Clinical and treatment perspectives for heart failure with preserved ejection fraction

2016 ◽  
Author(s):  
◽  
Jessica Ann Hiemstra
Keyword(s):  
Heart Failure ◽  
Ejection Fraction ◽  
Contractile Function ◽  
Pressure Overload ◽  
The United States ◽  
Calcium Handling ◽  
Swine Model ◽  
Preserved Ejection Fraction ◽  
Novel Treatment ◽  
Hormone Status

[ACCESS RESTRICTED TO THE UNIVERSITY OF MISSOURI AT AUTHOR'S REQUEST.] Heart failure with preserved ejection fraction (HFpEF) currently represents half of the ~6 million heart failure patients in the United States, and is increasing at a rate of ~1% per year. Conventional treatments commonly used for heart failure with reduced ejection fraction (HFrEF) patients have proven ineffective for HFpEF, highlighting the critical need for development of novel treatment options for this HF sub-population. Further, population studies have repeatedly found HFpEF to disproportionally effect women 2:1 over the age of sixty-five compared to men. Therefore the purpose of my dissertation was two-fold: (1) To examine novel treatment perspectives testing pharmacological interventions for treatment of heart failure with preserved ejection fraction; and (2) A clinical perspective examining mechanisms responsible for the increased prevalence of HFpEF in women. A novel miniature swine model displaying key characteristics of HFpEF was used to assess both of these aims. Aim one evaluated the efficacy of three different pharmacological treatments. The first drug cyclospsorine, aimed at inhibiting cylophilin D and preventing mitochondria permeability transition and the second drug tadalafil, aimed at inhibiting phosphodiesterase 5 and preserving cyclic guanine monophosphate (cGMP) both were ineffective in treating HFpEF. However, the third drug tested, saxagliptin; a dipeptidyl-peptidase 4 inhibitor, aimed at preserving cGMP, improved both cellular and functional cardiovascular outcomes in our mini-swine HFpEF model. This study highlighted the potential benefit of saxagliptin's for treatment of HFpEF, which currently lacks any viable therapeutic options. The purpose of the second aim was to evaluate HFpEF from a clinical prospective, in effort to uncover what mechanisms actually lead to the development of HFpEF. We hypothesized female sex hormones would protect against pressure overload-induced cardiomyocyte calcium handling and contractile abnormalities, thus preserving overall cardiomyocyte function. In contrast to our hypothesis, our results found regardless of hormone status, compromised cardiomyocyte excitation-contraction coupling (ECC) was evident by impaired calcium release and reuptake in parallel with diminished contractile function. Cardiomyocyte dysfunction was associated with distinct alterations to the protein levels and phosphorylation state of important calcium handling and contractile proteins. Our results show impaired cardiomyocyte function contributes to pressure-overload HF regardless of hormone status in a translational model with potential relevance to human HFpEF. While important advances have been made in our understanding of the haemodynamic and cellular pathophysiology HFpEF as well as contributing mechanisms associated with the disease, further research is urgently required to determine how to better target these abnormalities to reduce the substantial burden of morbidity and mortality in this form of HF, which is reaching epidemic proportions.

Abstract 87: Alterations to Cardiac Mechanics Do Not Preserve Normal Cardiac Function in a Novel Ossabaw Swine Model of Heart Failure with Preserved Ejection Fraction

2017 ◽  
Vol 121 (suppl_1) ◽  
Author(s):  
Jenna C Edwards ◽  
Madeleine Dionne ◽  
T. D Olver ◽  
Jan R Ivey ◽  
Pamela K Thorne ◽  
...  
Keyword(s):  
Heart Failure ◽  
Ejection Fraction ◽  
Cardiac Function ◽  
Strain Rate ◽  
Pressure Overload ◽  
Left Ventricular ◽  
Volume Index ◽  
Lv Function ◽  
Swine Model ◽  
Preserved Ejection Fraction

