New insights into SERCA2a gene therapy in heart failure: pay attention to the negative effects of B-type natriuretic peptides

2018 ◽  
Vol 55 (5) ◽  
pp. 287-296 ◽  
Author(s):  
Yuting Zhai ◽  
Yuanyuan Luo ◽  
Pei Wu ◽  
Dongye Li
Keyword(s):  
Heart Failure ◽  
Gene Therapy ◽  
Gene Transfer ◽  
Ejection Fraction ◽  
Current Knowledge ◽  
Potential Interaction ◽  
Future Research ◽  
Therapeutic Effects ◽  
Reduced Ejection Fraction ◽  
Negative Results

Sarcoplasmic/endoplasmic reticulum calcium ATPase 2a (SERCA2a) is a target of interest in gene therapy for heart failure with reduced ejection fraction (HFrEF). However, the results of an important clinical study, the Calcium Upregulation by Percutaneous Administration of Gene Therapy in Cardiac Disease (CUPID) trial, were controversial. Promising results were observed in the CUPID 1 trial, but the results of the CUPID 2 trial were negative. The factors that caused the controversial results remain unclear. Importantly, enrolled patients were required to have a higher plasma level of B-type natriuretic peptide (BNP) in the CUPID 2 trial. Moreover, BNP was shown to inhibit SERCA2a expression. Therefore, it is possible that high BNP levels interact with treatment effects of SERCA2a gene transfer and accordingly lead to negative results of CUPID 2 trial. From this point of view, effects of SERCA2a gene therapy should be explored in heart failure with preserved ejection fraction, which is characterised by lower BNP levels compared with HFrEF. In this review, we summarise the current knowledge of SERCA2a gene therapy for heart failure, analyse potential interaction between BNP levels and therapeutic effects of SERCA2a gene transfer and provide directions for future research to solve the identified problems.

scholarly journals Targeting Endothelial Function to Treat Heart Failure with Preserved Ejection Fraction: The Promise of Exercise Training

2017 ◽  
Vol 2017 ◽  
pp. 1-17 ◽  
Author(s):  
Andreas B. Gevaert ◽  
Katrien Lemmens ◽  
Christiaan J. Vrints ◽  
Emeline M. Van Craenenbroeck
Keyword(s):  
Heart Failure ◽  
Endothelial Dysfunction ◽  
Exercise Training ◽  
Ejection Fraction ◽  
Current Knowledge ◽  
Beta Blockers ◽  
Preserved Ejection Fraction ◽  
Cellular Mechanisms ◽  
Converting Enzyme Inhibitors ◽  
Reduced Ejection Fraction

Although the burden of heart failure with preserved ejection fraction (HFpEF) is increasing, there is no therapy available that improves prognosis. Clinical trials using beta blockers and angiotensin converting enzyme inhibitors, cardiac-targeting drugs that reduce mortality in heart failure with reduced ejection fraction (HFrEF), have had disappointing results in HFpEF patients. A new “whole-systems” approach has been proposed for designing future HFpEF therapies, moving focus from the cardiomyocyte to the endothelium. Indeed, dysfunction of endothelial cells throughout the entire cardiovascular system is suggested as a central mechanism in HFpEF pathophysiology. The objective of this review is to provide an overview of current knowledge regarding endothelial dysfunction in HFpEF. We discuss the molecular and cellular mechanisms leading to endothelial dysfunction and the extent, presence, and prognostic importance of clinical endothelial dysfunction in different vascular beds. We also consider implications towards exercise training, a promising therapy targeting system-wide endothelial dysfunction in HFpEF.

scholarly journals Treatment of Heart Failure with Mid-Range Ejection Fraction: What Is the Evidence

2021 ◽  
Vol 10 (2) ◽  
pp. 203
Author(s):  
Eleni-Evangelia Koufou ◽  
Angelos Arfaras-Melainis ◽  
Sahil Rawal ◽  
Andreas P. Kalogeropoulos
Keyword(s):  
Heart Failure ◽  
Ejection Fraction ◽  
Current Knowledge ◽  
Systolic Function ◽  
Angiotensin Receptor Blockers ◽  
Systolic Dysfunction ◽  
Left Ventricular ◽  
Current Evidence ◽  
Converting Enzyme Inhibitors ◽  
Reduced Ejection Fraction

