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Heart Failure: From Molecular Basis to Therapy

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A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Pathology, Diagnostics, and Therapeutics".

Deadline for manuscript submissions: closed (30 November 2019) | Viewed by 64562

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Prof. Dr. Francesco Fedele

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Department of Clinical, Internal, Anesthesiology and Cardiovascular Sciences, Sapienza University of Rome, 00161 Rome, Italy
Interests: heart failure; acute coronary syndrome; pulmonary hypertension; coronary microvascular dysfuntion; coronary artery disease
Special Issues, Collections and Topics in MDPI journals

Prof. Dr. Paul J. Mather

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Heart Failure—Transplant Program, Perelman School of Medicine, University of Pennsylvania, 2 East Perelman Center for Advanced Medicine, 3400 Civic Center Blvd, Philadelphia, PA 19104, USA
Special Issues, Collections and Topics in MDPI journals

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Dear Colleagues,

As is well known, globally, heart failure represents the epidemic of the third millennium in terms of prevalence, costs, and mortality. Despite prevention, efficient screening, and early-treatment programs, heart failure is still a great problem for both physicians and healthcare systems. The Special Issue “Heart Failure: From Molecular Basis to Therapy” aims to stimulate comprehensive research for a holistic approach. This Special Issue will accept articles on the pathophysiology of heart failure and its etiologies, molecular basis, multimodality imaging, echocardiography, magnetic resonance imaging, therapy including pharmacological and non-pharmacological treatment as implantable defibrillators, resynchronization therapy, ventricular assistance devices, and transplantation.

This Special Issue wants to focus on both basic science and translational researches as well as clinical evidences in order to have a more complete comprehension of the pathophysiology of heart failure, considering all the aspects of this complex puzzle.

Prof. Dr. Francesco Fedele
Prof. Dr. Paul J. Mather
Guest Editors

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. International Journal of Molecular Sciences is an international peer-reviewed open access semimonthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. There is an Article Processing Charge (APC) for publication in this open access journal. For details about the APC please see here. Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

heart failure
ischemic heart-disease
cardiomyopathy
pulmonary hypertension
pulmonary heart-disease
valve heart-disease
rhythm disorders
risk factors, ion channels
energy metabolism
inotropism
echocardiography
magnetic-resonance imaging
remodeling
ventricular assistant device
transplantation

Related Special Issue

Heart Failure: From Molecular Basis to Therapy 2.0 in International Journal of Molecular Sciences (8 articles)

Published Papers (11 papers)

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Research

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20 pages, 2016 KiB

Open AccessArticle

Enhanced Inflammation is a Marker for Risk of Post-Infarct Ventricular Dysfunction and Heart Failure

by Iwona Świątkiewicz, Przemysław Magielski, Jacek Kubica, Adena Zadourian, Anthony N. DeMaria and Pam R. Taub

Int. J. Mol. Sci. 2020, 21(3), 807; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms21030807 - 26 Jan 2020

Cited by 28 | Viewed by 2957

Abstract

Acute ST-segment elevation myocardial infarction (STEMI) activates inflammation that can contribute to left ventricular systolic dysfunction (LVSD) and heart failure (HF). The objective of this study was to examine whether high-sensitivity C-reactive protein (CRP) concentration is predictive of long-term post-infarct LVSD and HF. In 204 patients with a first STEMI, CRP was measured at hospital admission, 24 h (CRP₂₄), discharge (CRP_DC), and 1 month after discharge (CRP_1M). LVSD at 6 months after discharge (LVSD_6M) and hospitalization for HF in long-term multi-year follow-up were prospectively evaluated. LVSD_6M occurred in 17.6% of patients. HF hospitalization within a median follow-up of 5.6 years occurred in 45.7% of patients with LVSD_6M vs. 4.9% without LVSD_6M (p < 0.0001). Compared to patients without LVSD_6M, the patients with LVSD_6M had higher CRP₂₄ and CRP_DC and persistent CRP_1M ≥ 2 mg/L. CRP levels were also higher in patients in whom LVSD persisted at 6 months (51% of all patients who had LVSD at discharge upon index STEMI) vs. patients in whom LVSD resolved. In multivariable analysis, CRP₂₄ ≥ 19.67 mg/L improved the prediction of LVSD_6M with an increased odds ratio of 1.47 (p < 0.01). Patients with LVSD_6M who developed HF had the highest CRP during index STEMI. Elevated CRP concentration during STEMI can serve as a synergistic marker for risk of long-term LVSD and HF. Full article

