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1.
Alpha and beta myosin isoforms and human atrial and ventricular contraction.
Walklate, J, Ferrantini, C, Johnson, CA, Tesi, C, Poggesi, C, Geeves, MA
Cellular and molecular life sciences : CMLS. 2021;(23):7309-7337
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Abstract
Human atrial and ventricular contractions have distinct mechanical characteristics including speed of contraction, volume of blood delivered and the range of pressure generated. Notably, the ventricle expresses predominantly β-cardiac myosin while the atrium expresses mostly the α-isoform. In recent years exploration of the properties of pure α- & β-myosin isoforms have been possible in solution, in isolated myocytes and myofibrils. This allows us to consider the extent to which the atrial vs ventricular mechanical characteristics are defined by the myosin isoform expressed, and how the isoform properties are matched to their physiological roles. To do this we Outline the essential feature of atrial and ventricular contraction; Explore the molecular structural and functional characteristics of the two myosin isoforms; Describe the contractile behaviour of myocytes and myofibrils expressing a single myosin isoform; Finally we outline the outstanding problems in defining the differences between the atria and ventricles. This allowed us consider what features of contraction can and cannot be ascribed to the myosin isoforms present in the atria and ventricles.
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2.
Mechanisms of flecainide induced negative inotropy: An in silico study.
Yang, PC, Giles, WR, Belardinelli, L, Clancy, CE
Journal of molecular and cellular cardiology. 2021;:26-37
Abstract
It is imperative to develop better approaches to predict how antiarrhythmic drugs with multiple interactions and targets may alter the overall electrical and/or mechanical function of the heart. Safety Pharmacology studies have provided new insights into the multi-target effects of many different classes of drugs and have been aided by the addition of robust new in vitro and in silico technology. The primary focus of Safety Pharmacology studies has been to determine the risk profile of drugs and drug candidates by assessing their effects on repolarization of the cardiac action potential. However, for decades experimental and clinical studies have described substantial and potentially detrimental effects of Na+ channel blockers in addition to their well-known conduction slowing effects. One such side effect, associated with administration of some Na+ channel blocking drugs is negative inotropy. This reduces the pumping function of the heart, thereby resulting in hypotension. Flecainide is a well-known example of a Na+ channel blocking drug, that exhibits strong rate-dependent block of INa and may cause negative cardiac inotropy. While the phenomenon of Na+ channel suppression and resulting negative inotropy is well described, the mechanism(s) underlying this effect are not. Here, we set out to use a modeling and simulation approach to reveal plausible mechanisms that could explain the negative inotropic effect of flecainide. We utilized the Grandi-Bers model [1] of the cardiac ventricular myocyte because of its robust descriptions of ion homeostasis in order to characterize and resolve the relative effects of QRS widening, flecainide off-target effects and changes in intracellular Ca2+ and Na+ homeostasis. The results of our investigations and predictions reconcile multiple data sets and illustrate how multiple mechanisms may play a contributing role in the flecainide induced negative cardiac inotropic effect.
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Levosimendan Efficacy and Safety: 20 Years of SIMDAX in Clinical Use.
Papp, Z, Agostoni, P, Alvarez, J, Bettex, D, Bouchez, S, Brito, D, Černý, V, Comin-Colet, J, Crespo-Leiro, MG, Delgado, JF, et al
Journal of cardiovascular pharmacology. 2020;(1):4-22
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Abstract
Levosimendan was first approved for clinical use in 2000, when authorization was granted by Swedish regulatory authorities for the hemodynamic stabilization of patients with acutely decompensated chronic heart failure (HF). In the ensuing 20 years, this distinctive inodilator, which enhances cardiac contractility through calcium sensitization and promotes vasodilatation through the opening of adenosine triphosphate-dependent potassium channels on vascular smooth muscle cells, has been approved in more than 60 jurisdictions, including most of the countries of the European Union and Latin America. Areas of clinical application have expanded considerably and now include cardiogenic shock, takotsubo cardiomyopathy, advanced HF, right ventricular failure, pulmonary hypertension, cardiac surgery, critical care, and emergency medicine. Levosimendan is currently in active clinical evaluation in the United States. Levosimendan in IV formulation is being used as a research tool in the exploration of a wide range of cardiac and noncardiac disease states. A levosimendan oral form is at present under evaluation in the management of amyotrophic lateral sclerosis. To mark the 20 years since the advent of levosimendan in clinical use, 51 experts from 23 European countries (Austria, Belgium, Croatia, Cyprus, Czech Republic, Estonia, Finland, France, Germany, Greece, Hungary, Italy, the Netherlands, Norway, Poland, Portugal, Russia, Slovenia, Spain, Sweden, Switzerland, the United Kingdom, and Ukraine) contributed to this essay, which evaluates one of the relatively few drugs to have been successfully introduced into the acute HF arena in recent times and charts a possible development trajectory for the next 20 years.