Introduction: Heart failure with preserved ejection fraction (HFpEF) is clinically characterized by an increased incidence in females and many comorbidities including type 2 diabetes (T2D) and obesity. Animal models accurately representing clinical HFpEF are lacking; thus, the purpose of this study was to examine left ventricular (LV) mechanics in a novel Ossabaw swine model of chronic pressure-overload (aortic-banding; AB) and T2D (Western diet; WD) using two dimensional speckle tracking echocardiography (2D-STE). We hypothesized that global LV strain would be decreased primarily in the longitudinal direction in WD-AB animals. Methods: Female Ossabaws were randomly divided into 2 groups: CON (n=5) and WD-AB (n=5). LV function and strain were measured at 1 year of age after 6 mo. of AB and 9 mo. of WD via pressure-volume relations and 2D-STE. Significance was set at P < 0.05 using t-test vs. CON. Results: In the WD-AB group, ejection fraction (EF%) and end diastolic volume were normal (>50%), and observed in parallel with increased LV weight, lung weight, and LV diastolic wall thickness (i.e. concentric hypertrophy). WD-AB group had increased HOMA-IR and body surface area, two common features in T2D. In WD-AB animals, although global longitudinal systolic strain rate and end systolic displacement were increased, stroke volume index was decreased. Early diastolic rotation rate was decreased, while global longitudinal late diastolic strain rate was increased in the WD-AB group. These changes, considered in parallel with an increased end diastolic pressure-volume relationship in WD-AB animals, are consistent with diastolic dysfunction. In contrast, longitudinal, radial, and circumferential early diastolic strain rates increased in the WD-AB group. Conclusion: Contrary to our hypothesis, LV longitudinal strain was increased during both systole and diastole, and observed in parallel with decreased early diastolic untwisting in WD-AB animals. Our results suggest alterations to LV mechanics do not preserve normal systolic and diastolic cardiac function, despite normal resting EF%, in this novel translational model of pressure-overload HF with potential relevance to human HFpEF including associated clinical comorbidities (sex, obesity, and T2D).

Abstract 17264: Predictive Value of Plasma Ceramide C24:0/C16:0 Ratio in Patients With Heart Failure With Preserved Ejection Fraction in the TOPCAT Study

Circulation ◽  
2020 ◽  
Vol 142 (Suppl_3) ◽  
Author(s):  
Linda R Peterson ◽  
Xuntian Jiang ◽  
Hannah Campbell ◽  
Sharon Cresci
Keyword(s):  
Heart Failure ◽  
Ejection Fraction ◽  
Cell Structure ◽  
Univariate Analysis ◽  
The United States ◽  
Preserved Ejection Fraction ◽  
Bioactive Lipids ◽  
Confidence Bounds ◽  
Liquid Chromatograph ◽  
Reduced Ejection Fraction

Introduction: Heart failure (HF) with preserved ejection fraction (HFpEF) is an “emerging epidemic” as nearly half of all patients with HF have HFpEF. However, most HF biomarkers, including plasma brain natriuretic peptide, have less robust utility in HFpEF than in those with HF with reduced ejection fraction. In order to better understand HFpEF and its associated morbidity and mortality, it is vital to identify robust biomarkers that predict outcomes in patients who suffer from HFpEF. Ceramides are bioactive lipids involved in signaling, cell death programs, mitochondrial function, and cell structure. Our group showed that the ratio of specific plasma ceramides (C24:0/C16:0) is inversely related to primary incident HF and to death in large community-based cohorts. Whether plasma C24:0/C16:0 has utility in prediction of secondary events/outcomes in patients with HFpEF is unclear. Hypothesis: We hypothesized that there is an association between plasma C24:0/16:0 ratio and outcomes in HFpEF. Methods: Data and plasma was obtained from 477 subjects in the TOPCAT study via the BioLINCC biobank. Plasma ceramides C24:0 and C16:0 were measured using targeted liquid chromatograph/tandem mass spectrometry. Results: Inclusion criteria for TOPCAT was age >50 years, ejection fraction of 45% or higher and diagnosis of HF. Subjects were randomized to treatment with spironolactone or placebo. In the 477 subjects who provided samples to BioLINCC, the mean age was 69.3 years; 47% were women; 43.9% were from the United States; 94.4% had hypertension; 31 were African American. Mean follow-up was 3.3 years. Univariate analysis showed that time to hospitalization for heart failure was inversely related to plasma C24:0/C16:0 concentration (Hazard ratio 0.901 [Confidence bounds 0.82,0.99], P = 0.026. Conclusions: Plasma ceramide (C24:0/C16:0) is inversely related to time to hospitalization in patients with HFpEF. Plasma C24:0/C16:0 may be a useful new biomarker in HFpEF and may point to novel, targetable pathophysiologic pathways .