(This article belongs to the Special Issue Heart Failure: From Molecular Basis to Therapy)

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11 pages, 1837 KiB

Open AccessArticle

The Ubiquitin Proteasome System in Ischemic and Dilated Cardiomyopathy

by Sabine Spänig, Kristina Kellermann, Maja-Theresa Dieterlen, Thilo Noack, Sven Lehmann, Michael A. Borger, Jens Garbade, Yaron D. Barac and Fabian Emrich

Int. J. Mol. Sci. 2019, 20(24), 6354; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms20246354 - 17 Dec 2019

Cited by 13 | Viewed by 3330

Abstract

Dilated (DCM) and ischemic cardiomyopathies (ICM) are associated with cardiac remodeling, where the ubiquitin–proteasome system (UPS) holds a central role. Little is known about the UPS and its alterations in patients suffering from DCM or ICM. The aim of this study is to characterize the UPS activity in human heart tissue from cardiomyopathy patients. Myocardial tissue from ICM (n = 23), DCM (n = 28), and control (n = 14) patients were used to quantify ubiquitinylated proteins, E3-ubiquitin-ligases muscle-atrophy-F-box (MAFbx)/atrogin-1, muscle-RING-finger-1 (MuRF1), and eukaryotic-translation-initiation-factor-4E (eIF4E), by Western blot. Furthermore, the proteasomal chymotrypsin-like and trypsin-like peptidase activities were determined fluorometrically. Enzyme activity of NAD(P)H oxidase was assessed as an index of reactive oxygen species production. The chymotrypsin- (p = 0.71) and caspase-like proteasomal activity (p = 0.93) was similar between the groups. Trypsin-like proteasomal activity was lower in ICM (0.78 ± 0.11 µU/mg) compared to DCM (1.06 ± 0.08 µU/mg) and control (1.00 ± 0.06 µU/mg; p = 0.06) samples. Decreased ubiquitin expression in both cardiomyopathy groups (ICM vs. control: p < 0.001; DCM vs. control: p < 0.001), as well as less ubiquitin-positive deposits in ICM-damaged tissue (ICM: 4.19% ± 0.60%, control: 6.28% ± 0.40%, p = 0.022), were detected. E3-ligase MuRF1 protein expression (p = 0.62), NADPH-oxidase activity (p = 0.63), and AIF-positive cells (p = 0.50). Statistical trends were detected for reduced MAFbx protein expression in the DCM-group (p = 0.07). Different levels of UPS components, E3 ligases, and UPS activation markers were observed in myocardial tissue from patients affected by DCM and ICM, suggesting differential involvement of the UPS in the underlying pathologies. Full article

(This article belongs to the Special Issue Heart Failure: From Molecular Basis to Therapy)

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22 pages, 5186 KiB

Open AccessArticle

Inducible Cardiac-Specific Deletion of Sirt1 in Male Mice Reveals Progressive Cardiac Dysfunction and Sensitization of the Heart to Pressure Overload

by Maria-Nieves Sanz, Lucile Grimbert, Maryline Moulin, Mélanie Gressette, Catherine Rucker-Martin, Christophe Lemaire, Mathias Mericskay, Vladimir Veksler, Renée Ventura-Clapier, Anne Garnier and Jérôme Piquereau

Int. J. Mol. Sci. 2019, 20(20), 5005; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms20205005 - 10 Oct 2019

Cited by 35 | Viewed by 3618

Abstract

Heart failure is associated with profound alterations of energy metabolism thought to play a major role in the progression of this syndrome. SIRT1 is a metabolic sensor of cellular energy and exerts essential functions on energy metabolism, oxidative stress response, apoptosis, or aging. Importantly, SIRT1 deacetylates the peroxisome proliferator-activated receptor gamma co-activator 1α (PGC-1α), the master regulator of energy metabolism involved in mitochondrial biogenesis and fatty acid utilization. However, the exact role of SIRT1 in controlling cardiac energy metabolism is still incompletely understood and conflicting results have been obtained. We generated a cardio-specific inducible model of Sirt1 gene deletion in mice (Sirt1^ciKO) to decipher the role of SIRT1 in control conditions and following cardiac stress induced by pressure overload. SIRT1 deficiency induced a progressive cardiac dysfunction, without overt alteration in mitochondrial content or properties. Sixteen weeks after Sirt1 deletion an increase in mitochondrial reactive oxygen species (ROS) production and a higher rate of oxidative damage were observed, suggesting disruption of the ROS production/detoxification balance. Following pressure overload, cardiac dysfunction and alteration in mitochondrial properties were exacerbated in Sirt1^ciKO mice. Overall the results demonstrate that SIRT1 plays a cardioprotective role on cardiac energy metabolism and thereby on cardiac function. Full article

