Abstract 17053: Cardiac AKAP12 Signalosome Overexpression Exacerbation of Heart Failure and Cardiac Calcium Handling

Circulation ◽  
2020 ◽  
Vol 142 (Suppl_3) ◽  
Author(s):  
Hanan Qasim ◽  
Bradley K McConnell
Keyword(s):  
Heart Failure ◽  
Protein Expression ◽  
Left Ventricular ◽  
Cardiac Contraction ◽  
Calcium Handling ◽  
Left Ventricular Ejection ◽  
Mrna Levels ◽  
Control Groups ◽  
Ventricular Ejection Fraction ◽  
Males And Females

Introduction: Heart failure (HF) is responsible for 1 out of 8 deaths per year in the U.S.A. and is the major cause of death globally. Calcium cycling is crucial for proper signaling processes and efficient cardiac contraction. In failing hearts, remodeled calcium handling contributes to cardiac dysfunction. Previously we reported enhanced cardiac function in mice lacking a functional A-Kinase Anchoring Protein 12 (AKAP12). In this study, we aim to investigate the role of AKAP12 overexpression (oxAKAP12) on heart failure progression through assessing Sarco/Endoplasmic Reticulum Ca2+-ATPase (SERCA2) and its regulatory protein Phospholamban (PLN). Hypothesis: Cardiac AKAP12 overexpression potentiates HF development through its action on SERCA2. Methods: HF was developed in WT and oxAKAP12-Tg mice of 8-10 weeks old males and females, through chronic Isoproterenol (ISO) administration (60 mg/kg/day for 14-days). Left ventricular homogenates were used for gene expression analysis. Furthermore, AKAP12 was transiently overexpressed in AC16 cells (human cardiomyocytes cell line), to assess protein expression levels upon treatment with 100 nM of ISO for 12-hrs. Results: Cardiac oxAKAP12 in both males and females reduced left ventricular ejection fraction (EF) by 14.5±2.5% and fractional shortening (FS) by 22.7±2.0% after 14-days of chronic ISO treatment when compared to control groups. Both RNA sequencing and RTqPCR analysis showed a significant reduction of SERCA2 and PLN mRNA levels, respectively, in left ventricular homogenates of male (53.5±2.0%, 39.0±2.5%) and female (50.0±2.5%, 45.0±2.0%) groups overexpressing AKAP12 treated with ISO (14-days) compared to control groups (p<0.005). In AC16 cells overexpressing AKAP12 and treated with ISO, SERCA2 protein expression was reduced by 37% (p=0.0413) while PLN protein expression was not significantly reduced compared to control groups. Conclusions: Cardiac oxAKAP12 negatively influences systolic function in both male and female mice, potentially through affecting calcium handling, which will be assessed in future experiments by evaluating calcium transients and sarcomere shortening in isolated primary cardiomyocytes from oxAKAP12 and control mice.

scholarly journals Velvet Antler Ameliorates Cardiac Function by Restoring Sarcoplasmic Reticulum Ca2+-ATPase Activity in Rats With Heart Failure After Myocardial Infarction

2021 ◽  
Vol 12 ◽  
Author(s):  
Haoyue Shi ◽  
Tianzi Zhao ◽  
Yanjun Li ◽  
Xiang Xiao ◽  
Jiayun Wu ◽  
...  
Keyword(s):  
Heart Failure ◽  
Cardiac Function ◽  
Protein Expression ◽  
Ischemia Reperfusion ◽  
Left Ventricular ◽  
Left Ventricular Ejection ◽  
Histopathological Analysis ◽  
Mrna Levels ◽  
Ventricular Ejection Fraction ◽  
Velvet Antler

