Abstract:Patients with heart failure often develop cardiac arrhythmias. The mechanisms and interrelations linking heart failure and arrhythmias are not fully understood. Historically, research into arrhythmias has been performed on affected individuals or in vivo (animal) models. The latter however is constrained by interspecies variation, demands to reduce animal experiments and cost. Recent developments in in vitro induced pluripotent stem cell technology and in silico modelling have expanded the number of models ava… Show more
“…These early cellular changes likely cause an increased propensity for VA during disease development [ 51 ]. There is further scope using in-vivo and ex-vivo models for evaluation of arrhythmia used in combination in FD [ 54 ]. Fig.…”
Purpose of Review
Fabry Disease (FD) is a rare lysosomal storage disorder characterised by multiorgan accumulation of glycosphingolipid due to deficiency in the enzyme α-galactosidase A. Cardiac sphingolipid accumulation triggers various types of arrhythmias, predominantly ventricular arrhythmia, bradyarrhythmia, and atrial fibrillation. Arrhythmia is likely the primary contributor to FD mortality with sudden cardiac death, the most frequent cardiac mode of death. Traditionally FD was seen as a storage cardiomyopathy triggering left ventricular hypertrophy, diastolic dysfunction, and ultimately, systolic dysfunction in advanced disease. The purpose of this review is to outline the current evidence exploring novel mechanisms underlying the arrhythmia substrate.
Recent Findings
There is growing evidence that FD cardiomyopathy is a primary arrhythmic disease with each stage of cardiomyopathy (accumulation, hypertrophy, inflammation, and fibrosis) contributing to the arrhythmia substrate via various intracellular, extracellular, and environmental mechanisms. It is therefore important to understand how these mechanisms contribute to an individual’s risk of arrhythmia in FD.
Summary
In this review, we outline the epidemiology of arrhythmia, pathophysiology of arrhythmogenesis, risk stratification, and cardiac therapy in FD. We explore how advances in conventional cardiac investigations performed in FD patients including 12-lead electrocardiography, transthoracic echocardiography, and cardiac magnetic resonance imaging have enabled early detection of pro-arrhythmic substrate. This has allowed for appropriate risk stratification of FD patients. This paves the way for future work exploring the development of therapeutic initiatives and risk prediction models to reduce the burden of arrhythmia.
“…These early cellular changes likely cause an increased propensity for VA during disease development [ 51 ]. There is further scope using in-vivo and ex-vivo models for evaluation of arrhythmia used in combination in FD [ 54 ]. Fig.…”
Purpose of Review
Fabry Disease (FD) is a rare lysosomal storage disorder characterised by multiorgan accumulation of glycosphingolipid due to deficiency in the enzyme α-galactosidase A. Cardiac sphingolipid accumulation triggers various types of arrhythmias, predominantly ventricular arrhythmia, bradyarrhythmia, and atrial fibrillation. Arrhythmia is likely the primary contributor to FD mortality with sudden cardiac death, the most frequent cardiac mode of death. Traditionally FD was seen as a storage cardiomyopathy triggering left ventricular hypertrophy, diastolic dysfunction, and ultimately, systolic dysfunction in advanced disease. The purpose of this review is to outline the current evidence exploring novel mechanisms underlying the arrhythmia substrate.
Recent Findings
There is growing evidence that FD cardiomyopathy is a primary arrhythmic disease with each stage of cardiomyopathy (accumulation, hypertrophy, inflammation, and fibrosis) contributing to the arrhythmia substrate via various intracellular, extracellular, and environmental mechanisms. It is therefore important to understand how these mechanisms contribute to an individual’s risk of arrhythmia in FD.
Summary
In this review, we outline the epidemiology of arrhythmia, pathophysiology of arrhythmogenesis, risk stratification, and cardiac therapy in FD. We explore how advances in conventional cardiac investigations performed in FD patients including 12-lead electrocardiography, transthoracic echocardiography, and cardiac magnetic resonance imaging have enabled early detection of pro-arrhythmic substrate. This has allowed for appropriate risk stratification of FD patients. This paves the way for future work exploring the development of therapeutic initiatives and risk prediction models to reduce the burden of arrhythmia.
