scholarly journals Dysfunction of the β2-spectrin-based pathway in human heart failure

2016 ◽  
Vol 310 (11) ◽  
pp. H1583-H1591 ◽  
Author(s):  
Sakima A. Smith ◽  
Langston D. Hughes ◽  
Crystal F. Kline ◽  
Amber N. Kempton ◽  
Lisa E. Dorn ◽  
...  
Keyword(s):  
Heart Failure ◽  
Cardiovascular Disease ◽  
Left Ventricle ◽  
Small Animal ◽  
Left Ventricular ◽  
Effector Proteins ◽  
Human Heart Failure ◽  
Protein Levels ◽  
Ankyrin B

β2-Spectrin is critical for integrating membrane and cytoskeletal domains in excitable and nonexcitable cells. The role of β2-spectrin for vertebrate function is illustrated by dysfunction of β2-spectrin-based pathways in disease. Recently, defects in β2-spectrin association with protein partner ankyrin-B were identified in congenital forms of human arrhythmia. However, the role of β2-spectrin in common forms of acquired heart failure and arrhythmia is unknown. We report that β2-spectrin protein levels are significantly altered in human cardiovascular disease as well as in large and small animal cardiovascular disease models. Specifically, β2-spectrin levels were decreased in atrial samples of patients with atrial fibrillation compared with tissue from patients in sinus rhythm. Furthermore, compared with left ventricular samples from nonfailing hearts, β2-spectrin levels were significantly decreased in left ventricle of ischemic- and nonischemic heart failure patients. Left ventricle samples of canine and murine heart failure models confirm reduced β2-spectrin protein levels. Mechanistically, we identify that β2-spectrin levels are tightly regulated by posttranslational mechanisms, namely Ca2+- and calpain-dependent proteases. Furthermore, consistent with this data, we observed Ca2+- and calpain-dependent loss of β2-spectrin downstream effector proteins, including ankyrin-B in heart. In summary, our findings illustrate that β2-spectrin and downstream molecules are regulated in multiple forms of cardiovascular disease via Ca2+- and calpain-dependent proteolysis.

scholarly journals Role of the fatty acid-binding protein 4 in heart failure and cardiovascular disease

2017 ◽  
Vol 233 (3) ◽  
pp. R173-R184 ◽  
Author(s):  
Ricardo Rodríguez-Calvo ◽  
Josefa Girona ◽  
Josep M Alegret ◽  
Alba Bosquet ◽  
Daiana Ibarretxe ◽  
...  
Keyword(s):  
Heart Failure ◽  
Cardiovascular Disease ◽  
Fatty Acid ◽  
Fatty Acid Binding Protein ◽  
Binding Protein ◽  
Left Ventricular ◽  
Aetiological Factor ◽  
Fatty Acid Binding ◽  
Acid Binding Protein

Obesity and ectopic fat accumulation in non-adipose tissues are major contributors to heart failure (HF) and cardiovascular disease (CVD). Adipocytes act as endocrine organs by releasing a large number of bioactive molecules into the bloodstream, which participate in a communication network between white adipose tissue and other organs, including the heart. Among these molecules, fatty acid-binding protein 4 (FABP4) has recently been shown to increase cardiometabolic risk. Both clinical and experimental evidence have identified FABP4 as a relevant player in atherosclerosis and coronary artery disease, and it has been directly related to cardiac alterations such as left ventricular hypertrophy (LVH) and both systolic and diastolic cardiac dysfunction. The available interventional studies preclude the establishment of a direct causal role of this molecule in CVD and HF and propose FABP4 as a biomarker rather than as an aetiological factor. However, several experimental reports have suggested that FABP4 may act as a direct contributor to cardiac metabolism and physiopathology, and the pharmacological targeting of FABP4 may restore some of the metabolic alterations that are conducive to CVD and HF. Here, we review the current knowledge regarding FABP4 in the context of HF and CVD as well as the molecular basis by which this protein participates in the regulation of cardiac function.