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4.
Impact of Nutrition on Cardiovascular Function.
Bianchi, VE
Current problems in cardiology. 2020;(1):100391
Abstract
The metabolic sources of energy for myocardial contractility include mainly free fatty acids (FFA) for 95%, and in lesser amounts for 5% from glucose and minimal contributions from other substrates such lactate, ketones, and amino acids. However, myocardial efficiency is influenced by metabolic condition, overload, and ischemia. During cardiac stress, cardiomyocytes increase glucose oxidation and reduce FFA oxidation. In patients with ischemic coronary disease and heart failure, the low oxygen availability limits myocardial reliance on FFA and glucose utilization must increase. Although glucose uptake is fundamental to cardiomyocyte function, an excessive intracellular glucose level is detrimental. Insulin plays a fundamental role in maintaining myocardial efficiency and in reducing glycemia and inflammation; this is particularly evident in obese and type-2 diabetic patients. An excess of F availability increase fat deposition within cardiomyocytes and reduces glucose oxidation. In patients with high body mass index, a restricted diet or starvation have positive effects on cardiac metabolism and function while, in patients with low body mass index, restrictive diets, or starvation have a deleterious effect. Thus, weight loss in obese patients has positive impacts on ventricular mass and function, whereas, in underweight heart failure patients, such weight reduction adds to the risk of heart damage, predisposing to cachexia. Nutrition plays an essential role in the evolution of cardiovascular disease and should be taken into account. An energy-restricted diet improves myocardial efficiency but can represent a potential risk of heart damage, particularly in patients affected by cardiovascular disease. Micronutrient integration has a marginal effect on cardiovascular efficiency.
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5.
Cardiac contractility modulation: mechanisms of action in heart failure with reduced ejection fraction and beyond.
Tschöpe, C, Kherad, B, Klein, O, Lipp, A, Blaschke, F, Gutterman, D, Burkhoff, D, Hamdani, N, Spillmann, F, Van Linthout, S
European journal of heart failure. 2019;(1):14-22
Abstract
Heart failure (HF) is responsible for substantial morbidity and mortality and is increasing in prevalence. Although there has been remarkable progress in the treatment of HF with reduced ejection fraction (HFrEF), morbidity and mortality are still substantial. Cardiac contractility modulation (CCM) signals, consisting of biphasic high-voltage bipolar signals delivered to the right ventricular septum during the absolute refractory period, have been shown to improve symptoms, exercise tolerance and quality of life and reduce the rate of HF hospitalizations in patients with ejection fractions (EF) between 25% and 45%. CCM therapy is currently approved in the European Union, China, India, Australia and Brazil for use in symptomatic HFrEF patients with normal or slightly prolonged QRS duration. CCM is particularly beneficial in patients with baseline EF between 35% and 45%, which includes half the range of HF patients with mid-range EFs (HFmrEF). At the cellular level, CCM has been shown in HFrEF patients to improve calcium handling, to reverse the foetal myocyte gene programme associated with HF, and to facilitate reverse remodelling. This review highlights the preclinical and clinical literature related to CCM in HFrEF and HFmrEF and outlines the potential of CCM for HF with preserved EF, concluding that CCM may fill an important unmet need in the therapeutic approach to HF across the range of EFs.
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6.