“…Extensive theoretical discussions conclude that ‘window’ current results from overlap of activation and inactivation curves for L-type Ca 2+ currents. Computer modelling shows that these currents can support EADs [ 11 , 64 ]. The extent to which a component of L-type Ca 2+ current persists during the late plateau of the AP remains difficult to establish by experimental methods but many recent studies continue to consider ‘late’ Ca 2+ current as a major mechanism supporting EADs (e.g.…”
Section: The Role Of the Sarcoplasmic Reticulum In The Generation Of ...mentioning
confidence: 99%
“…[1][2][3][4][5][6][7]) and it is widely accepted that arrhythmias are a major health problem (e.g. [8][9][10][11]). The focus of this review is on diverse roles of a variety of intracellular organelles in initiating or influencing the timing of electrical activity in myocytes throughout the heart, including their importance in the generation of arrhythmias.…”
Rhythms of electrical activity in all regions of the heart can be influenced by a variety of intracellular membrane bound organelles. This is true both for normal pacemaker activity and for abnormal rhythms including those caused by early and delayed afterdepolarizations under pathological conditions. The influence of the sarcoplasmic reticulum (SR) on cardiac electrical activity is widely recognized, but other intracellular organelles including lysosomes and mitochondria also contribute. Intracellular organelles can provide a timing mechanism (such as an SR clock driven by cyclic uptake and release of Ca
2+
, with an important influence of intraluminal Ca
2+
), and/or can act as a Ca
2+
store involved in signalling mechanisms. Ca
2+
plays many diverse roles including carrying electric current, driving electrogenic sodium–calcium exchange (NCX) particularly when Ca
2+
is extruded across the surface membrane causing depolarization, and activation of enzymes which target organelles and surface membrane proteins. Heart function is also influenced by Ca
2+
mobilizing agents (cADP-ribose, nicotinic acid adenine dinucleotide phosphate and inositol trisphosphate) acting on intracellular organelles. Lysosomal Ca
2+
release exerts its effects via calcium/calmodulin-dependent protein kinase II to promote SR Ca
2+
uptake, and contributes to arrhythmias resulting from excessive beta-adrenoceptor stimulation. A separate arrhythmogenic mechanism involves lysosomes, mitochondria and SR. Interacting intracellular organelles, therefore, have profound effects on heart rhythms and NCX plays a central role.
This article is part of the theme issue ‘The heartbeat: its molecular basis and physiological mechanisms’.
“…As previously mentioned, ion channels play key roles in the excitability of cardiac cells (the sinoatrial node, atria, atrioventricular node, Purkinje fibers, and ventricles cells), and in the regulation of vascular smooth muscle and in endothelial cells. Thus, any alteration in the activity or structures of ion channels in these cells may induce cardiovascular pathologies [ 33 , 34 ].…”
Section: Effects Of Bpa On Animal Modelsmentioning
Currently, the plastic monomer and plasticizer bisphenol A (BPA) is one of the most widely used chemicals. BPA is present in polycarbonate plastics and epoxy resins, commonly used in food storage and industrial or medical products. However, the use of this synthetic compound is a growing concern, as BPA is an endocrine-disrupting compound and can bind mainly to estrogen receptors, interfering with different functions at the cardiovascular level. Several studies have investigated the disruptive effects of BPA; however, its cardiotoxicity remains unclear. Therefore, this review’s purpose is to address the most recent studies on the implications of BPA on the cardiovascular system. Our findings suggest that BPA impairs cardiac excitability through intracellular mechanisms, involving the inhibition of the main ion channels, changes in Ca2+ handling, the induction of oxidative stress, and epigenetic modifications. Our data support that BPA exposure increases the risk of developing cardiovascular diseases (CVDs) including atherosclerosis and its risk factors such as hypertension and diabetes. Furthermore, BPA exposure is also particularly harmful in pregnancy, promoting the development of hypertensive disorders during pregnancy. In summary, BPA exposure compromises human health, promoting the development and progression of CVDs and risk factors. Further studies are needed to clarify the human health effects of BPA-induced cardiotoxicity.
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.