Accelerated onset of heart failure in mice during pressure overload with chronically decreased SERCA2 calcium pump activity

2004 ◽  
Vol 286 (3) ◽  
pp. H1146-H1153 ◽  
Author(s):  
Jo El J. Schultz ◽  
Betty J. Glascock ◽  
Sandra A. Witt ◽  
Michelle L. Nieman ◽  
Kalpana J. Nattamai ◽  
...  
Keyword(s):  
Heart Failure ◽  
Cardiac Contractility ◽  
Pressure Overload ◽  
Left Ventricular ◽  
Wild Type ◽  
Human Heart Failure ◽  
Protein Levels ◽  
Plasmic Reticulum ◽  
Lv Mass ◽  
Pump Activity

We recently developed a mouse model with a single functional allele of Serca2 ( Serca2+/–) that shows impaired cardiac contractility and relaxation without overt heart disease. The goal of this study was to test the hypothesis that chronic reduction in sarco(endo)plasmic reticulum Ca2+-ATPase (SERCA)2 levels in combination with an increased hemodynamic load will result in an accelerated pathway to heart failure. Age-matched wild-type and Serca2+/– mice were subjected to 10 wk of pressure overload via transverse aortic coarctation surgery. Cardiac hypertrophy and heart failure were assessed by echocardiography, gravimetry/histology, hemodynamics, and Western blotting analyses. Our results showed that ∼64% of coarcted Serca2+/– mice were in heart failure compared with 0% of coarcted wild-type mice ( P < 0.05). Overall, morbidity and mortality were greatly increased in Serca2+/– mice under pressure overload. Echocardiography assessment revealed a significant increase in left ventricular (LV) mass, and LV hypertrophy in coarcted Serca2+/– mice converted from a concentric to an eccentric pattern, similar to that seen in human heart failure. Coarcted Serca2+/– mice had decreased contractile/systolic and relaxation/diastolic performance and/or function compared with coarcted wild-type mice ( P < 0.05), despite a similar duration and degree of pressure overload. SERCA2a protein levels were significantly reduced (>50%) in coarcted Serca2+/– mice compared with noncoarcted and coarcted wild-type mice. Our findings suggest that reduction in SERCA2 levels in combination with an increased hemodynamic load results in an accelerated pathway to heart failure.

Abstract 86: Cardiomyocyte-Specific Ablation of Nuclear Respiratory Factor 1 in the Mouse Leads to Dysregulation of Mitochondrial Biogenesis, Apoptosis, and Heart Failure

2014 ◽  
Vol 115 (suppl_1) ◽  
Author(s):  
Jeffrey E Keenan ◽  
Hagir Sulliman ◽  
Allison Ulrich ◽  
Lan Mao ◽  
Claude A Piantadosi
Keyword(s):  
Heart Failure ◽  
Mitochondrial Biogenesis ◽  
Structural Integrity ◽  
Left Ventricular ◽  
Nuclear Condensation ◽  
Nuclear Respiratory Factor ◽  
Protein Levels ◽  
Mitochondrial Homeostasis ◽  
Nuclear Respiratory Factor 1

The DNA-binding transcription factor Nuclear Respiratory Factor 1 (NRF1) regulates mitochondrial homeostasis. Its constitutive ablation in the mouse is embryonically lethal (~E3.5). This has limited our understanding of NRF1 functionality in the heart, where mitochondrial dysfunction is often a major pathogenic factor. Therefore, we generated conditional cardiomyocyte-specific NRF1 knockout mice (MYH6-mer-Cre-mer-NRF1fl/fl or NRFfl/fl) to elucidate the role of cardiac NRF1. Two weeks after NRF1 silencing, echocardiography of NRF1fl/fl hearts revealed significant reductions in left ventricular fractional shortening (Figure A). Histology demonstrated degradation of cellular structural integrity and nuclear condensation (Figure B), with a high number of TUNEL positive nuclei compared to littermate controls (MYH6-mer-Cre-mer-NRF-1wt), indicative of apoptosis (37.8% vs. 1.1%, p < 0.001). The mRNA and protein levels of key mediators of mitochondrial biogenesis were evaluated by real-time RT-PCR and immunoblotting (Figure C & D). Compared to littermate controls, there was down-regulation of the mitochondrial encoded NADH dehydrogenase 1, implying a reduction of functional mitochondrial mass. Key biogenesis regulators PGC1-α (protein only), Nfe2l2, and NRF2 were also reduced. In total, these data support that dysregulation of mitochondrial biogenesis after loss of NRF1 results in cardiomyocyte apoptosis and reduced left ventricular function. These findings and further delineation of the mechanisms involved should lay the foundation for the exploitation of NRF1 as a therapeutic target in heart failure.