Effects of DAPAgliflozin on CARDiac substrate uptake, myocardial efficiency, and myocardial contractile work in type 2 diabetes patients-a description of the DAPACARD study.
Åkerblom, A, Oldgren, J, Latva-Rasku, A, Johansson, L, Lisovskaja, V, Karlsson, C, Oscarsson, J, Nuutila, P
Upsala journal of medical sciences. 2019;(1):59-64
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Abstract
BACKGROUND Diabetes increases the risk for cardiovascular (CV) events. It has recently been shown that the use of sodium-glucose cotransporter 2 (SGLT2) inhibitors leads to a reduction in CV outcomes in patients with type 2 diabetes mellitus (T2DM), including mortality and heart failure hospitalization. The exact mechanisms of how SGLT2 inhibitors lead to this CV risk reduction remain incompletely understood. The study of DAPAgliflozin on CARDiac substrate uptake, myocardial efficiency and myocardial contractile work in type 2 diabetes patients (DAPACARD) (NCT03387683) explores the possible effects of dapagliflozin, an SGLT2 inhibitor, on cardiac work, metabolism, and biomarker levels. METHODS DAPACARD is an international, randomized, double-blind trial that aims to examine the effects of dapagliflozin versus matching placebo in 52 patients with T2DM that are on stable metformin therapy prior to and during the 6 weeks of treatment. The primary efficacy endpoint is change in global longitudinal strain of the left ventricle (GLSLV) measured with magnetic resonance imaging (MRI) between baseline (pre-treatment) and end of study (on-treatment). The secondary endpoint is the corresponding change in myocardial efficiency measured as external left ventricular work divided by total left ventricular work, which is estimated using [11C]-acetate clearance using positron emission tomography (PET). CONCLUSION The DAPACARD study is an extensive investigation of cardiac function and metabolism, by advanced imaging with PET and MRI, as well as biomarkers, performed in order to further explore how the SGLT2 inhibitor dapagliflozin could influence cardiovascular outcomes in patients with T2DM.
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Hyperglycemia-induced cardiac contractile dysfunction in the diabetic heart.
Singh, RM, Waqar, T, Howarth, FC, Adeghate, E, Bidasee, K, Singh, J
Heart failure reviews. 2018;(1):37-54
Abstract
The development of a diabetic cardiomyopathy is a multifactorial process, and evidence is accumulating that defects in intracellular free calcium concentration [Ca2+]i or its homeostasis are related to impaired mechanical performance of the diabetic heart leading to a reduction in contractile dysfunction. Defects in ryanodine receptor, reduced activity of the sarcoplasmic reticulum calcium pump (SERCA) and, along with reduced activity of the sodium-calcium exchanger (NCX) and alterations in myofilament, collectively cause a calcium imbalance within the diabetic cardiomyocytes. This in turn is characterized by cytosolic calcium overloading or elevated diastolic calcium leading to heart failure. Numerous studies have been performed to identify the cellular, subcellular, and molecular derangements in diabetes-induced cardiomyopathy (DCM), but the precise mechanism(s) is still unknown. This review focuses on the mechanism behind DCM, the onset of contractile dysfunction, and the associated changes with special emphasis on hyperglycemia, mitochondrial dysfunction in the diabetic heart. Further, management strategies, including treatment and emerging therapeutic modalities, are discussed.
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8.
Levosimendan in Acute and Advanced Heart Failure: an Expert Perspective on Posology and Therapeutic Application.
