Calcium Handling Remodeling Research Articles

Sex Differences in Electrophysiology and Calcium Handling in Atrial Health and Fibrillation.

The importance of biological sex on disease etiology and outcomes has long been underinvestigated. While recent focus on characterizing sex differences in cardiac pathophysiology has led to improved inclusion of both sexes in scientific studies and clinical trials, much is still unknown about underlying differences in normal cardiac physiology. This is particularly true for the atria, where the most common arrhythmia, atrial fibrillation (AF), occurs. AF is associated with adverse structural, electrophysiological, and calcium handling remodeling that leads to patient morbidity and mortality. Differences in the onset, prevalence, presentation, and prognosis of AF are known to differ between males and females, yet the sex-specific baseline phenotypes from which AF arises are not well characterized. This review examines what is currently known about sex differences in atrial physiology, the alterations that occur in AF, potential mechanisms underlying sex divergence, and the need for sex-targeted therapeutic strategies.

Nanoscale Study of Calcium Handling Remodeling in Right Ventricular Cardiomyocytes Following Pulmonary Hypertension.

Pulmonary hypertension is a complex disorder characterized by pulmonary vascular remodeling and right ventricular hypertrophy, leading to right heart failure. The mechanisms underlying this process are not well understood. We hypothesize that the structural remodeling occurring in the cardiomyocytes of the right ventricle affects the cytosolic Ca2+ handling leading to arrhythmias. After 12 days of monocrotaline-induced pulmonary hypertension in rats, epicardial mapping showed electrical remodeling in both ventricles. In myocytes isolated from the hypertensive rats, a combination of high-speed camera and confocal line-scan documented a prolongation of Ca2+ transients along with a higher local Ca2+-release activity. These Ca2+ transients were less synchronous than in controls, likely due to disorganized transverse-axial tubular system. In fact, following pulmonary hypertension, hypertrophied right ventricular myocytes showed significantly reduced number of transverse tubules and increased number of axial tubules; however, Stimulation Emission Depletion microscopy demonstrated that the colocalization of L-type Ca2+ channels and RyR2 (ryanodine receptor 2) remained unchanged. Finally, Stimulation Emission Depletion microscopy and super-resolution scanning patch-clamp analysis uncovered a decrease in the density of active L-type Ca2+ channels in right ventricular myocytes with an elevated open probability of the T-tubule anchored channels. This may represent a general mechanism of how nanoscale structural changes at the early stage of pulmonary hypertension impact on the development of the end stage failing phenotype in the right ventricle.

Profibrotic, Electrical, and Calcium-Handling Remodeling of the Atria in Heart Failure Patients With and Without Atrial Fibrillation.

Atrial fibrillation (AF) and heart failure (HF) are common cardiovascular diseases that often co-exist. Animal models have suggested complex AF-promoting atrial structural, electrical, and Ca2+-handling remodeling in the setting of HF, but data in human samples are scarce, particularly regarding Ca2+-handling remodeling. Here, we evaluated atrial remodeling in patients with severe left ventricular (LV) dysfunction (HFrEF), long-standing persistent (‘chronic’) AF (cAF) or both (HFrEF-cAF), and sinus rhythm controls with normal LV function (Ctl) using western blot in right-atrial tissue, sharp-electrode action potential (AP) measurements in atrial trabeculae and voltage-clamp experiments in isolated right-atrial cardiomyocytes. Compared to Ctl, expression of profibrotic markers (collagen-1a, fibronectin, periostin) was higher in HFrEF and HFrEF-cAF patients, indicative of structural remodeling. Connexin-43 expression was reduced in HFrEF patients, but not HFrEF-cAF patients. AP characteristics were unchanged in HFrEF, but showed classical indices of electrical remodeling in cAF and HFrEF-cAF (prolonged AP duration at 20% and shorter AP duration at 50% and 90% repolarization). L-type Ca2+ current (ICa,L) was significantly reduced in HFrEF, cAF and HFrEF-cAF, without changes in voltage-dependence. Potentially proarrhythmic spontaneous transient-inward currents were significantly more frequent in HFrEF and HFrEF-cAF compared to Ctl, likely resulting from increased sarcoplasmic reticulum (SR) Ca2+ load (integrated caffeine-induced current) in HFrEF and increased ryanodine-receptor (RyR2) single-channel open probability in HFrEF and HFrEF-cAF. Although expression and phosphorylation of the SR Ca2+-ATPase type-2a (SERCA2a) regulator phospholamban were unchanged in HFrEF and HFrEF-cAF patients, protein levels of SERCA2a were increased in HFrEF-cAF and sarcolipin expression was decreased in both HFrEF and HFrEF-cAF, likely increasing SR Ca2+ uptake and load. RyR2 protein levels were decreased in HFrEF and HFrEF-cAF patients, but junctin levels were higher in HFrEF and relative Ser2814-RyR2 phosphorylation levels were increased in HFrEF-cAF, both potentially contributing to the greater RyR2 open probability. These novel insights into the molecular substrate for atrial arrhythmias in HF-patients position Ca2+-handling abnormalities as a likely trigger of AF in HF patients, which subsequently produces electrical remodeling that promotes the maintenance of the arrhythmia. Our new findings may have important implications for the development of novel treatment options for AF in the context of HF.