scholarly journals Bilirubin and cardiovascular risk

2021 ◽  
Vol 26 (9) ◽  
pp. 4511
Author(s):  
O. M. Drapkina ◽  
A. Ya. Kravchenko ◽  
A. V. Budnevsky ◽  
A. V. Kontsevaya ◽  
M. S. Ryaskina ◽  
...  
Keyword(s):  
Heart Failure ◽  
Cardiovascular Disease ◽  
Cardiovascular Diseases ◽  
Collateral Circulation ◽  
Cardiovascular Events ◽  
Left Ventricular ◽  
Ischemic Damage ◽  
Endogenous Antioxidant ◽  
Atherosclerotic Cardiovascular Diseases

This literature review demonstrates the results of experimental and clinical studies, as well as data from meta-analyzes on the effect of bilirubin levels on cardiovascular system. Recent studies provided a new look at the role of bilirubin in cardiovascular disease. Modern concepts consider bilirubin as a powerful endogenous antioxidant with anti-inflammatory effects, capable of influencing the course of atherosclerotic cardiovascular diseases and reducing ischemic damage. The change in bilirubin levels affects the coronary blood flow, the development of collateral circulation and the morphology of coronary plaques. A low bilirubin level is associated with an increase in left ventricular mass and a decrease in its contractility, which, in turn, leads to heart failure and increases the risk of rehospitalizations. Taking into account the above effects of bilirubin, there was interest in assessing the effect of its blood level on the risk of atherosclerotic cardiovascular diseases. Recent studies have attempted to create risk stratification models for adverse cardiovascular events based on bilirubin levels.

The Results of the Use of Angiotensin Receptor Inhibitors and Neprilisin in Secondary Functional Mitral Regurgitation in Outpatient Practice

2020 ◽  
Vol 75 (5) ◽  
pp. 514-522
Author(s):  
Alexey S. Ryazanov ◽  
Konstantin I. Kapitonov ◽  
Mariya V. Makarovskaya ◽  
Alexey A. Kudryavtsev
Keyword(s):  
Heart Failure ◽  
Left Ventricle ◽  
Mitral Regurgitation ◽  
Effective Area ◽  
Left Ventricular ◽  
Functional Mitral Regurgitation ◽  
Angiotensin Receptor ◽  
Optimal Drug ◽  
Patients With Heart Failure ◽  
Valsartan Group

Background. Morbidity and mortality in patients with functional mitral regurgitation (FMR) remains high, however, no pharmacological therapy has been proven to be effective.Aimsto study the effect of sacubitrile/valsartan and valsartan on functional mitral regurgitation in chronic heart failure.Methods.This double-blind study randomly assigned sacubitrile/valsartan or valsartan in addition to standard drug therapy for heart failure among 100 patients with heart failure with chronic FMR (secondary to left ventricular (LV) dysfunction). The primary endpoint was a change in the effective area of the regurgitation hole during the 12-month follow-up. Secondary endpoints included changes in the volume of regurgitation, the final systolic volume of the left ventricle, the final diastolic volume of the left ventricle, and the area of incomplete closure of the mitral valves.Results.The decrease in the effective area of the regurgitation hole was significantly more pronounced in the sacubitrile/valsartan group than in the valsartan group (0.070.066against0.030.058sm2; p=0.018)in the treatment efficacy analysis, which included 100patients (100%). The regurgitation volume also significantly decreased in the sacubitrile/valsartan group compared to the valsartan group (mean difference:8.4ml; 95%CI, from 13.2 until 1.9;р=0.21). There were no significant differences between the groups regarding changes in the area ofincomplete closure of the mitral valves and LV volumes, with the exception of the index of the final LV diastolic volume (p=0.07).Conclusion.Among patients with secondary FMR, sacubitril/valsartan reduced MR more than valsartan. Thus, angiotensin receptor inhibitors and neprilysin can be considered for optimal drug treatment of patients with heart failure and FMR.

scholarly journals Intracellular Na+ Modulates Pacemaking Activity in Murine Sinoatrial Node Myocytes: An In Silico Analysis

2021 ◽  
Vol 22 (11) ◽  
pp. 5645
Author(s):  
Stefano Morotti ◽  
Haibo Ni ◽  
Colin H. Peters ◽  
Christian Rickert ◽  
Ameneh Asgari-Targhi ◽  
...  
Keyword(s):  
Heart Failure ◽  
Membrane Potential ◽  
In Silico ◽  
Sinoatrial Node ◽  
In Silico Analysis ◽  
Ankyrin B ◽  
Deficient Mice ◽  
Silico Analysis ◽  
Bursting Activity