Objective: Velvet antler (VA; cornu cervi pantotrichum), a well-known traditional Chinese medicine, has been shown to exert cardioprotective effects. The purpose of this study was to investigate the effect of VA on heart failure (HF) caused by ischemia-reperfusion, and explore its possible mechanism from the regulation of sarcoplasmic/endoplasmic reticulum Ca2+-ATPase 2 alpha (SERCA2a).Methods: A rat model of HF was established by ligating the left anterior descending coronary artery of male Sprague–Dawley rats (n = 88). One week after surgery, VA (200, 400, or 800 mg/[kg day−1]) or enalapril (1 mg/[kg day−1]) was administered daily for the next 4 weeks. Heart function was detected by echocardiography and histopathological analysis. The serum BNP level was measured by ELISA, and the expression of SERCA2a, PLB, PLB-Ser16, and PKA was determined by western blotting. SERCA2a and PLB mRNA levels were determined by real-time quantitative PCR.Results: Compared with the sham group, cardiac function in the HF group, including the serum BNP level, heart mass index, myocardial collagen deposition, and left ventricular ejection fraction, was markedly reduced; however, these changes could be reversed by VA treatment. In addition, VA (200 mg/[kg·d−1]) inhibited the decrease of SERCA2a and PLB mRNA levels and SERCA2a, PLB, PLB-Ser16, and PKA protein expression and restored the activity of SERCA2a and PKA. Enalapril affected only PLB protein expression.Conclusion: VA can improve myocardial fibrosis and ventricular remodeling in rats, thereby helping to restore cardiac function. The underlying mechanism may be related to the upregulation of the expression and activation of PKA and PLB and the restoration of the expression and activity of SERCA2a.

scholarly journals Current evidence-based therapy does not restore plasma apelin level in phenotypically diverse chronic heart failure patients

2017 ◽  
Vol 6 (2) ◽  
pp. 316 ◽  
Author(s):  
Vinu Wilson ◽  
Pankaj Prabhakar ◽  
Sandeep Seth ◽  
Subir K. Maulik
Keyword(s):  
Heart Failure ◽  
Chronic Heart Failure ◽  
Nonparametric Tests ◽  
Left Ventricular ◽  
Left Ventricular Ejection ◽  
Current Evidence ◽  
Evidence Based ◽  
Mrna Levels ◽  
Ventricular Ejection Fraction ◽  
Plasma Apelin

Background: Apelin, endogenous peptide acting through its receptor (APJ), is the most potent inotropic agent known to man. Plasma apelin and cardiac APJ mRNA levels rise in early stages of chronic heart failure (CHF) but fall later in decompensated CHF. The effect of current evidence-based management of CHF on plasma apelin level is not known. We estimated change in plasma apelin level in CHF patients of diverse phenotypes treated with standard pharmacotherapy and compared it with the corresponding change in left ventricular ejection fraction (LVEF), plasma brain natriuretic peptide (BNP) level and quality of life (QoL).Methods: With ethical approval and written informed consent, venous blood samples were collected from 39 CHF [dilated cardiomyopathy (DCM) (n=21), restrictive cardiomyopathy (RCM) (n=9) and chronic constrictive pericarditis (CCP) (n=9)] patients and 10 age-matched healthy controls, at baseline and after 12 weeks. Plasma apelin and BNP were estimated by competitive ELISA (RayBiotech Inc.) and an auto-analyzer (Triage, Allere Inc.), respectively. QoL was assessed using Kansas City Cardiomyopathy Questionnaire (KCCQ). Nonparametric tests were applied and p-value <0.05 was considered significant.Results: Low LVEF, KCCQ score and high BNP levels were observed in all CHF patients compared to controls. Plasma apelin level was depressed in RCM and CCP patients compared to controls but not in DCM patients. These parameters did not change in any group after 3 months of standard pharmacotherapy.Conclusions: Current evidence-based management of CHF does not restore the depressed apelin-APJ axis. New drugs are required for specifically modulating this promising therapeutic target in CHF.

