Genetics of cardiac arrhythmias.
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ABSTRACT:
SUBMITTER: Wilde AA
PROVIDER: S-EPMC1769155 | biostudies-literature | 2005 Oct
REPOSITORIES: biostudies-literature
Publications
Genetics of cardiac arrhythmias.
Wilde Arthur A M AA Bezzina Connie R CR
Heart (British Cardiac Society) 20051001 10
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Project description:Voltage-gated ion channels respond to changes in membrane potential with conformational shifts that either facilitate or stem the movement of charged ions across the cell membrane. This controlled movement of ions is particularly important for the action potentials of excitable cells such as cardiac myocytes and therefore essential for timely beating of the heart. Inherited mutations in ion channel genes and in the genes encoding proteins that regulate them can cause lethal cardiac arrhythmias either by direct channel disruption or by altering interactions with therapeutic drugs, the best-understood example of both these scenarios being long QT syndrome (LQTS). Unsurprisingly, mutations in the genes encoding ion channel pore-forming α subunits underlie the large majority (~90%) of identified cases of inherited LQTS. Given that inherited LQTS is comparatively rare in itself (~0.04% of the US population), is pursuing study of the remaining known and unknown LQTS-associated genes subject to the law of diminishing returns? Here, with a particular focus on the KCNE family of single transmembrane domain K(+) channel ancillary subunits, the significance to cardiac pharmacogenetics of ion channel regulatory subunits is discussed.
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Project description:There has been a significant progress in our understanding of the molecular mechanisms by which calcium (Ca2+) ions mediate various types of cardiac arrhythmias. A growing list of inherited gene defects can cause potentially lethal cardiac arrhythmia syndromes, including catecholaminergic polymorphic ventricular tachycardia, congenital long QT syndrome, and hypertrophic cardiomyopathy. In addition, acquired deficits of multiple Ca2+-handling proteins can contribute to the pathogenesis of arrhythmias in patients with various types of heart disease. In this review article, we will first review the key role of Ca2+ in normal cardiac function-in particular, excitation-contraction coupling and normal electric rhythms. The functional involvement of Ca2+ in distinct arrhythmia mechanisms will be discussed, followed by various inherited arrhythmia syndromes caused by mutations in Ca2+-handling proteins. Finally, we will discuss how changes in the expression of regulation of Ca2+ channels and transporters can cause acquired arrhythmias, and how these mechanisms might be targeted for therapeutic purposes.
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Project description:Early afterdepolarizations (EADs) are an important cause of lethal ventricular arrhythmias in long QT syndromes and heart failure, but the mechanisms by which EADs at the cellular scale cause arrhythmias such as polymorphic ventricular tachycardia (PVT) and torsades de pointes (TdP) at the tissue scale are not well understood. Here we summarize recent progress in this area, discussing (1) the ionic basis of EADs, (2) evidence that deterministic chaos underlies the irregular behavior of EADs, (3) mechanisms by which chaotic EADs synchronize in large numbers of coupled cells in tissue to overcome source-sink mismatches, (4) how this synchronization process allows EADs to initiate triggers and generate mixed focal reentrant ventricular arrhythmias underlying PVT and TdP, and (5) therapeutic implications.
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Project description:AimsIn 2003, an Australian woman was convicted by a jury of smothering and killing her four children over a 10-year period. Each child died suddenly and unexpectedly during a sleep period, at ages ranging from 19 days to 18 months. In 2019 we were asked to investigate if a genetic cause could explain the children's deaths as part of an inquiry into the mother's convictions.Methods and resultsWhole genomes or exomes of the mother and her four children were sequenced. Functional analysis of a novel CALM2 variant was performed by measuring Ca2+-binding affinity, interaction with calcium channels and channel function. We found two children had a novel calmodulin variant (CALM2 G114R) that was inherited maternally. Three genes (CALM1-3) encode identical calmodulin proteins. A variant in the corresponding residue of CALM3 (G114W) was recently reported in a child who died suddenly at age 4 and a sibling who suffered a cardiac arrest at age 5. We show that CALM2 G114R impairs calmodulin's ability to bind calcium and regulate two pivotal calcium channels (CaV1.2 and RyR2) involved in cardiac excitation contraction coupling. The deleterious effects of G114R are similar to those produced by G114W and N98S, which are considered arrhythmogenic and cause sudden cardiac death in children.ConclusionA novel functional calmodulin variant (G114R) predicted to cause idiopathic ventricular fibrillation, catecholaminergic polymorphic ventricular tachycardia, or mild long QT syndrome was present in two children. A fatal arrhythmic event may have been triggered by their intercurrent infections. Thus, calmodulinopathy emerges as a reasonable explanation for a natural cause of their deaths.
