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Cardiac Contractility Modulation

Alexis V Mickelson, Sampath K Gollapudi, Murali Chandra
The present study investigated the functional consequences of the human hypertrophic cardiomyopathy (HCM) mutation, A28V, in cardiac troponin T (TnT). The A28V mutation is located within the N-terminus of TnT, a region known to be important for full activation of cardiac thin filaments. The functional consequences of the A28V mutation in TnT remain unknown. Given how α- and β-myosin heavy chain (MHC) isoforms differently alter the effect of the N-terminus of TnT, we hypothesized that the A28V-induced effects would be differently modulated by α- and β-MHC isoforms...
October 21, 2016: American Journal of Physiology. Heart and Circulatory Physiology
Sampath K Gollapudi, Murali Chandra
Many studies have demonstrated that depressed myofilament Ca(2+) sensitivity is common to dilated cardiomyopathy (DCM) in humans. However, it remains unclear whether a single determinant-such as myofilament Ca(2+) sensitivity-is sufficient to characterize all cases of DCM because the severity of disease varies widely with a given mutation. Because dynamic features dominate in the heart muscle, alterations in dynamic contractile parameters may offer better insight on the molecular mechanisms that underlie disparate effects of DCM mutations on cardiac phenotypes...
2016: Frontiers in Physiology
Ameh Omede, Min Zi, Sukhpal Prehar, Arfa Maqsood, Nicholas Stafford, Mamas Mamas, Elizabeth Cartwright, Delvac Oceandy
The G-protein-coupled receptors (GPCRs) family of proteins play essential roles in the heart, including in the regulation of cardiac hypertrophy. One member of this family, the oxoglutarate receptor 1 (OXGR1), may have a crucial role in the heart because it acts as a receptor for α-ketoglutarate, a metabolite that is elevated in heart failure patients. OXGR1 is expressed in the heart but its precise function during cardiac pathophysiological process is unknown. Here we used both in vivo and in vitro approaches to investigate the role of OXGR1 in cardiac hypertrophy...
October 28, 2016: Biochemical and Biophysical Research Communications
Xuan Zhang, Hailong An, Junwei Li, Yuanyuan Zhang, Yang Liu, Zhanfeng Jia, Wei Zhang, Li Chu, Hailin Zhang
BACKGROUND AND PURPOSE: Kv7 (Kv7.1-7.5) channels play an important role in the regulation of neuronal excitability and the cardiac action potential. Growing evidence suggests a crucial role for Kv7.4/Kv7.5 channels in regulating vascular smooth muscle contractility. Most of the reported Kv7 openers shown poor selectivity across these five subtypes. In this study, fasudil-a drug for cerebral vasospasm-has been found to be a selective opener of Kv7.4/Kv7.5 channels. EXPERIMENTAL APPROACH: A perforated whole-cell patch technique was used to record the currents and membrane potential...
September 28, 2016: British Journal of Pharmacology
Asmaa I Matouk, Ashraf Taye, Mohamed A El-Moselhy, Gehan H Heeba, Abdel A Abdel-Rahman
While acute activation of the novel endocannabinoid receptor GPR18 causes hypotension, there are no reports on GPR18 expression in the heart or its chronic modulation of cardiovascular function. In this study, after demonstrating GPR18 expression in the heart, we show that chronic (2 weeks) GPR18 activation with its agonist abnormal cannabidiol (abn-cbd; 100 µg/kg/day; i.p) produced hypotension, suppressed the cardiac sympathetic dominance, and improved left ventricular (LV) function (increased the contractility index dp/dtmax, and reduced LV end diastolic pressure, LVEDP) in conscious rats...
September 20, 2016: Journal of Cardiovascular Pharmacology
S Imbrogno, R Mazza, C Pugliese, M Filice, T Angelone, Y P Loh, B Tota, M C Cerra
Chromogranin A (CgA) is an acidic protein co-stored with catecholamines, hormones and neuropeptides in the secretory granules of endocrine, neuronal and other cell types (including cardiomyocytes). Proteolytic cleavage in the C terminus of CgA generates a 2.9kDa peptide named serpinin (Serp; Ala26Leu) that can be modified at its N terminus to form a pyroglutamate residue (pGlu-Serp). In the rat heart, both peptides increase contractility and relaxation through a β-adrenergic-like action mechanism. Accordingly, Serp and pGlu-Serp were proposed as novel myocardial sympatho-adrenergic modulators in mammals...
September 12, 2016: General and Comparative Endocrinology
Bochra Tourki, Philippe Matéo, Jessica Morand, Mohamed Elayeb, Diane Godin-Ribuot, Naziha Marrakchi, Elise Belaidi, Erij Messadi
Cardiac ischemia is one of the leading causes of death worldwide. It is now well established that natriuretic peptides can attenuate the development of irreversible ischemic injury during myocardial infarction. Lebetin 2 (L2) is a new discovered peptide isolated from Macrovipera lebetina venom with structural similarity to B-type natriuretic peptide (BNP). Our objectives were to define the acute cardioprotective actions of L2 in isolated Langendorff-perfused rat hearts after regional or global ischemia-reperfusion (IR)...