(This article belongs to the Special Issue Heart Failure: From Molecular Basis to Therapy)

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17 pages, 2752 KiB

Open AccessArticle

Normalizing Plasma Renin Activity in Experimental Dilated Cardiomyopathy: Effects on Edema, Cachexia, and Survival

by Ryan D. Sullivan, Radhika M. Mehta, Ranjana Tripathi, Inna P. Gladysheva and Guy L. Reed

Int. J. Mol. Sci. 2019, 20(16), 3886; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms20163886 - 09 Aug 2019

Cited by 10 | Viewed by 6445

Abstract

Heart failure (HF) patients frequently have elevated plasma renin activity. We examined the significance of elevated plasma renin activity in a translationally-relevant model of dilated cardiomyopathy (DCM), which replicates the progressive stages (A–D) of human HF. Female mice with DCM and elevated plasma renin activity concentrations were treated with a direct renin inhibitor (aliskiren) in a randomized, blinded fashion beginning at Stage B HF. By comparison to controls, aliskiren treatment normalized pathologically elevated plasma renin activity (p < 0.001) and neprilysin levels (p < 0.001), but did not significantly alter pathological changes in plasma aldosterone, angiotensin II, atrial natriuretic peptide, or corin levels. Aliskiren improved cardiac systolic function (ejection fraction, p < 0.05; cardiac output, p < 0.01) and significantly reduced the longitudinal development of edema (extracellular water, p < 0.0001), retarding the transition from Stage B to Stage C HF. The normalization of elevated plasma renin activity reduced the loss of body fat and lean mass (cachexia/sarcopenia), p < 0.001) and prolonged survival (p < 0.05). In summary, the normalization of plasma renin activity retards the progression of experimental HF by improving cardiac systolic function, reducing the development of systemic edema, cachexia/sarcopenia, and mortality. These data suggest that targeting pathologically elevated plasma renin activity may be beneficial in appropriately selected HF patients. Full article

(This article belongs to the Special Issue Heart Failure: From Molecular Basis to Therapy)

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Review

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18 pages, 2115 KiB

Open AccessReview

Ischemic Heart Disease and Heart Failure: Role of Coronary Ion Channels

by Paolo Severino, Andrea D’Amato, Mariateresa Pucci, Fabio Infusino, Lucia Ilaria Birtolo, Marco Valerio Mariani, Carlo Lavalle, Viviana Maestrini, Massimo Mancone and Francesco Fedele

Int. J. Mol. Sci. 2020, 21(9), 3167; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms21093167 - 30 Apr 2020

Cited by 76 | Viewed by 10879

Abstract

Heart failure is a complex syndrome responsible for high rates of death and hospitalization. Ischemic heart disease is one of the most frequent causes of heart failure and it is normally attributed to coronary artery disease, defined by the presence of one or more obstructive plaques, which determine a reduced coronary blood flow, causing myocardial ischemia and consequent heart failure. However, coronary obstruction is only an element of a complex pathophysiological process that leads to myocardial ischemia. In the literature, attention paid to the role of microcirculation, in the pathophysiology of ischemic heart disease and heart failure, is growing. Coronary microvascular dysfunction determines an inability of coronary circulation to satisfy myocardial metabolic demands, due to the imbalance of coronary blood flow regulatory mechanisms, including ion channels, leading to the development of hypoxia, fibrosis and tissue death, which may determine a loss of myocardial function, even beyond the presence of atherosclerotic epicardial plaques. For this reason, ion channels may represent the link among coronary microvascular dysfunction, ischemic heart disease and consequent heart failure. Full article

(This article belongs to the Special Issue Heart Failure: From Molecular Basis to Therapy)

