], p=0.043) and E/e' ratio (β=2.28 [0.33-4.22], p=0.022) after adjustment for GFR by CKD-EPIcr. CysC was predictive of the combined outcome in the univariate model and after adjustment for relevant medical comorbidities and estimated GFR by CKD-EPIcr (<b>Figure</b>). <h3>Conclusion</h3> In this prospective study, CysC estimated a lower median GFR in HFpEF patients as compared to Cr. CysC was predictive of worse diastolic function and adverse outcomes, even after accounting for GFR by CKD-EPIcr and relevant comorbidities. These results suggest CysC provides clinical and prognostic information beyond traditional Cr-based assessment of renal function in HFpEF. Further investigation of the use of CysC in clinical practice is warranted.

Ivabradine Ameliorates Cardiac Function in Heart Failure with Preserved and Reduced Ejection Fraction via Upregulation of miR-133a.

Heart failure (HF) is a clinical syndrome caused by impairment of ventricular filling, ejection of blood, or both and is categorized as HF with reduced ejection fraction (HFrEF) or HF with preserved ejection fraction (HFpEF) based on left ventricular function. Cardiac fibrosis contributes to left ventricular dysfunction and leads to the development of HF. Ivabradine, an If current selective specific inhibitor, has been shown to improve the prognosis of patients with HF. However, the effects of ivabradine on cardiac function and fibrosis in HFpEF and HFrEF and the underlying mechanism remain unclear. In the present study, we utilized mouse models to mimic HFpEF and HFrEF and evaluated the therapeutic effects of ivabradine. By treating mice with different doses (10 mg/kg/d and 20 mg/kg/d) of ivabradine for 4 or 8 weeks, we found that a high dose of ivabradine improved cardiac diastolic function in HFpEF mice and ameliorated cardiac diastolic and systolic function and ventricular tachycardia incidence in HFrEF mice. Moreover, ivabradine significantly reduced the activation of cardiac fibroblasts and myocardial fibrosis in mice. Mechanistically, microRNA-133a, which was upregulated by ivabradine, targeted connective tissue growth factor and collagen 1 in cardiac fibroblasts and might contribute to the protective role of ivabradine. Together, our work utilized mouse models to study HFpEF and HFrEF, demonstrated the protective role of ivabradine in HFpEF and HFrEF, and elucidated the potential underlying mechanism, which provides an effective strategy for related diseases.

Mathematical Modeling of Delayed Relaxation in Heart Failure with Preserved Ejection Fraction (HF‐pEF)‐ an Effect or a Cause?

The pathophysiological mechanisms underlying heart failure with preserved ejection fraction (HF-pEF) remain incompletely understood. One proposed hypothesis is that prolonged pressure decay of left ventricle during isovolumic relaxation, due to loss of enhancement of the ventricle, may lead to elevation of left ventricular end-diastolic pressure (LVEDP) and a reduction in stroke volume in HF-pEF subjects. However, while impaired relaxation is commonly observed in HF-pEF, it is unclear whether it is a contributing cause of HF-pEF or perhaps a consequence of other impairments. We sought to evaluate whether direct impairment in cardiac relaxation can contribute to a state of HF-pEF using a mathematical modeling approach. We utilized an existing mathematical model of cardio-renal hemodynamics in which a rectified sinusoidal twitch shape function drives left ventricular contraction and relaxation. To evaluate the effect of impaired relaxation, we altered the falling side of the twitch shape function so that isovolumetric relaxation time (IVRT) increased from 100 ms to 150 ms. In addition, we also evaluated the effect of delayed relaxation coupled with other ventricular changes associated with HF-pEF, including increased ventricular stiffness. Our simulations showed that when IVRT was increased, left ventricular pressure (LV pressure) fell more slowly during diastole. However, there was minimal effect on LVEDP. Pulmonary venous pressure also fell more slowly during diastole, and the peak pulmonary venous pressure during systole was slightly increased. Ejection fraction (EF) was minimally changed. The simulated presence of hypertension, hypertrophy, and/or increased cardiac stiffness did not impact the effect of slowed relaxation. While experimental validation is needed, our simulations suggest that impaired relaxation alone may not be a primary cause for increased preload experienced by many HF-pEF patients. It is possible that delayed relaxation is a consequence of other contributing mechanisms (e.g. impaired bioenergetics, calcium handling, or fibrosis which may impact ventricle stiffness and contractility) rather than a direct cause for elevated LV preload. While impaired relaxation had minimal effect on LVEDP, the small increases in peak pulmonary venous pressure and slower fall during diastole could impact pulmonary and atrial function in HF-pEF.