2016: PloS One
Yaowen Liu, Jinfu Lu, Guisen Xu, Jiaojun Wei, Zhibin Zhang, Xiaohong Li
The key to addressing the challenges facing cardiac tissue engineering is the integration of physical, chemical, and electrical cues into scaffolds. Aligned and conductive scaffolds have been fabricated as synthetic microenvironments to improve the function of cardiomyocytes. However, up to now, the influence of conductive capability and inner structure of fibrous scaffolds have not been determined on the cardiomyocyte morphologies and beating patterns. In the current study, highly aligned fibers were fabricated with loaded up to 6% of carbon nanotubes (CNTs) to modulate the electrical conductivity, while blend and coaxial electrospinning were utilized to create a bulk distribution of CNTs in fiber matrices and a spatial embedment in fiber cores, respectively...
December 1, 2016: Materials Science & Engineering. C, Materials for Biological Applications
Raúl J Domenech, Víctor M Parra
The contractile state of the heart is the result of myocardial contractility, the intrinsic mechanism that regulates the force and the shortening of the ventricle and determines the ventricular ejection volume. However, the ejection volume is also modulated by ventricular preload (diastolic ventricular volume) and afterload (resistance to ejection). Accordingly, a decrease in contractility may be masked by changes in preload or afterload, maintaining a normal ejection volume and delaying the diagnosis of myocardial damage...
June 2016: Revista Médica de Chile
Peter Taggart, Hugo Critchley, Stefan van Duijvendoden, Pier D Lambiase
Advances in investigative techniques have led to an increasing awareness and understanding of the role of central neural control in the autonomic nervous system regulation of the heart. Substantial evidence exists for a role of the higher centres in neuro-cardiac control including the effect of focal brain stimulation and acute brain lesions on cardiac electrophysiology, blood pressure, contractile function and the development of arrhythmias. Mental stress and strong emotions have long been associated with sudden cardiac death...
August 2016: Autonomic Neuroscience: Basic & Clinical
Susanne Röger, Samir Said, Axel Kloppe, Thomas Lawo, Ulf Emig, Benny Rousso, David Gutterman, Martin Borggrefe, Jürgen Kuschyk
BACKGROUND: Cardiac contractility modulation (CCM) is an electrical stimulation treatment for symptomatic heart failure (HF) patients. The procedure involves implantation of two ventricular leads for delivery of CCM impulses. The purpose of this study is to compare the efficacy and safety of CCM when the signal is delivered through one vs. two ventricular leads. METHODS: This prospective blinded randomized trial enrolled 48 patients. Eligible subjects had symptoms despite optimal HF medications, left ventricular ejection fraction <40% and peakVO2≥9ml O2/kg/min...
August 30, 2016: Journal of Cardiology
Dmitry Terentyev, Shanna Hamilton
The amount and timing of Ca(2+) release from the sarcoplasmic reticulum (SR) during cardiac cycle are the main determinants of cardiac contractility. Reversible phosphorylation of the SR Ca(2+) release channel, ryanodine receptor type 2 (RyR2) is the central mechanism of regulation of Ca(2+) release in cardiomyocytes. Three major serine-threonine phosphatases including PP1, PP2A and PP2B (calcineurin) have been implicated in modulation of RyR2 function. Changes in expression levels of these phosphatases, their activity and targeting to the RyR2 macromolecular complex were demonstrated in many animal models of cardiac disease and humans and are implicated in cardiac arrhythmia and heart failure...
August 29, 2016: Journal of Molecular and Cellular Cardiology
Dongwu Lai, Jing Gao, Xukun Bi, Hong He, Xiaolu Shi, Shaoxiang Weng, Yu Chen, Ying Yang, Yang Ye, Guosheng Fu
: Previous study showed inhibition of RhoA and Rho kinase (ROCK) activity with fasudil could alleviate diabetes-induced cardiac dysfunction partially due to improvement of myocardial fibrosis. However, the effect of fasudil on intracellular calcium cycling and actin remodeling, both of which are important to regulate excitation-contract coupling, is still not fully elucidated. In this study, a diabetic cardiomyopathy model was induced by a single intraperitoneal injection of streptozotocin (STZ) in male Sprague Dawley rats...
August 30, 2016: Journal of Molecular Medicine: Official Organ of the "Gesellschaft Deutscher Naturforscher und Ärzte"
Benjamin P Woodall, Meryl C Woodall, Timothy S Luongo, Laurel A Grisanti, Douglas G Tilley, John W Elrod, Walter J Koch
GRK2, a G protein-coupled receptor kinase, plays a critical role in cardiac physiology. Adrenergic receptors are the primary target for GRK2 activity in the heart; phosphorylation by GRK2 leads to desensitization of these receptors. As such, levels of GRK2 activity in the heart directly correlate with cardiac contractile function. Furthermore, increased expression of GRK2 after cardiac insult exacerbates injury and speeds progression to heart failure. Despite the importance of this kinase in both the physiology and pathophysiology of the heart, relatively little is known about the role of GRK2 in skeletal muscle function and disease...