Metformin improves cardiac function in a nondiabetic rat model of post-MI heart failure

2011 ◽  
Vol 301 (2) ◽  
pp. H459-H468 ◽  
Author(s):  
Meimei Yin ◽  
Iwan C. C. van der Horst ◽  
Joost P. van Melle ◽  
Cheng Qian ◽  
Wiek H. van Gilst ◽  
...  
Keyword(s):  
Myocardial Infarction ◽  
Heart Failure ◽  
Cardiac Function ◽  
Left Ventricular ◽  
Left Ventricular Ejection ◽  
Oral Glucose ◽  
Mrna Levels ◽  
Ventricular Ejection Fraction ◽  
Glucose Levels ◽  
First Choice

Metformin is the first choice drug for the treatment of patients with diabetes, but its use is debated in patients with advanced cardiorenal disease. Epidemiological data suggest that metformin may reduce cardiac events, in patients both with and without heart failure. Experimental evidence suggests that metformin reduces cardiac ischemia-reperfusion injury. It is unknown whether metformin improves cardiac function (remodeling) in a long-term post-MI remodeling model. We therefore studied male, nondiabetic, Sprague-Dawley rats that were subjected to either myocardial infarction (MI) or sham operation. Animals were randomly allocated to treatment with normal water or metformin-containing water (250 mg·kg−1·day−1). At baseline, 6 wk, and 12 wk, metabolic parameters were analyzed and oral glucose tolerance tests (OGTT) were performed. Echocardiography and hemodynamic parameters were assessed 12 wk after MI. In the MI model, infarct size was significantly smaller after 12-wk metformin treatment (29.6 ± 3.2 vs. 38.0 ± 2.2%, P < 0.05). Moreover, metformin resulted in less left ventricular dilatation (6.0 ± 0.4 vs. 7.6 ± 0.6 mm, P < 0.05) and preservation of left ventricular ejection fraction (65.8 ± 3.7% vs. 48.6 ± 5.6%, P < 0.05) compared with MI control. The improved cardiac function was associated with decreased atrial natriuretic peptide mRNA levels in the metformin-treated group (50% reduction compared with MI, P < 0.05). Insulin resistance did not occur during cardiac remodeling (as indicated by normal OGTT) and fasting glucose levels and the pattern of the OGTT were not affected by metformin. Molecular analyses suggested that altered AMP kinase phosphorylation status and low insulin levels mediate the salutary effects of metformin. Altogether our results indicate that metformin may have potential to attenuate heart failure development after myocardial infarction, in the absence of diabetes and independent of systemic glucose levels.

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

2021 ◽  
Vol 22 (12) ◽  
pp. 6617
Author(s):  
Yu-Jen Chen ◽  
Chian-Shiu Chien ◽  
Chern-En Chiang ◽  
Chen-Huan Chen ◽  
Hao-Min Cheng
Keyword(s):  
Heart Failure ◽  
Molecular Basis ◽  
Oxygen Demand ◽  
Left Ventricular ◽  
Cardiac Contraction ◽  
Left Ventricular Ejection ◽  
Genetic Mutations ◽  
Ventricular Ejection Fraction ◽  
Novel Therapeutic Strategies ◽  
New Treatments

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.

Abstract 264: Nitrite Therapy Ameliorates Myocardial Injury via H2S and Nuclear Factor-Erythroid 2-Related Factor 2 (Nrf2)-Dependent Signaling in Chronic Heart Failure

2015 ◽  
Vol 117 (suppl_1) ◽  
Author(s):  
Kazi N Islam ◽  
Erminia Donnarumma ◽  
Shashi Bhushan ◽  
David J Lefer
Keyword(s):  
Heart Failure ◽  
Ischemia Reperfusion Injury ◽  
Ischemia Reperfusion ◽  
Left Ventricular ◽  
Antioxidant Defenses ◽  
Left Ventricular Ejection ◽  
Related Factor ◽  
Mrna Levels ◽  
Ventricular Ejection Fraction ◽  
Nrf2 Activation

