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

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 ?-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.

SUBMITTER: Bonsu KO

PROVIDER: S-EPMC4902145 | biostudies-literature | 2016

REPOSITORIES: biostudies-literature

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

Bonsu Kwadwo Osei KO Owusu Isaac Kofi IK Buabeng Kwame Ohene KO Reidpath Daniel Diamond DD Kadirvelu Amudha A

Therapeutics and clinical risk management 20160603

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-co ...[more]

PMID: 27350750

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Project description:BackgroundHeart failure (HF) is a highly prevalent disorder for which disease mechanisms are incompletely understood. The discovery of disease-associated proteins with causal genetic evidence provides an opportunity to identify new therapeutic targets.MethodsWe investigated the observational and causal associations of 90 cardiovascular proteins, which were measured using affinity-based proteomic assays. First, we estimated the associations of 90 cardiovascular proteins with incident heart failure by means of a fixed-effect meta-analysis of 4 population-based studies, composed of a total of 3019 participants with 732 HF events. The causal effects of HF-associated proteins were then investigated by Mendelian randomization, using cis-protein quantitative loci genetic instruments identified from genomewide association studies in more than 30 000 individuals. To improve the precision of causal estimates, we implemented an Mendelian randomization model that accounted for linkage disequilibrium between instruments and tested the robustness of causal estimates through a multiverse sensitivity analysis that included up to 120 combinations of instrument selection parameters and Mendelian randomization models per protein. The druggability of candidate proteins was surveyed, and mechanism of action and potential on-target side effects were explored with cross-trait Mendelian randomization analysis.ResultsForty-four of ninety proteins were positively associated with risk of incident HF (P<6.0×10-4). Among these, 8 proteins had evidence of a causal association with HF that was robust to multiverse sensitivity analysis: higher CSF-1 (macrophage colony-stimulating factor 1), Gal-3 (galectin-3) and KIM-1 (kidney injury molecule 1) were positively associated with risk of HF, whereas higher ADM (adrenomedullin), CHI3L1 (chitinase-3-like protein 1), CTSL1 (cathepsin L1), FGF-23 (fibroblast growth factor 23), and MMP-12 (matrix metalloproteinase-12) were protective. Therapeutics targeting ADM and Gal-3 are currently under evaluation in clinical trials, and all the remaining proteins were considered druggable, except KIM-1.ConclusionsWe identified 44 circulating proteins that were associated with incident HF, of which 8 showed evidence of a causal relationship and 7 were druggable, including adrenomedullin, which represents a particularly promising drug target. Our approach demonstrates a tractable roadmap for the triangulation of population genomic and proteomic data for the prioritization of therapeutic targets for complex human diseases.

Project description:BackgroundHeart failure self-management is essential to avoid decompensation and readmissions. Mobile apps seem promising in supporting heart failure self-management, and there has been a rapid growth in publications in this area. However, to date, systematic reviews have mostly focused on remote monitoring interventions using nonapp types of mobile technologies to transmit data to health care providers, rarely focusing on supporting patient self-management of heart failure.ObjectiveThis study aims to systematically review the evidence on the effect of heart failure self-management apps on health outcomes, patient-reported outcomes, and patient experience.MethodsFour databases (PubMed, Embase, CINAHL, and PsycINFO) were searched for studies examining interventions that comprised a mobile app targeting heart failure self-management and reported any health-related outcomes or patient-reported outcomes or perspectives published from 2008 to December 2021. The studies were independently screened. The risk of bias was appraised using Cochrane tools. We performed a narrative synthesis of the results. The protocol was registered on PROSPERO (International Prospective Register of Systematic Reviews; CRD42020158041).ResultsA total of 28 articles (randomized controlled trials [RCTs]: n=10, 36%), assessing 23 apps, and a total of 1397 participants were included. The most common app features were weight monitoring (19/23, 83%), symptom monitoring (18/23, 78%), and vital sign monitoring (15/23, 65%). Only 26% (6/23) of the apps provided all guideline-defined core components of heart failure self-management programs: education, symptom monitoring, medication support, and physical activity support. RCTs were small, involving altogether 717 participants, had ≤6 months of follow-up, and outcomes were predominantly self-reported. Approximately 20% (2/10) of RCTs reported a significant improvement in their primary outcomes: heart failure knowledge (P=.002) and self-care (P=.004). One of the RCTs found a significant reduction in readmissions (P=.02), and 20% (2/10) of RCTs reported higher unplanned clinic visits. Other experimental studies also found significant improvements in knowledge, self-care, and readmissions, among others. Less than half of the studies involved patients and clinicians in the design of apps. Engagement with the intervention was poorly reported, with only 11% (3/28) of studies quantifying app engagement metrics such as frequency of use over the study duration. The most desirable app features were automated self-monitoring and feedback, personalization, communication with clinicians, and data sharing and integration.ConclusionsMobile apps may improve heart failure self-management; however, more robust evaluation studies are needed to analyze key end points for heart failure. On the basis of the results of this review, we provide a road map for future studies in this area.

Project description:Background and Objective Heart failure (HF) is a global public health problem with high morbidity, readmission, and mortality rates. The central mediators of cardiomyocyte survival and death are mitochondria. Mitochondria are a key therapeutic target for HF and are closely involved in the pathophysiological process of HF. A recent study proposes that cuproptosis, a novel cell death mechanism, is closely related to mitochondrial respiration. Therefore, this study aims to explore the link between cuproptosis and HF, and to find novel therapeutic targets and treatments for HF. Methods A literature search (up to April 2022) was conducted through PubMed database, and the search range was limited to publications in English. After further literature search and screening, we found that we are currently the first study to explore the association between HF and cuproptosis. Key Content and Findings Research has found that mitochondria are a key therapeutic target in HF and are involved in the pathophysiological processes of energy metabolism, oxidative stress, calcium regulation, and cell death in HF. The micronutrient copper is involved in regulating mitochondrial biological processes, and high serum copper levels are significantly associated with HF. Copper overload affects mitochondrial function and exacerbates the development of HF. And cuproptosis induced by copper overload targeting lipoylated tricarboxylic acid cycle proteins, is closely related to mitochondrial respiration. Copper chelators not only treat HF but also partially rescue copper-mediated cell death. Copper binding to lipoylated components may be the reason for the hyperacetylation of mitochondrial proteins in HF. Ferredoxin 1 (FDX1) may be an upstream regulator of protein lipoylation and is closely related to cuproptosis. Conclusions This study demonstrates the important roles of mitochondria and micronutrient copper in HF. Cuproptosis may be involved in the pathophysiological process of HF and is responsible for the hyperacetylation of mitochondrial proteins in HF. Cuproptosis has the potential to be a novel therapeutic mechanism for HF, and FDX1 may be a key target for cuproptosis-based treatment of HF. This study provides a new research direction for the treatment of HF and new ideas for the development of new drugs.

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

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

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