Impact of Chronic Obstructive Pulmonary Disease in Heart Failure With Preserved Ejection Fraction

COPD often coexists with HFpEF, but its impact on cardiovascular structure and function in HFpEF is incompletely understood. We aimed to compare cardiovascular phenotypes in patients with Chronic Obstructive Pulmonary Disease (COPD), Heart Failure with Preserved Ejection Fraction (HFpEF), or both. We studied 159 subjects with COPD alone (n = 48), HFpEF alone (n = 79) and HFpEF + COPD (n = 32). We used MRI and arterial tonometry to assess cardiac structure and function, thoracic aortic stiffness, and measures of body composition. Relative to participants with COPD only, those with HFpEF with or without COPD exhibited a greater prevalence of female sex and obesity, whereas those with HFpEF + COPD were more often African-American. Compared to the other groups, participants with HFpEF and COPD demonstrated a more concentric LV geometry (LV wall-cavity ratio 1.2, 95%CI: 1.1-1.3; p = 0.003), a greater LV mass (67.4, 95%CI: 60.7-74.2; p = 0.03, and LV extracellular volume (49.4, 95%CI: 40.9-57.9; p = 0.002). Patients with comorbid HFpEF + COPD also exhibited greater thoracic aortic stiffness assessed by pulse-wave velocity (11.3, 95% CI: 8.7-14.0 m/s; p = 0.004) and pulsatile load imposed by the ascending aorta as measured by aortic characteristic impedance (139 dsc; 95%CI=111-166; p = 0.005). Participants with HFpEF, with or without COPD, exhibited greater abdominal and pericardial fat, without difference in thoracic skeletal muscle size. In conclusion, individuals with co-morbid HFpEF and COPD have a greater degree of systemic large artery stiffening, LV remodeling, and LV fibrosis than those with either condition alone.

TrimetaziDine as aPerformance-enhancING drug in heart failure with preserved ejection fraction (DoPING-HFpEF): rationale and design of aplacebo-controlled cross-over intervention study.

BackgroundCurrently, no specific treatment exists for heart failure with preserved ejection fraction (HFpEF). Left ventricular (LV) relaxation during diastole is a highly energy-demanding process, while energy homeostasis is known to be compromised in HFpEF. We hypothesise that trimetazidine – a fatty acid β‑oxidation inhibitor – improves LV diastolic function in HFpEF, by altering myocardial substrate use and improving the myocardial energy status.ObjectivesTo assess whether trimetazidine improves LV diastolic function by improving myocardial energy metabolism in HFpEF.MethodsThe DoPING-HFpEF trial is a randomised, double-blind, placebo-controlled cross-over intervention trial comparing the efficacy of trimetazidine and placebo in 25 patients with stable HFpEF. The main inclusion criteria are: New York Heart Association functional class II to IV, LV ejection fraction ≥50%, and evidence of LV diastolic dysfunction. Patients are treated with one 20-mg trimetazidine tablet or placebo thrice daily (twice daily in the case of moderate renal dysfunction) for two periods of 3 months separated by a 2-week washout period. The primary endpoint is the change in pulmonary capillary wedge pressure during different intensities of exercise measured by right heart catheterisation. Our key secondary endpoint is the myocardial phosphocreatine (PCr)/ATP ratio measured by phosphorus-31 magnetic resonance spectroscopy and its relation to the primary endpoint. Exploratory endpoints are 6‑min walk distance, N-terminal pro-brain natriuretic peptide levels, and quality of life.ConclusionThe DoPING-HFpEF is a phase-II trial that evaluates the effect of trimetazidine, a metabolic modulator, on diastolic function and myocardial energy status in HFpEF. [EU Clinical Trial Register: 2018-002170-52; NTR registration: NL7830]

Endothelium-dependent and independent coronary microvascular dysfunction in patients with heart failure with preserved ejection fraction.

Coronary microvascular inflammation is hypothesized to play a fundamental role in the pathophysiology of heart failure with preserved ejection fraction (HFpEF). No study has directly evaluated both endothelium-dependent and independent coronary microvascular function in HFpEF. Consecutive patients with HFpEF undergoing invasive coronary physiologic testing and echocardiography were examined. Endothelial function was quantified by the increase in coronary blood flow in response to intracoronary infusion of acetylcholine (10-6 -10-4 mol/L) using a Doppler flow wire with quantitative angiography. Endothelium-independent coronary microvascular function was assessed by the hyperaemic increase in coronary flow reserve in response to adenosine infusion. Among 162 HFpEF patients (67% women), coronary microvascular function was abnormal in 117 (72%). Isolated endothelium-dependent microvascular dysfunction was present in 47 patients (29%), isolated endothelium-independent microvascular dysfunction in 53 patients (33%), and combined microvascular dysfunction in 17 patients (10%). The presence of coronary microvascular dysfunction was not identifiable from medical co-morbidities or other clinical characteristics. As compared to patients with normal endothelium-independent function, HFpEF patients with endothelium-independent coronary microvascular dysfunction displayed lower diastolic relaxation velocities (7.0± 1.8 vs. 8.4± 2.9cm/s, P= 0.002) and higher estimated filling pressures (E/e' 13.1± 4.1 vs. 9.6± 3.4, P< 0.001). There were no relationships between left ventricular structure, function, or haemodynamics and endothelium-dependent coronary vasodilatation. Endothelium-independent microvascular dysfunction was associated with increased mortality. Coronary microvascular dysfunction is common in patients with HFpEF and is caused equally by endothelium-dependent and independent mechanisms, but the presence of microvascular dysfunction cannot be identified from clinical markers and co-morbidities alone. Patients with HFpEF and endothelium-independent microvascular dysfunction display worse diastolic dysfunction and outcomes.

