International Journal of Molecular Sciences

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24 pages, 2979 KiB

Open AccessArticle

Investigation of the Antihypertrophic and Antifibrotic Effects of Losartan in a Rat Model of Radiation-Induced Heart Disease

by Mónika Gabriella Kovács, Zsuzsanna Z. A. Kovács, Zoltán Varga, Gergő Szűcs, Marah Freiwan, Katalin Farkas, Bence Kővári, Gábor Cserni, András Kriston, Ferenc Kovács, Péter Horváth, Imre Földesi, Tamás Csont, Zsuzsanna Kahán and Márta Sárközy

Int. J. Mol. Sci. 2021, 22(23), 12963; https://doi.org/10.3390/ijms222312963 - 30 Nov 2021

Cited by 12 | Viewed by 2822

Abstract

Radiation-induced heart disease (RIHD) is a potential late side-effect of thoracic radiotherapy resulting in left ventricular hypertrophy (LVH) and fibrosis due to a complex pathomechanism leading to heart failure. Angiotensin-II receptor blockers (ARBs), including losartan, are frequently used to control heart failure of [...] Read more.

Radiation-induced heart disease (RIHD) is a potential late side-effect of thoracic radiotherapy resulting in left ventricular hypertrophy (LVH) and fibrosis due to a complex pathomechanism leading to heart failure. Angiotensin-II receptor blockers (ARBs), including losartan, are frequently used to control heart failure of various etiologies. Preclinical evidence is lacking on the anti-remodeling effects of ARBs in RIHD, while the results of clinical studies are controversial. We aimed at investigating the effects of losartan in a rat model of RIHD. Male Sprague-Dawley rats were studied in three groups: (1) control, (2) radiotherapy (RT) only, (3) RT treated with losartan (per os 10 mg/kg/day), and were followed for 1, 3, or 15 weeks. At 15 weeks post-irradiation, losartan alleviated the echocardiographic and histological signs of LVH and fibrosis and reduced the overexpression of chymase, connective tissue growth factor, and transforming growth factor-beta in the myocardium measured by qPCR; likewise, the level of the SMAD2/3 protein determined by Western blot decreased. In both RT groups, the pro-survival phospho-AKT/AKT and the phospho-ERK1,2/ERK1,2 ratios were increased at week 15. The antiremodeling effects of losartan seem to be associated with the repression of chymase and several elements of the TGF-β/SMAD signaling pathway in our RIHD model. Full article

(This article belongs to the Special Issue Heart Failure: From Molecular Basis to Therapy 2.0)

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18 pages, 5150 KiB

Open AccessArticle

Apolipoprotein E4 Is Associated with Right Ventricular Dysfunction in Dilated Cardiomyopathy—An Animal and In-Human Comparative Study

by Rodica Diaconu, Nicole Schaaps, Mamdouh Afify, Peter Boor, Anne Cornelissen, Roberta A. Florescu, Sakine Simsekyilmaz, Teddy El-Khoury, David Schumacher, Mihai Ioana, Ioana Streata, Constantin Militaru, Ionut Donoiu, Felix Vogt and Elisa A. Liehn

Int. J. Mol. Sci. 2021, 22(18), 9688; https://doi.org/10.3390/ijms22189688 - 7 Sep 2021

Cited by 4 | Viewed by 2205

Abstract

ApoE abnormality represents a well-known risk factor for cardiovascular diseases. Beyond its role in lipid metabolism, novel studies demonstrate a complex involvement of apoE in membrane homeostasis and signaling as well as in nuclear transcription. Due to the large spread of apoE isoforms [...] Read more.

ApoE abnormality represents a well-known risk factor for cardiovascular diseases. Beyond its role in lipid metabolism, novel studies demonstrate a complex involvement of apoE in membrane homeostasis and signaling as well as in nuclear transcription. Due to the large spread of apoE isoforms in the human population, there is a need to understand the apoE’s role in pathological processes. Our study aims to dissect the involvement of apoE in heart failure. We showed that apoE-deficient rats present multiple organ damages (kidney, liver, lung and spleen) besides the known predisposition for obesity and affected lipid metabolism (two-fold increase in tissular damages in liver and one-fold increase in kidney, lung and spleen). Heart tissue also showed significant morphological changes in apoE^−/− rats, mostly after a high-fat diet. Interestingly, the right ventricle of apoE^−/− rats fed a high-fat diet showed more damage and affected collagen content (~60% less total collagen content and double increase in collagen1/collagen3 ratio) compared with the left ventricle (no significant differences in total collagen content or collagen1/collagen3 ratio). In patients, we were able to find a correlation between the presence of ε4 allele and cardiomyopathy (χ² = 10.244; p = 0.001), but also with right ventricle dysfunction with decreased TAPSE (15.3 ± 2.63 mm in ε4-allele-presenting patients vs. 19.8 ± 3.58 mm if the ε4 allele is absent, p < 0.0001*) and increased in systolic pulmonary artery pressure (50.44 ± 16.47 mmHg in ε4-allele-presenting patients vs. 40.68 ± 15.94 mmHg if the ε4 allele is absent, p = 0.0019). Our results confirm that the presence of the ε4 allele is a lipid-metabolism-independent risk factor for heart failure. Moreover, we show for the first time that the presence of the ε4 allele is associated with right ventricle dysfunction, implying different regulatory mechanisms of fibroblasts and the extracellular matrix in both ventricles. This is essential to be considered and thoroughly investigated before the design of therapeutical strategies for patients with heart failure. Full article