October 14, 2016: Journal of Biological Chemistry
E V Lopatina, A V Kipenko, V A Penniyaynen, N A Pasatetckaia, V A Tsyrline
Literature and our data suggest the regulatory action of a number of biologically active substances (catecholamines, cardiac glycosides, β-blockers, angiotensin-converting-enzyme inhibitor) on the growth and proliferation of heart cells. By using of organotypic tissue culture has proved that the basis of this regulation is the ability of test substances, receptor- or transducer-mediated signaling to modulate the function of Na⁺, K⁺-ATPase. There is a delay in the development of vascular smooth muscle in the late postnatal period in rats with the blockade of the sympathetic nervous system in the prenatal period...
April 2016: Uspekhi Fiziologicheskikh Nauk
Alejandra Z Vielma, Luisa León, Ignacio C Fernández, Daniel R González, Mauricio P Boric
S-nitrosylation of several Ca2+ regulating proteins in response to β-adrenergic stimulation was recently described in the heart; however the specific nitric oxide synthase (NOS) isoform and signaling pathways responsible for this modification have not been elucidated. NOS-1 activity increases inotropism, therefore, we tested whether β-adrenergic stimulation induces NOS-1-dependent S-nitrosylation of total proteins, the ryanodine receptor (RyR2), SERCA2 and the L-Type Ca2+ channel (LTCC). In the isolated rat heart, isoproterenol (10 nM, 3-min) increased S-nitrosylation of total cardiac proteins (+46±14%) and RyR2 (+146±77%), without affecting S-nitrosylation of SERCA2 and LTCC...
2016: PloS One
Ken T MacLeod
The aim of this review is to provide the reader with a synopsis of some of the emerging ideas and experimental findings in cardiac physiology and pathophysiology that were published in 2015. To provide context for the non-specialist, a brief summary of cardiac contraction and calcium (Ca) regulation in the heart in health and disease is provided. Thereafter, some recently published articles are introduced that indicate the current thinking on (1) the Ca regulatory pathways modulated by Ca/calmodulin-dependent protein kinase II, (2) the potential influences of nitrosylation by nitric oxide or S-nitrosated proteins, (3) newly observed effects of reactive oxygen species (ROS) on contraction and Ca regulation following myocardial infarction and a possible link with changes in mitochondrial Ca, and (4) the effects of some of these signaling pathways on late Na current and pro-arrhythmic afterdepolarizations as well as the effects of transverse tubule disturbances...
2016: F1000Research
Ursula Paula Renó Soci, Tiago Fernandes, Valerio Garrone Barauna, Nara Yumi Hashimoto, Gloria de Fátima Alves Mota, Kaleizu Teodoro Rosa, Maria Claudia Irigoyen, Michael Ian Phillips, Edilamar Menezes de Oliveira
: Aerobic exercise-induced cardiac hypertrophy is a physiological response involving accurate orchestration of gene and protein expression of contractile and metabolic components. The microRNAs: miR-208a, miR-208b and miR-499 are each encoded by a myosin gene and thus are also known as "MyomiRs", regulating several mRNA targets that in turn regulate cardiac hypertrophy and metabolic pathways. AIMS: To understand the role of myomiRs in the fine-tuning of cardiac MHC isoform expression by exercise training-induced physiological hypertrophy...
August 8, 2016: Clinical Science (1979-)
Fanny Vaillant, Benjamin Lauzier, Matthieu Ruiz, Yanfen Shi, Dominic Lachance, Marie-Eve Rivard, Virginie Bolduc, Eric Thorin, Jean-Claude Tardif, Christine Des Rosiers
While heart rate reduction (HRR) is a target for the management of patients with heart disease, contradictory results were reported using ivabradine, which selectively inhibits the pacemaker If current, vs. β-blockers like metoprolol. This study aimed at testing whether similar HRR with ivabradine vs. metoprolol differentially modulates cardiac energy substrate metabolism, a factor determinant for cardiac function, in a mouse model of dyslipidemia (hApoB(+/+);LDLR(-/-)). Following a longitudinal study design, we used 3- and 6-mo-old mice, untreated or treated for 3 mo with ivabradine or metoprolol...
October 1, 2016: American Journal of Physiology. Heart and Circulatory Physiology
Chowdhury S Abdullah, Zhao Li, Xiuqing Wang, Zhu-Qiu Jin
T cell infiltration has been associated with increased coronary heart disease risk in patients with diabetes mellitus. Effect of modulation of T cell trafficking on diabetes-induced cardiac fibrosis has yet to be determined. Therefore, our aim was to investigate the circulatory T cell depletion-mediated cardioprotection in streptozotocin-induced diabetic cardiomyopathy. Fingolimod (FTY720), an immunomodulatory drug, was tested in wild-type (WT) C57BL/6 and recombination activating gene 1 (Rag1) knockout (KO) mice without mature lymphocytes in streptozotocin-induced type 1 diabetic model...
October 2016: International Immunopharmacology
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