Background: The mechanisms underlying dysfunction in the sinoatrial node (SAN), the heart’s primary pacemaker, are incompletely understood. Electrical and Ca2+-handling remodeling have been implicated in SAN dysfunction associated with heart failure, aging, and diabetes. Cardiomyocyte [Na+]i is also elevated in these diseases, where it contributes to arrhythmogenesis. Here, we sought to investigate the largely unexplored role of Na+ homeostasis in SAN pacemaking and test whether [Na+]i dysregulation may contribute to SAN dysfunction. Methods: We developed a dataset-specific computational model of the murine SAN myocyte and simulated alterations in the major processes of Na+ entry (Na+/Ca2+ exchanger, NCX) and removal (Na+/K+ ATPase, NKA). Results: We found that changes in intracellular Na+ homeostatic processes dynamically regulate SAN electrophysiology. Mild reductions in NKA and NCX function increase myocyte firing rate, whereas a stronger reduction causes bursting activity and loss of automaticity. These pathologic phenotypes mimic those observed experimentally in NCX- and ankyrin-B-deficient mice due to altered feedback between the Ca2+ and membrane potential clocks underlying SAN firing. Conclusions: Our study generates new testable predictions and insight linking Na+ homeostasis to Ca2+ handling and membrane potential dynamics in SAN myocytes that may advance our understanding of SAN (dys)function.

scholarly journals Association of Lipoprotein (a) variants with risk of cardiovascular disease: a Mendelian randomization study

2021 ◽  
Vol 20 (1) ◽  
Author(s):  
Juan Xia ◽  
Chunyue Guo ◽  
Kuo Liu ◽  
Yunyi Xie ◽  
Han Cao ◽  
...  
Keyword(s):  
Heart Failure ◽  
Atrial Fibrillation ◽  
Cardiovascular Disease ◽  
Chinese Population ◽  
Left Ventricular Mass Index ◽  
Mendelian Randomization ◽  
Left Ventricular ◽  
Han Chinese ◽  
Han Chinese Population ◽  
Internal Dimension

Abstract Background There is a well-documented empirical relationship between lipoprotein (a) [Lp(a)] and cardiovascular disease (CVD); however, causal evidence, especially from the Chinese population, is lacking. Therefore, this study aims to estimate the causal association between variants in genes affecting Lp(a) concentrations and CVD in people of Han Chinese ethnicity. Methods Two-sample Mendelian randomization analysis was used to assess the causal effect of Lp(a) concentrations on the risk of CVD. Summary statistics for Lp(a) variants were obtained from 1256 individuals in the Cohort Study on Chronic Disease of Communities Natural Population in Beijing, Tianjin and Hebei. Data on associations between single-nucleotide polymorphisms (SNPs) and CVD were obtained from recently published genome-wide association studies. Results Thirteen SNPs associated with Lp(a) levels in the Han Chinese population were used as instrumental variables. Genetically elevated Lp(a) was inversely associated with the risk of atrial fibrillation [odds ratio (OR), 0.94; 95% confidence interval (95%CI), 0.901–0.987; P = 0.012)], the risk of arrhythmia (OR, 0.96; 95%CI, 0.941–0.990; P = 0.005), the left ventricular mass index (OR, 0.97; 95%CI, 0.949–1.000; P = 0.048), and the left ventricular internal dimension in diastole (OR, 0.97; 95%CI, 0.950–0.997; P = 0.028) according to the inverse-variance weighted method. No significant association was observed for congestive heart failure (OR, 0.99; 95% CI, 0.950–1.038; P = 0.766), ischemic stroke (OR, 1.01; 95%CI, 0.981–1.046; P = 0.422), and left ventricular internal dimension in systole (OR, 0.98; 95%CI, 0.960–1.009; P = 0.214). Conclusions This study provided evidence that genetically elevated Lp(a) was inversely associated with atrial fibrillation, arrhythmia, the left ventricular mass index and the left ventricular internal dimension in diastole, but not with congestive heart failure, ischemic stroke, and the left ventricular internal dimension in systole in the Han Chinese population. Further research is needed to identify the mechanism underlying these results and determine whether genetically elevated Lp(a) increases the risk of coronary heart disease or other CVD subtypes.

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