Effect of oral administration of DHA on the remodeling of calcium handling proteins in congestive heart failure in male rats

Calcium (Ca2+) cycling is essential in cardiac contractile function, and remodeling of calcium handling is thought to be one of the factors contributing to the dysfunction in heart failure (HF). This study investigated the effect of DHA administration on remodeling of Ca2+handling proteins in congestive heart failure (CHF). Male rats were divided into 4 groups (n=8 for each group): C (normal, administered saline); D (normal, administered DHA‐ethyl ester (DHA‐Et)); H (CHF, administered saline); HD (CHF, administered DHA‐Et). CHF was produced by injection of monocrotaline (MCT) into 5‐week‐old rats. Starting from 3 days before MCT injection, saline or DHA‐Et wasorally administered(1g/kg body weight) daily. The right ventriclewas removed on day 24, and quantitative PCR was used to measure the expression of transcripts.The expression of sarcoplasmic reticulum Ca2+‐ATPase (SERCA) 2a, which is responsible to transport back Ca2+ to sarcoplasmic reticulum (SR), was significantly decreased in group H compared to groups C, D and HD (P 蠄 0.05). The expression of ryanodine receptor (RYR) 3, which releases Ca2+ from SR, in group H was significantly increased compared to groups C and D (P 蠄 0.05), and also tended to be increased in group H compared to group HD (P=0.06).The expression of Cav1.2, a component of L‐type Ca2+ channel,was significantly decreased in group H compared to groups C and D (P 蠄 0.05). Remodeling of intracellular Ca2+ handling may be caused by these changes in gene expression in CHF. Administration of DHA‐Et may improve abnormal Ca2+ handling through recovery of the expression of these proteins.

Remodeling of calcium handling in human heart failure.

Heart failure (HF) is an increasing public health problem accelerated by a rapidly aging global population. Despite considerable progress in managing the disease, the development of new therapies for effective treatment of HF remains a challenge. To identify targets for early diagnosis and therapeutic intervention, it is essential to understand the molecular and cellular basis of calcium handling and the signaling pathways governing the functional remodeling associated with HF in humans. Calcium (Ca(2+)) cycling is an essential mediator of cardiac contractile function, and remodeling of calcium handling is thought to be one of the major factors contributing to the mechanical and electrical dysfunction observed in HF. Active research in this field aims to bridge the gap between basic research and effective clinical treatments of HF. This chapter reviews the most relevant studies of calcium remodeling in failing human hearts and discusses their connections to current and emerging clinical therapies for HF patients.

Atrial remodeling in atrial fibrillation and association between microRNA network and atrial fibrillation

Atrial fibrillation (AF) remains one of the leading causes of morbidity and mortality in the world which are related to palpitations, fainting, congestive heart failure or stroke. The mechanism for atrial fibrillation has been identified as electrical remodeling, structure remodeling and intracellular calcium handling remodeling. microRNAs (miRNAs) have recently emerged as one of the important factors in regulating gene expression. So far, thousands of miRNA genes have been found in diverse animals with the function of regulating cell death, cell proliferation, haematopoiesis and even participate in the processing of cardiovascular disease. In this review, we summarize the mechanism of AF and the association of microRNAs network with AF. We provide a potential perspective of miRNAs as the therapeutic target for AF.