Background: Nitric oxide (NO) and hydrogen sulfide (H 2 S) are reduced in congestive heart failure. Recent studies suggest cross-talk between NO and H 2 S signaling. We previously reported that sodium nitrite (NaNO 2 ) significantly ameliorates myocardial ischemia-reperfusion injury and heart failure. Nrf2 regulates the expression of antioxidant protein genes and is upregulated by H 2 S. We examined the effects of NaNO 2 therapy on endogenous H 2 S bioavailability and Nrf2 activation in mice subjected to ischemia-induced heart failure. Materials and Methods: Mice underwent 60 min. of left coronary artery occlusion and 4 weeks (WKS) of reperfusion. NaNO 2 (165 μg/kg) or saline vehicle (VEH) was administered at reperfusion and then in drinking water (100 mg/L) for 4 wks. Left ventricular ejection fraction (LVEF) was determined at baseline and 4 wks of reperfusion. Myocardial tissue was collected and analyzed for oxidative stress status and respective gene/protein levels. Results: NaNO 2 therapy preserved LVEF (47 ± 4% vs. 32 ± 4%, p < 0.01) and LV diastolic and systolic dimensions (LVEDD/LVESD; 4.0/3.1 mm vs. 4.5/3.9 mm, p < 0.05) at 4 wks. MDA and protein carbonyl contents were significantly reduced in NaNO 2 treated mice as compared to VEH. NaNO 2 markedly increased expression of CuZn-superoxide dismutase and catalase at 4 wks. Furthermore, NaNO 2 increased mRNA levels of H 2 S producing enzymes and H 2 S bioavailabilty. Cardiac Nrf2 activation was also observed with NaNO 2 therapy. Conclusions: Our results demonstrate that NaNO 2 therapy significantly improves left ventricular function via by increasing H 2 S bioavailability, activation of Nrf2, and increased antioxidant defenses.1

Efficacy of Vitamin D on Chronic Heart Failure Among Adults

2020 ◽  
Vol 90 (1-2) ◽  
pp. 49-58 ◽  
Author(s):  
Wang Chunbin ◽  
Wang Han ◽  
Cai Lin
Keyword(s):  
Heart Failure ◽  
Vitamin D ◽  
Chronic Heart Failure ◽  
Left Ventricular Ejection Fraction ◽  
Confidence Interval ◽  
Left Ventricular ◽  
Left Ventricular Ejection ◽  
Controlled Trials ◽  
Ventricular Ejection Fraction ◽  
Randomized Controlled

Abstract. Vitamin D deficiency commonly occurs in chronic heart failure. Whether additional vitamin D supplementation can be beneficial to adults with chronic heart failure remains unclear. We conducted a meta-analysis to derive a more precise estimation. PubMed, Embase, and Cochrane databases were searched on September 8, 2016. Seven randomized controlled trials that investigated the effects of vitamin D on cardiovascular outcomes in adults with chronic heart failure, and comprised 592 patients, were included in the analysis. Compared to placebo, vitamin D, at doses ranging from 2,000 IU/day to 50,000 IU/week, could not improve left ventricular ejection fraction (Weighted mean difference, WMD = 3.31, 95% confidence interval, CL = −0.93 to 7.55, P < 0.001, I2 = 92.1%); it also exerts no beneficial effects on the 6 minute walk distance (WMD = 18.84, 95% CL = −24.85 to 62.52, P = 0.276, I2 = 22.4%) and natriuretic peptide (Standardized mean difference, SMD = −0.39, 95% confidence interval CL = −0.48 to 0.69, P < 0.001, I2 = 92.4%). However, a dose-response analysis from two studies demonstrated an improved left ventricular ejection fraction with vitamin D at a dose of 4,000 IU/day (WMD = 6.58, 95% confidence interval CL = −4.04 to 9.13, P = 0.134, I2 = 55.4%). The results showed that high dose vitamin D treatment could potentially benefit adults with chronic heart failure, but more randomized controlled trials are required to confirm this result.