Adenosine Kinase Inhibition Augments Conducted Vasodilation and Prevents Left Ventricle Diastolic Dysfunction in Heart Failure With Preserved Ejection Fraction.

Heart failure with preserved ejection fraction (HFpEF) is often manifested as impaired cardiovascular reserve. We sought to determine if conducted vasodilation, which coordinates microvascular resistance longitudinally to match tissue metabolic demand, becomes compromised in HFpEF. We hypothesized that the metabolic vasodilator adenosine facilitates and that inhibition of ADK (adenosine kinase) augments conducted vasodilation for a more efficient myocardial perfusion and improved left ventricle (LV) diastolic function in HFpEF. We assessed conducted vasodilation in obese ZSF1 rats that develop LV diastolic dysfunction and is used to model human HFpEF. Additionally, conducted vasodilation was measured in arterioles isolated from the right atrial appendages of patients with HFpEF. We found a markedly reduced conducted vasodilation both in obese ZSF1 rats and in patients with HFpEF. Impaired conducted vasodilation was accompanied by increased vascular ADK expression. Isolated rat and human arterioles incubated with adenosine (10 nmol/L) or ADK inhibitor ABT-702 (0.1 µmol/L) both displayed augmented conducted vasodilation. Treatment of obese ZSF1 rats with ABT-702 (1.5 mg/kg, IP for 8 weeks) prevented LV diastolic dysfunction, and in a crossover design augmented conducted vasodilation and improved LV diastolic function. ABT-702 treated obese ZSF1 rats exhibited reduced expression of myocardial carbonic anhydrase 9 and collagen, surrogate markers of myocardial hypoxia. Upregulation of vascular ADK mitigates adenosine-facilitated conducted vasodilation in obese ZSF1 rats and in patients with HFpEF. We propose that pharmacological inhibition of ADK could be beneficial for therapeutic augmentation of conducted vasodilation, thereby improving tissue perfusion and LV diastolic function in HFpEF.

The adenosine kinase inhibitor ABT‐702 improves coronary vasodilator and left ventricle diastolic dysfunction in obese ZSF1 rats

Coronary microvascular dysfunction contributes to the development of heart failure with preserved ejection fraction (HFpEF) for which no effective therapies are currently available. We tested the hypothesis that pharmacological inhibition of adenosine kinase (ADK), the major adenosine metabolizing enzyme, augments coronary artery vasodilation and improves left ventricle (LV) diastolic function in HFpEF. We employed the obese ZSF1 rat model of HFpEF. We assessed agonist‐induced coronary artery dilation and performed echocardiographic assessment of LV diastolic function before and after treatment with selective ADK inhibitor, ABT‐702 (1.5 mg/kg, i.p. for 8‐week). We found that obese ZSF1 rats exhibited impaired acetylcholine (ACh)‐induced coronary artery dilation and LV diastolic dysfunction, as indicated by reduced E/A ratio and increased deceleration time of mitral flow velocity. Treatment with ABT‐702 augmented ACh‐induced coronary vasodilation in obese ZSF1 rats, which was not affected by inhibition of NO synthase, with N(ω)‐nitro‐L‐arginine methyl ester (L‐NAME). ABT‐702 treatment also improved LV diastolic function in obese ZSF‐1 rats, but had no effect on lean controls. Collectively, these data suggest that a pharmacological inhibition of ADK provides beneficial effects on both coronary vasodilator and LV diastolic function in HFpEF.Support or Funding InformationAmerican Heart Association 17GRNT33680171, NIH F31 HL142183‐01 and NIH R01AG054651This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.

Exercise Training Improved Longitudinal Intrinsic Left Ventricle Function in Heart Failure with Preserved Ejection Fraction.

Exercise improves morbidity, fatality rate, and quality of life in heart failure with low ejection fraction, but fewer data available in heart failure with preserved ejection fraction (HFPEF). The purpose of this study is to test the hypothesis that exercise training might improve the longitudinal intrinsic left ventricular (LV) function in HFPEF patients. This quasi-experimental study had recruited 30 patients with HFPEF. Exercise training program had been performed for a month with a total of 20 times exercise sessions and evaluated every 2 weeks. Echocardiography was performed before sessions, second week and fourth week of exercise training. Six-minute walk tests (6MWTs) and quality-of-life variables using Minnesota living with HF scoring and the 5-item World Health Organization Well-Being Index scoring were measured before and after exercise as well. Left ventricular filling pressure, represented by the ratio of early diastolic mitral flow velocity/early diastolic annular velocity and left atrial volume index, improved during exercise. The longitudinal intrinsic LV function, represented by four-chamber longitudinal strain, augmented during exercise ( p < 0.001). Aerobic capacity, measured by 6MWT, increased significantly ( p = 0.001). Quality of life improved significantly during exercise ( p < 0.001). Exercise training was suggested to improve the longitudinal intrinsic LV function and quality of life in HFPEF. Clinical Trial Registration: ACTRN12614001042639.