In this review, we briefly outline our current knowledge on the epidemiology, outcomes, and pathophysiology of heart failure (HF) with mid-range ejection fraction (HFmrEF), and discuss in more depth the evidence on current treatment options for this group of patients. In most studies, the clinical background of patients with HFmrEF is intermediate between that of patients with HF and reduced ejection fraction (HFrEF) and patients with HF and preserved ejection fraction (HFpEF) in terms of demographics and comorbid conditions. However, the current evidence, stemming from observational studies and post hoc analyses of randomized controlled trials, suggests that patients with HFmrEF benefit from medications that target the neurohormonal axes, a pathophysiological behavior that resembles that of HFrEF. Use of β-blockers, angiotensin-converting enzyme inhibitors, angiotensin receptor blockers, mineralocorticoid receptor antagonists, and sacubitril/valsartan is reasonable in patients with HFmrEF, whereas evidence is currently scarce for other therapies. In clinical practice, patients with HFmrEF are treated more like HFrEF patients, potentially because of history of systolic dysfunction that has partially recovered. Assessment of left ventricular systolic function with contemporary noninvasive modalities, e.g., echocardiographic strain imaging, is promising for the selection of patients with HFmrEF who will benefit from neurohormonal antagonists and other HFrEF-targeted therapies.

scholarly journals Where are we in 2021 with heart failure with reduced ejection fraction?—current outlook and expectations from new promising clinical trials

2021 ◽  
Author(s):  
Agnieszka Dębska-Kozłowska ◽  
Marcin Książczyk ◽  
Małgorzata Lelonek
Keyword(s):  
Heart Failure ◽  
Ejection Fraction ◽  
Enzyme Inhibitor ◽  
Current Knowledge ◽  
Angiotensin Receptor ◽  
Mortality And Morbidity ◽  
Reduced Ejection Fraction ◽  
Prospective Comparison ◽  
Patients With Heart Failure ◽  
Simple Rules

AbstractGuideline-directed optimal medical therapy is a well-established therapy in treating patients with heart failure with reduced ejection fraction (HFrEF). Despite clear recommendations, the prognosis in this group of patients is still poor with high mortality. After publishing results of the PARADIGM-HF trial (Prospective Comparison of ARNI—Angiotensin Receptor/Neprilysin Inhibitors—with ACEI—Angiotensin-Converting Enzyme Inhibitor—to Determine Impact on Global Mortality and Morbidity in Heart Failure) clinical investigators accelerated their research. Recently, many new trials have been designed to evaluate the efficacy and safety of promising management, taking into account heterogeneity of population with chronic HFrEF. Determining target doses still poses the biggest problem in standard pharmacotherapy. Implementation of new substances for the HFrEF therapy makes it possible to formulate simple rules of treatment—in most cases, administering a dose of drug in one tablet provides a faster therapeutic effect. The aim of this article is to summarize current knowledge on recently announced findings on novel molecules and to propose a new revolutionary and individualised approach to treatment of HFrEF patients.

scholarly journals Cholesterol-Lowering Gene Therapy Prevents Heart Failure with Preserved Ejection Fraction in Obese Type 2 Diabetic Mice

2019 ◽  
Vol 20 (9) ◽  
pp. 2222 ◽  
Author(s):  
Joseph Pierre Aboumsallem ◽  
Ilayaraja Muthuramu ◽  
Mudit Mishra ◽  
Bart De Geest
Keyword(s):  
Heart Failure ◽  
Gene Therapy ◽  
Gene Transfer ◽  
Ejection Fraction ◽  
Plasma Cholesterol ◽  
Preserved Ejection Fraction ◽  
Ldlr Gene ◽  
Lung Weight ◽  
Cholesterol Lowering

Hypercholesterolemia may be causally related to heart failure with preserved ejection fraction (HFpEF). We aimed to establish a HFpEF model associated with hypercholesterolemia and type 2 diabetes mellitus by feeding a high-sucrose/high-fat (HSHF) diet to C57BL/6J low-density lipoprotein receptor (LDLr)−/− mice. Secondly, we evaluated whether cholesterol-lowering adeno-associated viral serotype 8 (AAV8)-mediated LDLr gene transfer prevents HFpEF. AAV8-LDLr gene transfer strongly (p < 0.001) decreased plasma cholesterol in standard chow (SC) mice (66.8 ± 2.5 mg/dl versus 213 ± 12 mg/dl) and in HSHF mice (84.6 ± 4.4 mg/dl versus 464 ± 25 mg/dl). The HSHF diet induced cardiac hypertrophy and pathological remodeling, which were potently counteracted by AAV8-LDLr gene transfer. Wet lung weight was 19.0% (p < 0.001) higher in AAV8-null HSHF mice than in AAV8-null SC mice, whereas lung weight was normal in AAV8-LDLr HSHF mice. Pressure–volume loop analysis was consistent with HFpEF in AAV8-null HSHF mice and showed a completely normal cardiac function in AAV8-LDLr HSHF mice. Treadmill exercise testing demonstrated reduced exercise capacity in AAV8-null HSHF mice but a normal capacity in AAV8-LDLr HSHF mice. Reduced oxidative stress and decreased levels of tumor necrosis factor-α may mediate the beneficial effects of cholesterol lowering. In conclusion, AAV8-LDLr gene therapy prevents HFpEF.

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