Emerging Cardiac Resynchronisation Therapy Indications

2011 ◽  
Vol 7 (1) ◽  
pp. 29
Author(s):  
Charlotte Eitel ◽  
Gerhard Hindricks ◽  
Christopher Piorkowski ◽  
◽  
◽  
...  
Keyword(s):  
Heart Failure ◽  
Systolic Heart Failure ◽  
Cardiac Resynchronisation Therapy ◽  
Left Ventricular ◽  
Left Ventricular Ejection ◽  
Current Evidence ◽  
Class Iii ◽  
Ventricular Ejection Fraction ◽  
Cardiac Resynchronisation ◽  
Resynchronisation Therapy

Cardiac resynchronisation therapy (CRT) is an efficacious and cost-effective therapy in patients with highly symptomatic systolic heart failure and delayed ventricular conduction. Current guidelines recommend CRT as a class I indication for patients with sinus rhythm, New York Heart Association (NYHA) functional class III or ambulatory class IV, a QRS duration ≥120ms, and left ventricular ejection fraction (LVEF) ≤35%, despite optimal pharmacological therapy. Recent trials resulted in an extension of current recommendations to patients with mild heart failure, patients with atrial fibrillation, and patients with an indication for permanent right ventricular pacing with the aim of morbidity reduction. The effectiveness of CRT in patients with narrow QRS, patients with end-stage heart failure and cardiogenic shock, and patients with an LVEF >35% still needs to be proved. This article reviews current evidence and clinical applications of CRT in heart failure and provides an outlook on future developments.

Heart Failure with Preserved Ejection Fraction – A Review

2012 ◽  
Vol 9 (1) ◽  
pp. 90-95 ◽  
Author(s):  
Otto A Smiseth ◽  
Anders Opdahl ◽  
Espen Boe ◽  
Helge Skulstad
Keyword(s):  
Heart Failure ◽  
Ejection Fraction ◽  
Diastolic Heart Failure ◽  
The Elderly ◽  
Left Ventricular ◽  
Filling Pressure ◽  
Left Ventricular Ejection ◽  
Ventricular Ejection Fraction ◽  
Reduced Ejection Fraction ◽  
Objective Evidence

Heart failure with preserved left ventricular ejection fraction (HF-PEF), sometimes named diastolic heart failure, is a common condition most frequently seen in the elderly and is associated with arterial hypertension and left ventricular (LV) hypertrophy. Symptoms are attributed to a stiff left ventricle with compensatory elevation of filling pressure and reduced ability to increase stroke volume by the Frank-Starling mechanism. LV interaction with stiff arteries aggravates these problems. Prognosis is almost as severe as for heart failure with reduced ejection fraction (HF-REF), in part reflecting co-morbidities. Before the diagnosis of HF-PEF is made, non-cardiac etiologies must be excluded. Due to the non-specific nature of heart failure symptoms, it is essential to search for objective evidence of diastolic dysfunction which, in the absence of invasive data, is done by echocardiography and demonstration of signs of elevated LV filling pressure, impaired LV relaxation, or increased LV diastolic stiffness. Antihypertensive treatment can effectively prevent HF-PEF. Treatment of HF-PEF is symptomatic, with similar drugs as in HF-REF.

A translational model of chronic heart failure in rats

2018 ◽  
pp. 136-148
Author(s):  
С.А. Крыжановский ◽  
И.Б. Цорин ◽  
Е.О. Ионова ◽  
В.Н. Столярук ◽  
М.Б. Вититнова ◽  
...  
Keyword(s):  
Myocardial Infarction ◽  
Heart Failure ◽  
Chronic Heart Failure ◽  
Left Ventricular ◽  
Compensatory Hypertrophy ◽  
Experimental Myocardial Infarction ◽  
Left Ventricular Ejection ◽  
Translational Model ◽  
Innovative Drug ◽  
Ventricular Ejection Fraction