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17 pages, 1211 KiB

Open AccessReview

Novel Basic Science Insights to Improve the Management of Heart Failure: Review of the Working Group on Cellular and Molecular Biology of the Heart of the Italian Society of Cardiology

by Pietro Ameri, Gabriele Giacomo Schiattarella, Lia Crotti, Margherita Torchio, Edoardo Bertero, Daniele Rodolico, Maurizio Forte, Vittoria Di Mauro, Roberta Paolillo, Cristina Chimenti, Daniele Torella, Daniele Catalucci, Sebastiano Sciarretta, Cristina Basso, Ciro Indolfi and Cinzia Perrino

Int. J. Mol. Sci. 2020, 21(4), 1192; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms21041192 - 11 Feb 2020

Cited by 8 | Viewed by 4811

Abstract

Despite important advances in diagnosis and treatment, heart failure (HF) remains a syndrome with substantial morbidity and dismal prognosis. Although implementation and optimization of existing technologies and drugs may lead to better management of HF, new or alternative strategies are desirable. In this regard, basic science is expected to give fundamental inputs, by expanding the knowledge of the pathways underlying HF development and progression, identifying approaches that may improve HF detection and prognostic stratification, and finding novel treatments. Here, we discuss recent basic science insights that encompass major areas of translational research in HF and have high potential clinical impact. Full article

(This article belongs to the Special Issue Heart Failure: From Molecular Basis to Therapy)

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18 pages, 3127 KiB

Open AccessReview

Heart Failure Differentially Modulates Natural (Sinoatrial Node) and Ectopic (Pulmonary Veins) Pacemakers: Mechanism and Therapeutic Implication for Atrial Fibrillation

by Chao-Shun Chan, Yung-Kuo Lin, Yao-Chang Chen, Yen-Yu Lu, Shih-Ann Chen and Yi-Jen Chen

Int. J. Mol. Sci. 2019, 20(13), 3224; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms20133224 - 30 Jun 2019

Cited by 9 | Viewed by 3988

Abstract

Heart failure (HF) frequently coexists with atrial fibrillation (AF) and dysfunction of the sinoatrial node (SAN), the natural pacemaker. HF is associated with chronic adrenergic stimulation, neurohormonal activation, abnormal intracellular calcium handling, elevated cardiac filling pressure and atrial stretch, and fibrosis. Pulmonary veins (PVs), which are the points of onset of ectopic electrical activity, are the most crucial AF triggers. A crosstalk between the SAN and PVs determines PV arrhythmogenesis. HF has different effects on SAN and PV electrophysiological characteristics, which critically modulate the development of AF and sick sinus syndrome. This review provides updates to improve our current understanding of the effects of HF in the electrical activity of the SAN and PVs as well as therapeutic implications for AF. Full article

(This article belongs to the Special Issue Heart Failure: From Molecular Basis to Therapy)

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17 pages, 1050 KiB

Open AccessReview

Endothelial Dysfunction in Chronic Heart Failure: Assessment, Findings, Significance, and Potential Therapeutic Targets

by Manal M. Alem

Int. J. Mol. Sci. 2019, 20(13), 3198; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms20133198 - 29 Jun 2019

Cited by 62 | Viewed by 4489

Abstract

Chronic heart failure (CHF) is a complex syndrome that results from structural and functional disturbances that affect the ability of the heart to supply oxygen to tissues. It largely affects and reduces the patient’s quality of life, socio-economic status, and imposes great costs on health care systems worldwide. Endothelial dysfunction (ED) is a newly discovered phenomenon that contributes greatly to the pathophysiology of numerous cardiovascular conditions and commonly co-exists with chronic heart failure. However, the literature lacks clarity as to which heart failure patients might be affected, its significance in CHF patients, and its reversibility with pharmacological and non-pharmacological means. This review will emphasize all these points and summarize them for future researchers interested in vascular pathophysiology in this particular patient population. It will help to direct future studies for better characterization of these two phenomena for the potential discovery of therapeutic targets that might reduce future morbidity and mortality in this “at risk” population. Full article

(This article belongs to the Special Issue Heart Failure: From Molecular Basis to Therapy)

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27 pages, 1965 KiB

Open AccessReview

Renin Activity in Heart Failure with Reduced Systolic Function—New Insights

by Ryan D. Sullivan, Radhika M. Mehta, Ranjana Tripathi, Guy L. Reed and Inna P. Gladysheva

Int. J. Mol. Sci. 2019, 20(13), 3182; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms20133182 - 28 Jun 2019