Abstract 284: Length Of Stay In Index Hospitalization Of Decompensated Heart Failure With Preserved Ejection Fraction As A Factor For 30-day Readmission And 1-year Mortality

2020 ◽  
Vol 13 (Suppl_1) ◽  
Author(s):  
Sunil Saith ◽  
Ciril Khorolsky ◽  
Anuragh Trikha ◽  
Tamta Chkhikvadze ◽  
Jung-eun Ha ◽  
...  
Keyword(s):  
Heart Failure ◽  
Length Of Stay ◽  
Ejection Fraction ◽  
Primary Care Physicians ◽  
The United States ◽  
P Value ◽  
Preserved Ejection Fraction ◽  
Index Hospitalization ◽  
One Year

Introduction: Heart Failure is one of the leading causes of readmission in the United States. Heart Failure with preserved Ejection Fraction (HFpEF) accounts for a growing proportion of heart failure hospitalizations and accounts for approximately half of hospitalizations today. Unlike Heart Failure with reduced Ejection Fraction (HFrEF), there are no consensus-driven guidelines for the management of HFpEF. Methods: We collected demographic data, co-morbidities, laboratory and echocardiographic data on patients hospitalized with HFpEF throughout our health care system between August 2016 to August 2017. We assessed length of stay (LOS), whether the patient was re-admitted for any cause within 30 days and whether the patient died within 1 year of index hospitalization. We performed a Wilcoxon rank-sum test comparing patients who were both readmitted within 30 days for any reason and died within 1 year, against patients who were readmitted but were verified alive at one-year follow-up. Results: There were 366 patients hospitalized for HFpEF during the study period. Overall 30-day readmission rate was 24.3%, with a one-year mortality of 19.9%. One-year outcomes was verifiable for 359 patients. There were 27 patients who were readmitted within 30 days and died within one year of follow-up. Median LOS was significantly greater in patients during index hospitalization who died within 1 year of follow-up (Median LOS: 8 days, IQR 5-10 days), compared to patients who were readmitted within 30 days, but were alive at 1-year follow-up (Median LOS: 5 days, IQR: 3-8 days; p-value = 0.001). Conclusions: Among patients who were re-hospitalized within 30 days of an index hospitalization for HFpEF, LOS was significantly greater than patients who died within one year, compared to patients who remained alive at one-year follow-up. This may help identify a high-risk subset on index hospitalization and assist care transition teams and primary care physicians at follow-up in regarding discussions on goals of care and life sustaining treatments.

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

2015 ◽  
Vol 119 (10) ◽  
pp. 1233-1242 ◽  
Author(s):  
Frank R. Heinzel ◽  
Felix Hohendanner ◽  
Ge Jin ◽  
Simon Sedej ◽  
Frank Edelmann
Keyword(s):  
Heart Failure ◽  
Ejection Fraction ◽  
Diastolic Dysfunction ◽  
Clinical Evidence ◽  
Mechanical Load ◽  
Contractile Function ◽  
Surrogate Marker ◽  
Left Ventricular ◽  
Structural Abnormality ◽  
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 Ca2+ 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.

scholarly journals Chronic interval exercise training prevents BKCa channel-mediated coronary vascular dysfunction in aortic-banded miniswine

2018 ◽  
Vol 125 (1) ◽  
pp. 86-96 ◽  
Author(s):  
T. Dylan Olver ◽  
Jenna C. Edwards ◽  
Brian S. Ferguson ◽  
Jessica A. Hiemstra ◽  
Pamela K. Thorne ◽  
...  
Keyword(s):  
Heart Failure ◽  
Exercise Training ◽  
Ejection Fraction ◽  
Vascular Dysfunction ◽  
Pressure Overload ◽  
Left Ventricular ◽  
Preserved Ejection Fraction ◽  
Interval Exercise

Conventional treatments have failed to improve the prognosis of heart failure with preserved ejection fraction (HFpEF) patients. Thus, the purpose of this study was to determine the therapeutic efficacy of chronic interval exercise training (IT) on large-conductance Ca2+-activated K+ (BKCa) channel-mediated coronary vascular function in heart failure. We hypothesized that chronic interval exercise training would attenuate pressure overload-induced impairments to coronary BKCa channel-mediated function. A translational large-animal model with cardiac features of HFpEF was used to test this hypothesis. Specifically, male Yucatan miniswine were divided into three groups ( n = 7/group): control (CON), aortic banded (AB)-heart failure (HF), and AB-interval trained (HF-IT). Coronary blood flow, vascular conductance, and vasodilatory capacity were measured after administration of the BKCa channel agonist NS-1619 both in vivo and in vitro in the left anterior descending coronary artery and isolated coronary arterioles, respectively. Skeletal muscle citrate synthase activity was decreased and left ventricular brain natriuretic peptide levels increased in HF vs. CON and HF-IT animals. A parallel decrease in NS-1619-dependent coronary vasodilatory reserve in vivo and isolated coronary arteriole vasodilatory responsiveness in vitro were observed in HF animals compared with CON, which was prevented in the HF-IT group. Although exercise training prevented BKCa channel-mediated coronary vascular dysfunction, it did not change BKCa channel α-subunit mRNA, protein, or cellular location (i.e., membrane vs. cytoplasm). In conclusion, these results demonstrate the viability of chronic interval exercise training as a therapy for central and peripheral adaptations of experimental heart failure, including BKCa channel-mediated coronary vascular dysfunction. NEW & NOTEWORTHY Conventional treatments have failed to improve the prognosis of heart failure with preserved ejection fraction (HFpEF) patients. Our findings show that chronic interval exercise training can prevent BKCa channel-mediated coronary vascular dysfunction in a translational swine model of chronic pressure overload-induced heart failure with relevance to human HFpEF.