(This article belongs to the Special Issue Heart Failure: From Molecular Basis to Therapy 2.0)

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17 pages, 26930 KiB

Open AccessArticle

A Low-Sodium Diet Boosts Ang (1–7) Production and NO-cGMP Bioavailability to Reduce Edema and Enhance Survival in Experimental Heart Failure

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

Int. J. Mol. Sci. 2021, 22(8), 4035; https://doi.org/10.3390/ijms22084035 - 14 Apr 2021

Cited by 9 | Viewed by 5733

Abstract

Sodium restriction is often recommended in heart failure (HF) to block symptomatic edema, despite limited evidence for benefit. However, a low-sodium diet (LSD) activates the classical renin-angiotensin-aldosterone system (RAAS), which may adversely affect HF progression and mortality in patients with dilated cardiomyopathy (DCM). [...] Read more.

Sodium restriction is often recommended in heart failure (HF) to block symptomatic edema, despite limited evidence for benefit. However, a low-sodium diet (LSD) activates the classical renin-angiotensin-aldosterone system (RAAS), which may adversely affect HF progression and mortality in patients with dilated cardiomyopathy (DCM). We performed a randomized, blinded pre-clinical trial to compare the effects of a normal (human-equivalent) sodium diet and a LSD on HF progression in a normotensive model of DCM in mice that has translational relevance to human HF. The LSD reduced HF progression by suppressing the development of pleural effusions (p < 0.01), blocking pathological increases in systemic extracellular water (p < 0.001) and prolonging median survival (15%, p < 0.01). The LSD activated the classical RAAS by increasing plasma renin activity, angiotensin II and aldosterone levels. However, the LSD also significantly up-elevated the counter-regulatory RAAS by boosting plasma angiotensin converting enzyme 2 (ACE2) and angiotensin (1–7) levels, promoting nitric oxide bioavailability and stimulating 3′-5′-cyclic guanosine monophosphate (cGMP) production. Plasma HF biomarkers associated with poor outcomes, such as B-type natriuretic peptide and neprilysin were decreased by a LSD. Cardiac systolic function, blood pressure and renal function were not affected. Although a LSD activates the classical RAAS system, we conclude that the LSD delayed HF progression and mortality in experimental DCM, in part through protective stimulation of the counter-regulatory RAAS to increase plasma ACE2 and angiotensin (1–7) levels, nitric oxide bioavailability and cGMP production. Full article

(This article belongs to the Special Issue Heart Failure: From Molecular Basis to Therapy 2.0)

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19 pages, 4533 KiB

Open AccessArticle

NMRK2 Gene Is Upregulated in Dilated Cardiomyopathy and Required for Cardiac Function and NAD Levels during Aging

by Cynthia Tannous, Robin Deloux, Ahmed Karoui, Nathalie Mougenot, Dean Burkin, Jocelyne Blanc, Dario Coletti, Gareth Lavery, Zhenlin Li and Mathias Mericskay

Int. J. Mol. Sci. 2021, 22(7), 3534; https://doi.org/10.3390/ijms22073534 - 29 Mar 2021

Cited by 15 | Viewed by 3753

Abstract

Dilated cardiomyopathy (DCM) is a disease of multifactorial etiologies, the risk of which is increased by male sex and age. There are few therapeutic options for patients with DCM who would benefit from identification of common targetable pathways. We used bioinformatics to identify [...] Read more.

