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      Review of novel therapeutic targets for improving heart failure treatment based on experimental and clinical studies

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          Abstract

          Heart failure (HF) is a major public health priority due to its epidemiological transition and the world’s aging population. HF is typified by continuous loss of contractile function with reduced, normal, or preserved ejection fraction, elevated vascular resistance, fluid and autonomic imbalance, and ventricular dilatation. Despite considerable advances in the treatment of HF over the past few decades, mortality remains substantial. Pharmacological treatments including β-blockers, angiotensin-converting enzyme inhibitors, angiotensin receptor blockers, and aldosterone antagonists have been proven to prolong the survival of patients with HF. However, there are still instances where patients remain symptomatic, despite optimal use of existing therapeutic agents. This understanding that patients with chronic HF progress into advanced stages despite receiving optimal treatment has increased the quest for alternatives, exploring the roles of additional pathways that contribute to the development and progression of HF. Several pharmacological targets associated with pathogenesis of HF have been identified and novel therapies have emerged. In this work, we review recent evidence from proposed mechanisms to the outcomes of experimental and clinical studies of the novel pharmacological agents that have emerged for the treatment of HF.

          Most cited references185

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          ESC guidelines for the diagnosis and treatment of acute and chronic heart failure 2012: The Task Force for the Diagnosis and Treatment of Acute and Chronic Heart Failure 2012 of the European Society of Cardiology. Developed in collaboration with the Heart Failure Association (HFA) of the ESC.

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            The war against heart failure: the Lancet lecture.

            Heart failure is a global problem with an estimated prevalence of 38 million patients worldwide, a number that is increasing with the ageing of the population. It is the most common diagnosis in patients aged 65 years or older admitted to hospital and in high-income nations. Despite some progress, the prognosis of heart failure is worse than that of most cancers. Because of the seriousness of the condition, a declaration of war on five fronts has been proposed for heart failure. Efforts are underway to treat heart failure by enhancing myofilament sensitivity to Ca(2+); transfer of the gene for SERCA2a, the protein that pumps calcium into the sarcoplasmic reticulum of the cardiomyocyte, seems promising in a phase 2 trial. Several other abnormal calcium-handling proteins in the failing heart are candidates for gene therapy; many short, non-coding RNAs--ie, microRNAs (miRNAs)--block gene expression and protein translation. These molecules are crucial to calcium cycling and ventricular hypertrophy. The actions of miRNAs can be blocked by a new class of drugs, antagomirs, some of which have been shown to improve cardiac function in animal models of heart failure; cell therapy, with autologous bone marrow derived mononuclear cells, or autogenous mesenchymal cells, which can be administered as cryopreserved off the shelf products, seem to be promising in both preclinical and early clinical heart failure trials; and long-term ventricular assistance devices are now used increasingly as a destination therapy in patients with advanced heart failure. In selected patients, left ventricular assistance can lead to myocardial recovery and explantation of the device. The approaches to the treatment of heart failure described, when used alone or in combination, could become important weapons in the war against heart failure.
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              Effect of nesiritide in patients with acute decompensated heart failure.

              Nesiritide is approved in the United States for early relief of dyspnea in patients with acute heart failure. Previous meta-analyses have raised questions regarding renal toxicity and the mortality associated with this agent. We randomly assigned 7141 patients who were hospitalized with acute heart failure to receive either nesiritide or placebo for 24 to 168 hours in addition to standard care. Coprimary end points were the change in dyspnea at 6 and 24 hours, as measured on a 7-point Likert scale, and the composite end point of rehospitalization for heart failure or death within 30 days. Patients randomly assigned to nesiritide, as compared with those assigned to placebo, more frequently reported markedly or moderately improved dyspnea at 6 hours (44.5% vs. 42.1%, P=0.03) and 24 hours (68.2% vs. 66.1%, P=0.007), but the prespecified level for significance (P≤0.005 for both assessments or P≤0.0025 for either) was not met. The rate of rehospitalization for heart failure or death from any cause within 30 days was 9.4% in the nesiritide group versus 10.1% in the placebo group (absolute difference, -0.7 percentage points; 95% confidence interval [CI], -2.1 to 0.7; P=0.31). There were no significant differences in rates of death from any cause at 30 days (3.6% with nesiritide vs. 4.0% with placebo; absolute difference, -0.4 percentage points; 95% CI, -1.3 to 0.5) or rates of worsening renal function, defined by more than a 25% decrease in the estimated glomerular filtration rate (31.4% vs. 29.5%; odds ratio, 1.09; 95% CI, 0.98 to 1.21; P=0.11). Nesiritide was not associated with an increase or a decrease in the rate of death and rehospitalization and had a small, nonsignificant effect on dyspnea when used in combination with other therapies. It was not associated with a worsening of renal function, but it was associated with an increase in rates of hypotension. On the basis of these results, nesiritide cannot be recommended for routine use in the broad population of patients with acute heart failure. (Funded by Scios; ClinicalTrials.gov number, NCT00475852.).
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                Author and article information

                Journal
                Ther Clin Risk Manag
                Ther Clin Risk Manag
                Therapeutics and Clinical Risk Management
                Therapeutics and Clinical Risk Management
                Dove Medical Press
                1176-6336
                1178-203X
                2016
                03 June 2016
                : 12
                : 887-906
                Affiliations
                [1 ]School of Medicine and Health Sciences, Monash University Sunway Campus, Jalan Lagoon Selatan, Bandar Sunway, Subang Jaya, Selangor, Malaysia
                [2 ]Accident and Emergency Directorate, Komfo Anokye Teaching Hospital, Kwame Nkrumah University of Science and Technology, Kumasi, Ghana
                [3 ]Department of Medicine, Kwame Nkrumah University of Science and Technology, Kumasi, Ghana
                [4 ]Department of Clinical and Social Pharmacy, College of Health Sciences, Kwame Nkrumah University of Science and Technology, Kumasi, Ghana
                Author notes
                Correspondence: Kwadwo Osei Bonsu, School of Medicine and Health Sciences, Monash University Sunway Campus, Jalan Lagoon Selatan, Bandar Sunway, Subang Jaya 47500, Selangor, Malaysia, Tel +60 35 514 6000 ext 44451, Fax +60 35 514 4451, Email kose1@ 123456student.monash.edu
                Article
                tcrm-12-887
                10.2147/TCRM.S106065
                4902145
                27350750
                a2bd048e-499b-46d9-9fba-76b6be7eb70a
                © 2016 Bonsu et al. This work is published and licensed by Dove Medical Press Limited

                The full terms of this license are available at https://www.dovepress.com/terms.php and incorporate the Creative Commons Attribution – Non Commercial (unported, v3.0) License ( http://creativecommons.org/licenses/by-nc/3.0/). By accessing the work you hereby accept the Terms. Non-commercial uses of the work are permitted without any further permission from Dove Medical Press Limited, provided the work is properly attributed.

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                Review

                Medicine
                novel treatment,experimental and clinical studies,therapeutic targets,heart failure
                Medicine
                novel treatment, experimental and clinical studies, therapeutic targets, heart failure

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