Cited by 29 | Viewed by 6681

Abstract

Regardless of the cause, symptomatic heart failure (HF) with reduced ejection fraction (rEF) is characterized by pathological activation of the renin–angiotensin–aldosterone system (RAAS) with sodium retention and extracellular fluid expansion (edema). Here, we review the role of active renin, a crucial, upstream enzymatic regulator of the RAAS, as a prognostic and diagnostic plasma biomarker of heart failure with reduced ejection fraction (HFrEF) progression; we also discuss its potential as a pharmacological bio-target in HF therapy. Clinical and experimental studies indicate that plasma renin activity is elevated with symptomatic HFrEF with edema in patients, as well as in companion animals and experimental models of HF. Plasma renin activity levels are also reported to be elevated in patients and animals with rEF before the development of symptomatic HF. Modulation of renin activity in experimental HF significantly reduces edema formation and the progression of systolic dysfunction and improves survival. Thus, specific assessment and targeting of elevated renin activity may enhance diagnostic and therapeutic precision to improve outcomes in appropriate patients with HFrEF. Full article

(This article belongs to the Special Issue Heart Failure: From Molecular Basis to Therapy)

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17 pages, 2611 KiB

Open AccessReview

Diagnostic and Treatment Approaches Involving Transthyretin in Amyloidogenic Diseases

by Gil Yong Park, Angelo Jamerlan, Kyu Hwan Shim and Seong Soo A. An

Int. J. Mol. Sci. 2019, 20(12), 2982; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms20122982 - 18 Jun 2019

Cited by 24 | Viewed by 9535

Abstract

Transthyretin (TTR) is a thyroid hormone-binding protein which transports thyroxine from the bloodstream to the brain. The structural stability of TTR in tetrameric form is crucial for maintaining its original functions in blood or cerebrospinal fluid (CSF). The altered structure of TTR due to genetic mutations or its deposits due to aggregation could cause several deadly diseases such as cardiomyopathy and neuropathy in autonomic, motor, and sensory systems. The early diagnoses for hereditary amyloid TTR with cardiomyopathy (ATTR-CM) and wild-type amyloid TTR (ATTRwt) amyloidosis, which result from amyloid TTR (ATTR) deposition, are difficult to distinguish due to the close similarities of symptoms. Thus, many researchers investigated the role of ATTR as a biomarker, especially its potential for differential diagnosis due to its varying pathogenic involvement in hereditary ATTR-CM and ATTRwt amyloidosis. As a result, the detection of ATTR became valuable in the diagnosis and determination of the best course of treatment for ATTR amyloidoses. Assessing the extent of ATTR deposition and genetic analysis could help in determining disease progression, and thus survival rate could be improved following the determination of the appropriate course of treatment for the patient. Here, the perspectives of ATTR in various diseases were presented. Full article

(This article belongs to the Special Issue Heart Failure: From Molecular Basis to Therapy)

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28 pages, 899 KiB

Open AccessReview

Inflammatory and Molecular Pathways in Heart Failure—Ischemia, HFpEF and Transthyretin Cardiac Amyloidosis

by Diana Michels da Silva, Harald Langer and Tobias Graf

Int. J. Mol. Sci. 2019, 20(9), 2322; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms20092322 - 10 May 2019

Cited by 60 | Viewed by 6818

Abstract

Elevated pro-inflammatory biomarkers and cytokines are associated with morbidity and mortality in heart failure (HF). Preclinical and clinical studies have shown multiple inflammatory mechanisms causing cardiac remodeling, dysfunction and chronic failure. Therapeutics in trials targeting the immune response in heart failure and its effects did not result in evident benefits regarding clinical endpoints and mortality. This review elaborates pathways of immune cytokines in pathogenesis and worsening of heart failure in clinical and cellular settings. Besides the well-known mechanisms of immune activation and inflammation in atherosclerosis causing ischemic cardiomyopathy or myocarditis, attention is focused on other mechanisms leading to heart failure such as transthyretin (TTR) amyloidosis or heart failure with preserved ejection fraction. The knowledge of the pathogenesis in heart failure and amyloidosis on a molecular and cellular level might help to highlight new disease defining biomarkers and to lead the way to new therapeutic targets. Full article

(This article belongs to the Special Issue Heart Failure: From Molecular Basis to Therapy)

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