Dilated cardiomyopathy (DCM) is a disease of multifactorial etiologies, the risk of which is increased by male sex and age. There are few therapeutic options for patients with DCM who would benefit from identification of common targetable pathways. We used bioinformatics to identify the Nmrk2 gene involved in nicotinamide adenine dinucleotde (NAD) coenzyme biosynthesis as activated in different mouse models and in hearts of human patients with DCM while the Nampt gene controlling a parallel pathway is repressed. A short NMRK2 protein isoform is also known as muscle integrin binding protein (MIBP) binding the α7β1 integrin complex. We investigated the cardiac phenotype of Nmrk2-KO mice to establish its role in cardiac remodeling and function. Young Nmrk2-KO mice developed an eccentric type of cardiac hypertrophy in response to pressure overload rather than the concentric hypertrophy observed in controls. Nmrk2-KO mice developed a progressive DCM-like phenotype with aging, associating eccentric remodeling of the left ventricle and a decline in ejection fraction and showed a reduction in myocardial NAD levels at 24 months. In agreement with involvement of NMRK2 in integrin signaling, we observed a defect in laminin deposition in the basal lamina of cardiomyocytes leading to increased fibrosis at middle age. The α7 integrin was repressed at both transcript and protein level at 24 months. Nmrk2 gene is required to preserve cardiac structure and function, and becomes an important component of the NAD biosynthetic pathways during aging. Molecular characterization of compounds modulating this pathway may have therapeutic potential. Full article

(This article belongs to the Special Issue Heart Failure: From Molecular Basis to Therapy 2.0)

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22 pages, 1748 KiB

Open AccessArticle

C-Reactive Protein as a Risk Marker for Post-Infarct Heart Failure over a Multi-Year Period

by Iwona Świątkiewicz, Przemysław Magielski and Jacek Kubica

Int. J. Mol. Sci. 2021, 22(6), 3169; https://doi.org/10.3390/ijms22063169 - 20 Mar 2021

Cited by 18 | Viewed by 2387

Abstract

Inflammatory activation during acute ST-elevation myocardial infarction (STEMI) can contribute to post-infarct heart failure (HF). This study aimed to determine prognostic value of high-sensitivity C-reactive protein concentration (CRP) for HF over a long-term follow-up in 204 patients with a first STEMI undergoing guideline-based [...] Read more.

Inflammatory activation during acute ST-elevation myocardial infarction (STEMI) can contribute to post-infarct heart failure (HF). This study aimed to determine prognostic value of high-sensitivity C-reactive protein concentration (CRP) for HF over a long-term follow-up in 204 patients with a first STEMI undergoing guideline-based therapies including percutaneous coronary intervention. CRP was measured at admission, 24 h (CRP₂₄), discharge (CRP_DC), and one month (CRP_1M) after index hospitalization for STEMI. Within a median period of 5.6 years post-index hospitalization for STEMI, hospitalization for HF (HFH) which is a primary endpoint, occurred in 24 patients (11.8%, HF+ group). During the study, 8.3% of HF+ patients died vs. 1.7% of patients without HFH (HF- group) (p = 0.047). CRP₂₄, CRP_DC, and CRP_1M were significantly higher in HF+ compared to HF- group. The median CRP_1M in HF+ group was 2.57 mg/L indicating low-grade systemic inflammation, in contrast to 1.54 mg/L in HF- group. CRP_1M ≥ 2 mg/L occurred in 58.3% of HF+ vs. 42.8% of HF- group (p = 0.01). Kaplan–Meier analysis showed decreased probability of survival free from HFH in patients with CRP₂₄ (p < 0.001), CRP_DC (p < 0.001), and CRP_1M (p = 0.03) in quartile IV compared to lower quartiles. In multivariable analysis, CRP_DC significantly improved prediction of HFH over a multi-year period post-STEMI. Persistent elevation in CRP post STEMI aids in risk stratification for long-term HF and suggests that ongoing cardiac and low-grade systemic inflammation promote HF development despite guideline-based therapies. Full article

(This article belongs to the Special Issue Heart Failure: From Molecular Basis to Therapy 2.0)

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Review

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18 pages, 723 KiB

Open AccessReview

Targeting Mediators of Inflammation in Heart Failure: A Short Synthesis of Experimental and Clinical Results

by Timea Magdolna Szabo, Attila Frigy and Előd Ernő Nagy

Int. J. Mol. Sci. 2021, 22(23), 13053; https://doi.org/10.3390/ijms222313053 - 2 Dec 2021

Cited by 16 | Viewed by 3265

Abstract

Inflammation has emerged as an important contributor to heart failure (HF) development and progression. Current research data highlight the diversity of immune cells, proteins, and signaling pathways involved in the pathogenesis and perpetuation of heart failure. Chronic inflammation is a major cardiovascular risk [...] Read more.