Цель исследования - разработка трансляционной модели хронической сердечной недостаточности (ХСН) у крыс, позволяющей, с одной стороны, изучить тонкие механизмы, лежащие в основе данной патологии, а с другой стороны, выявить новые биомишени для поиска и изучения механизма действия инновационных лекарственных средств. Методика. Использован комплекс эхокардиографических, морфологических, биохимических и молекулярно-биологических исследований, позволяющий оценивать и дифференцировать этапы формирования ХСН. Результаты. Динамические эхокардиографические исследования показали, что ХСН формируется через 90 дней после воспроизведения переднего трансмурального инфаркта миокарда. К этому времени у животных основной группы отмечается статистически значимое по сравнению со 2-ми сут. после воспроизведения экспериментального инфаркта миокарда снижение ФВ левого желудочка сердца (соответственно 55,9 ± 1,4 и 63,9 ± 1,6%, р = 0,0008). Снижение насосной функции сердца (на 13% по сравнению со 2-ми сут. после операции и на ~40% по сравнению с интактными животными) сопровождается увеличением КСР и КДР (соответственно с 2,49 ± 0,08 до 3,91 ± 0,17 мм, р = 0,0002, и с 3,56 ± 0,11 до 5,20 ± 0,19 мм, р = 0,0001), то есть к этому сроку развивается сердечная недостаточность. Результаты эхокардиографических исследований подтверждены данными морфометрии миокарда, продемонстрировавшими дилатацию правого и левого желудочков сердца. Параллельно проведенные гистологические исследования свидетельствуют о наличии патогномоничных для данной патологии изменений миокарда (постинфарктный кардиосклероз, компенсаторная гипертрофия кардиомиоцитов, очаги исчезновения поперечной исчерченности мышечных волокон и т.д.) и признаков венозного застоя в легких и печени. Биохимические исследования выявили значимое увеличение концентрации в плазме крови биохимического маркера ХСН - мозгового натрийуретического пептида. Данные молекулярно-биологических исследований позволяют говорить о наличии гиперактивности ренин-ангиотензин-альдостероновой и симпатоадреналовой систем, играющих ключевую роль в патогенезе ХСН. Заключение. Разработана трансляционная модель ХСН у крыс, воспроизводящая основные клинико-диагностические критерии этого заболевания. Показано наличие корреляции между морфометрическими, гистологическими, биохимическими и молекулярными маркерами прогрессирующей ХСН и эхокардиографическими диагностическими признаками, что позволяет использовать неинвазивный метод эхокардиографии, характеризующий состояние внутрисердечной гемодинамики, в качестве основного критерия оценки наличия/отсутствия данной патологии. Aim. Development of a translational model for chronic heart failure (CHF) in rats to identify new biotargets for finding and studying mechanisms of innovative drug effect in this disease. Methods. A set of echocardiographic, morphological, biochemical, and molecular methods was used to evaluate and differentiate stages of CHF development. Results. Dynamic echocardiographic studies showed that CHF developed in 90 days after anterior transmural myocardial infarction. By that time, left ventricular ejection fraction was significantly decreased in animals of the main group compared with rats studied on day 2 after experimental myocardial infarction (55.9 ± 1.4% vs . 63.9 ± 1.6%, respectively, p<0.0008). The decrease in heart’s pumping function (by 13% compared with day 2 after infarction and by approximately 40% compared to intact animals) was associated with increased ESD and EDD (from 2.49 ± 0.08 to 3.91 ± 0.17 mm, p = 0.0002, and from 3.56 ± 0.11 to 5.20 ± 0.19 mm, respectively, p = 0.0001); therefore, heart failure developed by that time. The results of echocardiographic studies were confirmed by myocardial morphometry, which demonstrated dilatation of both right and left ventricles. Paralleled histological studies indicated presence of the changes pathognomonic for this myocardial pathology (postinfarction cardiosclerosis, compensatory hypertrophy of cardiomyocytes, foci of disappeared transverse striation of muscle fibers, etc.) and signs of venous congestion in lungs and liver. Biochemical studies demonstrated a significant increase in plasma concentration of brain natriuretic peptide, a biochemical marker of CHF. Results of molecular studies suggested hyperactivity of the renin-angiotensin-aldosterone and sympathoadrenal systems, which play a key role in the pathogenesis of CHF. Conclusions. A translational model of CHF in rats was developed, which reproduced major clinical and diagnostic criteria for this disease. Morphometric, histological, biochemical, and molecular markers for progressive CHF were correlated with echocardiographic diagnostic signs, which allows using this echocardiographic, noninvasive method characterizing the intracardiac hemodynamics as a major criterion for the presence / absence of this pathology.

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