scholarly journals MO062CHRONIC KIDNEY DISEASE, INFLAMMATION, AND HEART FAILURE WITH PRESERVED EJECTION FRACTION: A RENAL-CARDIO AXIS?

2020 ◽  
Vol 35 (Supplement_3) ◽  
Author(s):  
Alejandro Chade ◽  
Maxx Williams ◽  
Jason Engel ◽  
Gene Bidwell
Keyword(s):  
Heart Failure ◽  
Cardiovascular Risk ◽  
Kidney Disease ◽  
Ejection Fraction ◽  
Diastolic Dysfunction ◽  
Left Ventricular ◽  
Swine Model ◽  
Preserved Ejection Fraction ◽  
Renal Inflammation ◽  
Tnf Α

Abstract Background and Aims Inflammation contributes to progressive renal dysfunction and increases cardiovascular mortality of patients with chronic kidney disease (CKD). The association of CKD and heart failure with preserved ejection fraction (HFpEF) is observed in up to 50%, suggesting the possibility of a shared pathophysiology. CKD and HFpEF are commonly associated with inflammation. Using a novel swine model of CKD and HFpEF, we propose that a renal-cardio inflammatory axis drives diastolic dysfunction and HFpEF in CKD and that targeting renal inflammation will improve cardiac health and reduce cardiovascular risk. Methods We developed a biopolymer-fused peptide of nuclear-factor kappa (NFk)B (ELP-p50i) that we show it blocks its activity in vitro and in vivo. NFkB is a key pro-inflammatory transcription factor that is upregulated in CKD. To test our hypothesis, we induced CKD in 10 pigs via bilateral renovascular disease and dyslipidemia. Pigs were observed for 6 weeks, renal hemodynamics quantified (multi-detector CT), then randomized to single intra-renal ELP-p50i or placebo (n=5 each), and studies repeated 8 weeks later accompanied by echocardiographic assessment. Blood pressure was continuously measured (telemetry). Blood was collected to measure circulating TNF-α and biomarkers of HF (ANP, BNP). Furthermore, kidneys and hearts were used to quantify expression of factors involved in NFkB signaling. Results CKD led to a significant loss of renal function, accompanied by left ventricular hypertrophy and diastolic dysfunction with pEF, increased renal mRNA expression of TNF-α and canonical and non-canonical mediators of NFkB signaling, and elevated systemic TNF-α, ANP, and BNP, indicating renal and cardiac dysfunction. Most of these changes were improved after intra-renal ELP-p50i, although cardiac inflammatory signaling was unchanged (Figure) suggesting the kidney as a source of inflammation that can target the heart in CKD. Conclusion We show that a renal anti-inflammatory strategy via targeted inhibition of renal NFkB improves renal and cardiac function in CKD, suggesting an inflammatory renal-cardio axis. The translational pathological features of CKD and HFpEF combined with the predictive power of the model may contribute to advance the field towards new treatments targeting renal inflammation to reduce cardiovascular risk in CKD.

scholarly journals Disturbed cardiac mitochondrial and cytosolic calcium handling in a metabolic risk‐related rat model of heart failure with preserved ejection fraction

2019 ◽  
Vol 228 (3) ◽  
Author(s):  
Daniela Miranda‐Silva ◽  
Rob C. I. Wüst ◽  
Glória Conceição ◽  
Patrícia Gonçalves‐Rodrigues ◽  
Nádia Gonçalves ◽  
...  
Keyword(s):  
Heart Failure ◽  
Ejection Fraction ◽  
Rat Model ◽  
Cytosolic Calcium ◽  
Calcium Handling ◽  
Metabolic Risk ◽  
Preserved Ejection Fraction

scholarly journals A Porcine Model of Heart Failure With Preserved Ejection Fraction Induced by Chronic Pressure Overload Characterized by Cardiac Fibrosis and Remodeling