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Project description:BackgroundCardiac sympathetic denervation (CSD) has been shown to reduce the burden of implantable cardioverter-defibrillator (ICD) shocks in small series of patients with structural heart disease (SHD) and recurrent ventricular tachyarrhythmias (VT).ObjectivesThis study assessed the value of CSD and the characteristics associated with outcomes in this population.MethodsPatients with SHD who underwent CSD for refractory VT or VT storm at 5 international centers were analyzed by the International Cardiac Sympathetic Denervation Collaborative Group. Kaplan-Meier analysis was used to estimate freedom from ICD shock, heart transplantation, and death. Cox proportional hazards models were used to analyze variables associated with ICD shock recurrence and mortality after CSD.ResultsBetween 2009 and 2016, 121 patients (age 55 ± 13 years, 26% female, mean ejection fraction of 30 ± 13%) underwent left or bilateral CSD. One-year freedom from sustained VT/ICD shock and ICD shock, transplant, and death were 58% and 50%, respectively. CSD reduced the burden of ICD shocks from a mean of 18 ± 30 (median 10) in the year before study entry to 2.0 ± 4.3 (median 0) at a median follow-up of 1.1 years (p < 0.01). On multivariable analysis, pre-procedure New York Heart Association functional class III and IV heart failure and longer VT cycle lengths were associated with recurrent ICD shocks, whereas advanced New York Heart Association functional class, longer VT cycle lengths, and a left-sided-only procedure predicted the combined endpoint of sustained VT/ICD shock recurrence, death, and transplantation. Of the 120 patients taking antiarrhythmic medications before CSD, 39 (32%) no longer required them at follow-up.ConclusionsCSD decreased sustained VT and ICD shock recurrence in patients with refractory VT. Characteristics independently associated with recurrence and mortality were advanced heart failure, VT cycle length, and a left-sided-only procedure.
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Project description:IntroductionCannabis use is known to be associated with significant cardiovascular morbidity. We describe three cases of cannabis-related malignant arrhythmias, who presented to the cardiac department at our institution within the last 2 years. All three patients were known to smoke cannabis on daily basis.Case summariesCase 1: A 30-year-old male, presented with recent onset of palpitations. A 12-lead electrocardiogram (ECG), transthoracic echocardiogram (TTE), and blood tests were all normal. During an inpatient exercise treadmill test (ETT) he developed polymorphic ventricular tachycardia (VT), which converted spontaneously to supraventricular tachycardia (SVT) in the recovery phase of the test. Subsequent risk stratification with cardiac magnetic resonance imaging and coronary angiography showed no abnormalities and an electrophysiological study was negative for sustained VT, however, SVT was easily induced with rapid conversion to atrial fibrillation. The patient successfully stopped smoking all tobacco products including cannabis and was treated with beta-blockers, with no further episodes of arrhythmia. Case 2: A 30-year-old male presented to the Emergency Department with palpitations, chest pain, and dizziness that improved during exertion. His initial ECG demonstrated complete atrioventricular block (AVB). Subsequent traces showed Mobitz Type I and second-degree AVB, which converted to atrial flutter after exertion. Routine blood tests, TTE, and an ETT were all normal and he was discharged home with no conduction abnormalities. Case 3: A 24-year-old male presented with two episodes of syncope. Baseline examination was normal, with an ECG showing a low atrial rhythm. Interrogation of his implantable loop recorder showed episodes of early morning bradycardia episodes with no associated symptoms.DiscussionCannabis-related arrhythmia can be multiform regarding their presentation. Therefore, ambiguous combinations of arrhythmia should raise suspicion of underlying cannabis abuse, where clinically appropriate. Although causality with regards to cannabis use cannot be proven definitively in these cases, the temporal relationship between drug use and the onset of symptoms suggests a strong association.
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