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Emerging Novel Therapies for Heart Failure.

ABSTRACT: Heart function fails when the organ is unable to pump blood at a rate proportional to the body's need for oxygen or when this function leads to elevated cardiac chamber filling pressures (cardiogenic pulmonary edema). Despite our sophisticated knowledge of heart failure, even so-called ejection fraction-preserved heart failure has high rates of mortality and morbidity. So, novel therapies are sorely needed. This review discusses current standard therapies for heart failure and launches an exploration into emerging novel treatments on the heels of recently-approved sacubitril and ivbradine. For example, Vasoactive Intestinal Peptide (VIP) is protective of the heart, so in the absence of VIP, VIP knockout mice have dysregulation in key heart failure genes: 1) Force Generation and Propagation; 2) Energy Production and Regulation; 3) Ca(+2) Cycling; 4) Transcriptional Regulators. VIP administration leads to coronary dilation in human subjects. In heart failure patients, VIP levels are elevated as a plausible endogenous protective effect. With the development of elastin polymers to stabilize VIP and prevent its degradation, VIP may therefore have a chance to satisfy the unmet need as a potential treatment for acute heart failure.

SUBMITTER: Szema AM

PROVIDER: S-EPMC4603524 | biostudies-literature | 2015

REPOSITORIES: biostudies-literature

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Emerging Novel Therapies for Heart Failure.

Szema Anthony M AM Dang Sophia S Li Jonathan C JC

Clinical Medicine Insights. Cardiology 20151011 Suppl 2

Heart function fails when the organ is unable to pump blood at a rate proportional to the body's need for oxygen or when this function leads to elevated cardiac chamber filling pressures (cardiogenic pulmonary edema). Despite our sophisticated knowledge of heart failure, even so-called ejection fraction-preserved heart failure has high rates of mortality and morbidity. So, novel therapies are sorely needed. This review discusses current standard therapies for heart failure and launches an explor ...[more]

PMID: 26512208

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Project description:Therapeutic options for right ventricular (RV) dysfunction and failure are strongly limited. Right heart failure (RHF) has been mostly addressed in the context of pulmonary arterial hypertension (PAH), where it is not possible to discern pulmonary vascular- and RV-directed effects of therapeutic approaches. In part, opposing pathomechanisms in RV and pulmonary vasculature, i.e., regarding apoptosis, angiogenesis and proliferation, complicate addressing RHF in PAH. Therapy effective for left heart failure is not applicable to RHF, e.g., inhibition of adrenoceptor signaling and of the renin-angiotensin system had no or only limited success. A number of experimental studies employing animal models for PAH or RV dysfunction or failure have identified beneficial effects of novel pharmacological agents, with most promising results obtained with modulators of metabolism and reactive oxygen species or inflammation, respectively. In addition, established PAH agents, in particular phosphodiesterase-5 inhibitors and soluble guanylate cyclase stimulators, may directly address RV integrity. Promising results are furthermore derived with microRNA (miRNA) and long non-coding RNA (lncRNA) blocking or mimetic strategies, which can target microvascular rarefaction, inflammation, metabolism or fibrotic and hypertrophic remodeling in the dysfunctional RV. Likewise, pre-clinical data demonstrate that cell-based therapies using stem or progenitor cells have beneficial effects on the RV, mainly by improving the microvascular system, however clinical success will largely depend on delivery routes. A particular option for PAH is targeted denervation of the pulmonary vasculature, given the sympathetic overdrive in PAH patients. Finally, acute and durable mechanical circulatory support are available for the right heart, which however has been tested mostly in RHF with concomitant left heart disease. Here, we aim to review current pharmacological, RNA- and cell-based therapeutic options and their potential to directly target the RV and to review available data for pulmonary artery denervation and mechanical circulatory support.

Project description:Approximately half of heart failure patients have a normal ejection fraction, a condition designated as heart failure with preserved ejection fraction (HFpEF). This heart failure subtype disproportionately affects women and the elderly and is commonly associated with other cardiovascular comorbidities, such as hypertension and diabetes. HFpEF is increasing at a steady rate and is predicted to become the leading cause of heart failure within a decade. HFpEF is characterized by impaired diastolic function, thought to be due to concentric remodeling of the heart along with increased stiffness of both the extracellular matrix and myofilaments. In addition, oxidative stress and inflammation are thought to have a role in HFpEF progression, along with endothelial dysfunction and impaired nitric oxide-cyclic guanosine monophosphate-protein kinase G signaling. Surprisingly a number of clinical studies have failed to demonstrate any benefit of drugs effective in heart failure with systolic dysfunction in HFpEF patients. Thus, HFpEF is one of the largest unmet needs in cardiovascular medicine, and there is a substantial need for new therapeutic approaches and strategies that target mechanisms specific for HFpEF. This conclusion is underscored by the recently reported disappointing results of the RELAX trial, which assessed the use of phosphodiesterase-5 inhibitor sildenafil for treating HFpEF. In animal models, endothelial nitric oxide synthase activators and If current inhibitors have shown benefit in improving diastolic function, and there is a rationale for assessing matrix metalloproteinase 9 inhibitors and nitroxyl donors. LCZ696, a combination drug of angiotensin II receptor blocker and neprilysin inhibitor, and the aldosterone receptor antagonist spironolactone are currently in clinical trial for treating HFpEF. Here we present an overview of the etiology and diagnosis of HFpEF that segues into a discussion of new therapeutic approaches emerging from basic research and drugs currently in clinical trial that primarily target diastolic dysfunction or imbalanced ventricular-arterial coupling.

Project description:Despite the current reductionist approach providing an optimal indication for diagnosis and treatment of patients with heart failure with reduced ejection fraction (HFrEF), there are no standard pharmacological therapies for heart failure with preserved ejection fraction (HFpEF). Although in its infancy in cardiovascular diseases, the epigenetic-based therapy ("epidrugs") is capturing the interest of physician community. In fact, an increasing number of controlled clinical trials is evaluating the putative beneficial effects of: 1) direct epigenetic-oriented drugs, eg, apabetalone, and 2) repurposed drugs with a possible indirect epigenetic interference, eg, metformin, statins, sodium glucose transporter inhibitors 2 (SGLT2i), and omega 3 polyunsaturated fatty acids (PUFAs) in both HFrEF and HFpEF, separately. Apabetalone is the first and unique direct epidrug tested in cardiovascular patients to date, and the BETonMACE trial has reported a reduction in first HF hospitalization (any EF value) and cardiovascular death in patients with type 2 diabetes and recent acute coronary syndrome, suggesting a possible role in secondary prevention. Patients with HFpEF seem to benefit from supplementation to the standard therapy with statins, metformin, and SGLT2i owing to their ability in reducing mortality. In contrast, the vasodilator hydralazine, with or without isosorbide dinitrate, did not provide beneficial effects. In HFrEF, metformin and SGLT2i could reduce the risk of incident HF and mortality in affected patients whereas clinical trials based on statins provided mixed results. Furthermore, PUFAs diet supplementation was significantly associated with reduced cardiovascular risk in both HFpEF and HFrEF. Future large trials will reveal whether direct and indirect epitherapy will remain a work in progress or become a useful way to customize the therapy in the real-world management of HFpEF and HFrEF. Our goal is to discuss the recent advancement in the epitherapy as a possible way to improve personalized therapy of HF.

Dataset Information

Emerging Novel Therapies for Heart Failure.

Publications

Emerging Novel Therapies for Heart Failure.

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