Bouchez, S, Fedele, F, Giannakoulas, G, Gustafsson, F, Harjola, VP, Karason, K, Kivikko, M, von Lewinski, D, Oliva, F, Papp, Z, et al
Cardiovascular drugs and therapy. 2018;(6):617-624
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Abstract
Levosimendan, a calcium sensitizer and potassium channel-opener, is widely appreciated by many specialist heart failure practitioners for its effects on systemic and pulmonary hemodynamics and for the relief of symptoms of acute heart failure. The drug's impact on mortality in large randomized controlled trials has been inconsistent or inconclusive but, in contrast to conventional inotropes, there have been no indications of worsened survival and some signals of improved heart failure-related quality of life. For this reason, levosimendan has been proposed as a safer inodilator option than traditional agents in settings, such as advanced heart failure. Positive effects of levosimendan on renal function have also been described. At the HEART FAILURE 2018 congress of the Heart Failure Association of the European Society of Cardiology, safe and effective use levosimendan in acute and advanced heart failure was examined in a series of expert tutorials. The proceedings of those tutorials are summarized in this review, with special reference to advanced heart failure and heart failure with concomitant renal dysfunction. Meta-analysis of clinical trials data is supportive of a renal-protective effect of levosimendan, while physiological observations suggest that this effect is exerted at least in part via organ-specific effects that may include selective vasodilation of glomerular afferent arterioles and increased renal blood flow, with no compromise of renal oxygenation. These lines of evidence require further investigation and their clinical significance needs to be evaluated in specifically designed prospective trials.
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Modeling calcium regulation of contraction, energetics, signaling, and transcription in the cardiac myocyte.
Winslow, RL, Walker, MA, Greenstein, JL
Wiley interdisciplinary reviews. Systems biology and medicine. 2016;(1):37-67
Abstract
Calcium (Ca(2+)) plays many important regulatory roles in cardiac muscle cells. In the initial phase of the action potential, influx of Ca(2+) through sarcolemmal voltage-gated L-type Ca(2+) channels (LCCs) acts as a feed-forward signal that triggers a large release of Ca(2+) from the junctional sarcoplasmic reticulum (SR). This Ca(2+) drives heart muscle contraction and pumping of blood in a process known as excitation-contraction coupling (ECC). Triggered and released Ca(2+) also feed back to inactivate LCCs, attenuating the triggered Ca(2+) signal once release has been achieved. The process of ECC consumes large amounts of ATP. It is now clear that in a process known as excitation-energetics coupling, Ca(2+) signals exert beat-to-beat regulation of mitochondrial ATP production that closely couples energy production with demand. This occurs through transport of Ca(2+) into mitochondria, where it regulates enzymes of the tricarboxylic acid cycle. In excitation-signaling coupling, Ca(2+) activates a number of signaling pathways in a feed-forward manner. Through effects on their target proteins, these interconnected pathways regulate Ca(2+) signals in complex ways to control electrical excitability and contractility of heart muscle. In a process known as excitation-transcription coupling, Ca(2+) acting primarily through signal transduction pathways also regulates the process of gene transcription. Because of these diverse and complex roles, experimentally based mechanistic computational models are proving to be very useful for understanding Ca(2+) signaling in the cardiac myocyte.
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10.
Calcium sensitizers: What have we learned over the last 25 years?
Pollesello, P, Papp, Z, Papp, JG
International journal of cardiology. 2016;:543-8
Abstract
The use of inotropes for correcting hemodynamic dysfunction in patients with congestive heart failure has been described over many decades. Drugs such as cardiac glycosides, cathecolamines, phosphodiestherase inhibitors, and calcium sensitizers have been in turn proposed. However, the number of new chemical entities in this therapeutic field has been surprisingly low, and the current selection of drugs is limited. One of the paradigm shifts in the discovery for new inotropes was to focus on 'calcium sensitizers' instead of 'calcium mobilizers'. This was designed to lead to the development of safer inotropes, devoid of the complications that arise due to increased intracellular calcium levels. However, only three such calcium sensitizers have been fully developed over the latest 30 years. Moreover, two of these, levosimendan and pimobendan, have multiple molecular targets and other pharmacologic effects in addition to inotropy, such as peripheral vasodilation. More recently, omecamtiv mecarbil was described, which is believed to have a pure inotropy action that is devoid of pleiotropic effects. When the clinical data of these three calcium sensitizers are compared, it appears that the less pure inotropes have the cutting edge over the purer inotrope, due to additional effects during the treatment of a complex syndrome such as acute congested heart failure. This review aims to answer the question whether calcium sensitization per se is a sufficient strategy for bringing required clinical benefits to patients with heart failure. This review is dedicated to the memory of Heimo Haikala, a true and passionate innovator in this challenging field.