2021 ◽  
Vol 8 ◽  
Author(s):  
Weijiang Tan ◽  
Xiang Li ◽  
Shuang Zheng ◽  
Xiaohui Li ◽  
Xiaoshen Zhang ◽  
...  
Keyword(s):  
Gene Expression ◽  
Heart Failure ◽  
Ejection Fraction ◽  
Cardiac Fibrosis ◽  
Pressure Overload ◽  
Left Ventricular ◽  
Left Ventricular Ejection ◽  
Pathological Examination ◽  
Type I ◽  
Preserved Ejection Fraction

Heart failure is induced by multiple pathological mechanisms, and current therapies are ineffective against heart failure with preserved ejection fraction (HFpEF). As there are limited animal models of HFpEF, its underlying mechanisms have not yet been elucidated. Here, we employed the descending aortic constriction (DAC) technique to induce chronic pressure overload in the left ventricles of Tibetan minipigs for 12 weeks. Cardiac function, pathological and cellular changes, fibrotic signaling activation, and gene expression profiles were explored. The left ventricles developed concentric hypertrophy from weeks 4 to 6 and transition to dilation starting in week 10. Notably, the left ventricular ejection fraction was maintained at &gt;50% in the DAC group during the 12-week period. Pathological examination, biochemical analyses, and gene profile analysis revealed evidence of inflammation, fibrosis, cell death, and myofilament dephosphorylation in the myocardium of HFpEF model animals, together with gene expression shifts promoting cardiac remodeling and downregulating metabolic pathways. Furthermore, we noted the activation of several signaling proteins that impact cardiac fibrosis and remodeling, including transforming growth factor-β/SMAD family members 2/3, type I/III/V collagens, phosphatidylinositol 3-kinase, extracellular signal-regulated kinase, matrix metalloproteinases 2 and 9, tissue inhibitor of metalloproteinases 1 and 2, interleukins 6 and 1β, and inhibitor of κBα/nuclear factor-κB. Our findings demonstrate that this chronic pressure overload-induced porcine HFpEF model is a powerful tool to elucidate the mechanisms of this disease and translate preclinical findings.

scholarly journals Left atrial pressure overload and prognosis in elderly patients with heart failure and preserved ejection fraction: a prospective multicenter observational study

BMJ Open ◽  
2021 ◽  
Vol 11 (9) ◽  
pp. e044605
Author(s):  
Shiro Hoshida ◽  
Koichi Tachibana ◽  
Yukinori Shinoda ◽  
Tomoko Minamisaka ◽  
Takahisa Yamada ◽  
...  
Keyword(s):  
Heart Failure ◽  
Ejection Fraction ◽  
Elderly Patients ◽  
Sinus Rhythm ◽  
Left Atrial ◽  
Pressure Overload ◽  
Volume Index ◽  
Preserved Ejection Fraction ◽  
Patients With Heart Failure ◽  
All Cause Mortality

ObjectivesThe severity of diastolic dysfunction is assessed using a combination of several indices of left atrial (LA) volume overload and LA pressure overload. We aimed to clarify which overload is more associated with the prognosis in patients with heart failure and preserved ejection fraction (HFpEF).SettingA prospective, multicenter observational registry of collaborating hospitals in Osaka, Japan.ParticipantsWe enrolled hospitalised patients with HFpEF showing sinus rhythm (men, 79; women, 113). Blood tests and transthoracic echocardiography were performed before discharge. The ratio of diastolic elastance (Ed) to arterial elastance (Ea) was used as a relative index of LA pressure overload.Primary outcome measuresAll-cause mortality and admission for heart failure were evaluated at >1 year after discharge.ResultsIn the multivariable Cox regression analysis, Ed/Ea, but not LA volume index, was significantly associated with all-cause mortality or admission for heart failure (HR 2.034, 95% CI 1.059 to 3.907, p=0.032), independent of age, sex, and the serum N-terminal pro-brain natriuretic peptide (NT-proBNP) level. In patients with a higher NT-proBNP level, the effect of higher Ed/Ea on prognosis was prominent (p=0.015).ConclusionsEd/Ea, an index of LA pressure overload, was significantly associated with the prognosis in elderly patients with HFpEF showing sinus rhythm.Trial registration numberUMIN000021831.

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