Inflammation has emerged as an important contributor to heart failure (HF) development and progression. Current research data highlight the diversity of immune cells, proteins, and signaling pathways involved in the pathogenesis and perpetuation of heart failure. Chronic inflammation is a major cardiovascular risk factor. Proinflammatory signaling molecules in HF initiate vicious cycles altering mitochondrial function and perturbing calcium homeostasis, therefore affecting myocardial contractility. Specific anti-inflammatory treatment represents a novel approach to prevent and slow HF progression. This review provides an update on the putative roles of inflammatory mediators involved in heart failure (tumor necrosis factor-alpha; interleukin 1, 6, 17, 18, 33) and currently available biological and non-biological therapy options targeting the aforementioned mediators and signaling pathways. We also highlight new treatment approaches based on the latest clinical and experimental research. Full article

(This article belongs to the Special Issue Heart Failure: From Molecular Basis to Therapy 2.0)

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28 pages, 1360 KiB

Open AccessReview

Myocardial Tissue Characterization in Heart Failure with Preserved Ejection Fraction: From Histopathology and Cardiac Magnetic Resonance Findings to Therapeutic Targets

by Paolo Severino, Andrea D’Amato, Silvia Prosperi, Francesca Fanisio, Lucia Ilaria Birtolo, Bettina Costi, Lucrezia Netti, Cristina Chimenti, Carlo Lavalle, Viviana Maestrini, Massimo Mancone and Francesco Fedele

Int. J. Mol. Sci. 2021, 22(14), 7650; https://doi.org/10.3390/ijms22147650 - 17 Jul 2021

Cited by 18 | Viewed by 3813

Abstract

Heart failure with preserved ejection fraction (HFpEF) is a complex clinical syndrome responsible for high mortality and morbidity rates. It has an ever growing social and economic impact and a deeper knowledge of molecular and pathophysiological basis is essential for the ideal management [...] Read more.

Heart failure with preserved ejection fraction (HFpEF) is a complex clinical syndrome responsible for high mortality and morbidity rates. It has an ever growing social and economic impact and a deeper knowledge of molecular and pathophysiological basis is essential for the ideal management of HFpEF patients. The association between HFpEF and traditional cardiovascular risk factors is known. However, myocardial alterations, as well as pathophysiological mechanisms involved are not completely defined. Under the definition of HFpEF there is a wide spectrum of different myocardial structural alterations. Myocardial hypertrophy and fibrosis, coronary microvascular dysfunction, oxidative stress and inflammation are only some of the main pathological detectable processes. Furthermore, there is a lack of effective pharmacological targets to improve HFpEF patients’ outcomes and risk factors control is the primary and unique approach to treat those patients. Myocardial tissue characterization, through invasive and non-invasive techniques, such as endomyocardial biopsy and cardiac magnetic resonance respectively, may represent the starting point to understand the genetic, molecular and pathophysiological mechanisms underlying this complex syndrome. The correlation between histopathological findings and imaging aspects may be the future challenge for the earlier and large-scale HFpEF diagnosis, in order to plan a specific and effective treatment able to modify the disease’s natural course. Full article

(This article belongs to the Special Issue Heart Failure: From Molecular Basis to Therapy 2.0)

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14 pages, 1739 KiB

Open AccessReview

From Genetic Mutations to Molecular Basis of Heart Failure Treatment: An Overview of the Mechanism and Implication of the Novel Modulators for Cardiac Myosin

by Yu-Jen Chen, Chian-Shiu Chien, Chern-En Chiang, Chen-Huan Chen and Hao-Min Cheng

Int. J. Mol. Sci. 2021, 22(12), 6617; https://doi.org/10.3390/ijms22126617 - 21 Jun 2021

Cited by 7 | Viewed by 5836

Abstract

Heart failure (HF) is a syndrome encompassing several important etiologies that lead to the imbalance between oxygen demand and supply. Despite the usage of guideline-directed medical therapy for HF has shown better outcomes, novel therapeutic strategies are desirable, especially for patients with preserved [...] Read more.

Heart failure (HF) is a syndrome encompassing several important etiologies that lead to the imbalance between oxygen demand and supply. Despite the usage of guideline-directed medical therapy for HF has shown better outcomes, novel therapeutic strategies are desirable, especially for patients with preserved or mildly reduced left ventricular ejection fraction. In this regard, understanding the molecular basis for cardiomyopathies is expected to fill in the knowledge gap and generate new therapies to improve prognosis for HF. This review discusses an evolutionary mechanism designed to regulate cardiac contraction and relaxation through the most often genetically determined cardiomyopathies associated with HF. In addition, both the myosin inhibitor and myosin activator are promising new treatments for cardiomyopathies. A comprehensive review from genetic mutations to the molecular basis of direct sarcomere modulators will help shed light on future studies for a better characterization of HF etiologies and potential therapeutic targets. Full article

(This article belongs to the Special Issue Heart Failure: From Molecular Basis to Therapy 2.0)

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