Progress, challenges and new concepts in microRNAs

MicroRNAs are a group of small noncoding RNAs. They have rapidly gained attention in the field as novel regulators of cellular morphology and function. Currently hundreds of microRNAs have been described in human genome. MicroRNAs play important roles in posttranscriptional regulation of gene expression by inhibiting protein translation and/or promoting mRNA degradation. MicroRNAs were initially thought to be subtle regulators of gene expression, but increasing evidence demonstrates that the regulatory functions of microRNAs are crucial for the cell. MicroRNAs have been found to be involved in the development, tissue homeostasis as well as diseases. However, at present, the pathological implications of deregulated microRNA expression in diseases remain largely unknown. In these reviews, the authors focus on recent advancement on regulation of microRNA biogenesis and function in cardiac and neuronal development and disease. Zhang Y et al. summarized the mechanism of electrical remodeling, structural remodeling and intracellular calcium handling remodeling in atrial fibrillation and the association of microRNAs network with them. Feng Y L et al. illustrated the current insights into the regulation of microRNAs in heart development and diseases, such as cardiac hypertrophy, ischemic cardiomyopathy and arrhythmia. Feng W et al. focused on microRNA biogenesis and function in neuronal and glial development in the mammalian brain, and dysregulation of the microRNA pathway in neurodevelopmental and neurodegenerative diseases. The value to readers is that three authors introduced the results studied by their groups in the reviews. The functions of microRNAs were better interpreted. Also they discussed that the potential perspective of microRNAs expression pattern serves as informative biomarkers that indicate the functional status as well as progression and prognosis in diseases. Based on the fast growing knowledge for microRNAs, they speculate a promising translational future for microRNA diagnostics and therapeutics.

Remodeling of calcium handling in skeletal muscle through PGC-1α: impact on force, fatigability, and fiber type

Regular endurance exercise remodels skeletal muscle, largely through the peroxisome proliferator-activated receptor-γ coactivator-1α (PGC-1α). PGC-1α promotes fiber type switching and resistance to fatigue. Intracellular calcium levels might play a role in both adaptive phenomena, yet a role for PGC-1α in the adaptation of calcium handling in skeletal muscle remains unknown. Using mice with transgenic overexpression of PGC-1α, we now investigated the effect of PGC-1α on calcium handling in skeletal muscle. We demonstrate that PGC-1α induces a quantitative reduction in calcium release from the sarcoplasmic reticulum by diminishing the expression of calcium-releasing molecules. Concomitantly, maximal muscle force is reduced in vivo and ex vivo. In addition, PGC-1α overexpression delays calcium clearance from the myoplasm by interfering with multiple mechanisms involved in calcium removal, leading to higher myoplasmic calcium levels following contraction. During prolonged muscle activity, the delayed calcium clearance might facilitate force production in mice overexpressing PGC-1α. Our results reveal a novel role of PGC-1α in altering the contractile properties of skeletal muscle by modulating calcium handling. Importantly, our findings indicate PGC-1α to be both down- as well as upstream of calcium signaling in this tissue. Overall, our findings suggest that in the adaptation to chronic exercise, PGC-1α reduces maximal force, increases resistance to fatigue, and drives fiber type switching partly through remodeling of calcium transients, in addition to promoting slow-type myofibrillar protein expression and adequate energy supply.

Remodeling of Calcium Handling in Rat Left Atrial Myocytes in a Surgical Model of Elevated Afterload

Remodeling of the atrial myocardium in heart disease is suggested to increase the risk of atrial fibrillation (AF). Abnormal Ca2+ handling is also thought to play a key role in the genesis of AF. In the present study we investigated Ca2+ handling in left atrial myocytes from a rat model of elevated afterload produced by surgical banding of the ascending aorta (AoB), which was compared with sham-operated controls (Sham). Cells were isolated at 20 weeks following surgery, corresponding to a pre-heart failure stage of remodeling. Isolated cells were either stained with the lipophilic dye di-8-ANEPPS, or loaded with the Ca2+-fluophore, fluo-3, and imaged using laser scanning confocal microscopy. Measurements of cell volume and surface area from di-8-ANEPPS-stained cells demonstrated that cells from AoB animals were hypertrophied in comparison with cells from Sham controls. Fluo-3-loaded cells were superfused with Tyrode's solution (∼22°C), stimulated via field electrodes and changes in [Ca2+]i monitored using line-scan imaging. The amplitude of the electrically stimulated Ca2+ transient was greater in AoB than in Sham cells. Rapid application of caffeine (10 mM) was used to deplete sarcoplasmic reticulum (SR) Ca2+: The amplitude of the caffeine-induced Ca2+ transient was greater in AoB than in Sham cells, consistent with a larger SR Ca2+ content in AoB than in Sham cells. The incidence and frequency of spontaneous Ca2+ transients following a burst of pacing at 4 Hz was greater in AoB cells than in Sham cells. In summary, our data demonstrate for the first time remodeling of atrial myocyte Ca2+ handling in a pre-heart failure model of elevated afterload. Changes in atrial Ca2+ handling in response to elevated afterload may contribute to increased susceptibility to AF in hypertension.Supported by the BHF (PG/07/101).