ResearchPad - arrhythmias---electrophysiology https://www.researchpad.co Default RSS Feed en-us © 2020 Newgen KnowledgeWorks <![CDATA[Novel coronavirus 19 (COVID-19) associated sinus node dysfunction: a case series]]> https://www.researchpad.co/article/elastic_article_12439 Novel coronavirus-19 disease (COVID-19) is associated with significant cardiovascular morbidity and mortality. To date, there have not been reports of sinus node dysfunction (SND) associated with COVID-19. This case series describes clinical characteristics, potential mechanisms, and short-term outcomes of COVID-19 patients who experience de novo SND.Case summaryWe present two cases of new-onset SND in patients recently diagnosed with COVID-19. Patient 1 is a 70-year-old female with no major past medical history who was intubated for acute hypoxic respiratory failure secondary to COVID-19 pneumonia and developed new-onset sinus bradycardia without a compensatory increase in heart rate in response to relative hypotension. Patient 2 is an 81-year-old male with a past medical history of an ascending aortic aneurysm, hypertension, and obstructive sleep apnoea who required intubation for COVID-19-induced acute hypoxic respiratory failure and exhibited new-onset sinus bradycardia followed by numerous episodes of haemodynamically significant accelerated idioventricular rhythm. Two weeks following the onset of SND, both patients remain in sinus bradycardia.DiscussionCOVID-19-associated SND has not previously been described. The potential mechanisms for SND in patients with COVID-19 include myocardial inflammation or direct viral infiltration. Patients diagnosed with COVID-19 should be monitored closely for the development of bradyarrhythmia and haemodynamic instability. ]]> <![CDATA[Fatal heart block from intentional yew tree (Taxus baccata) ingestion: a case report]]> https://www.researchpad.co/article/Na92a0bc8-ec2f-4903-990e-8247d5560c6d

Abstract

Background 

Taxus baccata, also known as English yew, is a poison that causes cardiac arrhythmias and can result in death from cardiogenic shock.

Case summary 

A 49-year-old gentleman was admitted following yew ingestion with suicidal intent. He was bradycardic at 30 b.p.m. and hypotensive on arrival. Electrocardiography revealed complete heart block with broad complex ventricular escape rate of 30 b.p.m. Bedside echocardiography revealed severe global impairment of right and left ventricular systolic function. Urgent temporary transvenous pacing was instituted, and the patient was considered for veno-arterial extracorporeal membrane oxygenation. Unfortunately, he deteriorated rapidly and cardiorespiratory arrest ensued, and despite prolonged in-hospital resuscitation, the patient died. Post-mortem examination revealed small needle-shaped plant leaves together with seeds found in the stomach. Ante mortem serum sample analysis sent to the Royal Botanical Gardens and revealed the presence of taxine Type B alkaloids in the patient’s blood.

Discussion 

Yew poisoning is a rare occurrence, and there is currently no effective antidote. Treatment involves supportive management, comprising prolonged effective cardiopulmonary resuscitation, pacing, and mechanical cardiac support. This case illustrates the importance of prompt recognition of yew poisoning, alongside early consideration of pacing and mechanical cardiac support. Due to the rarity of this cause of heart block, and since patients may not always volunteer a history of yew ingestion, yew poisoning is something that physicians should be aware of and this should be considered in the differential diagnosis in patients with unexpected heart block. Serum analysis for taxine alkaloids can be used to confirm the diagnosis.

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<![CDATA[False-positive ST-segment elevation]]> https://www.researchpad.co/article/N846ed87f-8e16-43bb-ac8c-d394dc7010e7 ]]> <![CDATA[A case report of arrhythmogenic ventricular cardiomyopathy presenting with sustained ventricular tachycardia arising from the right and the left ventricles before structural changes are documented]]> https://www.researchpad.co/article/N96757243-c3a8-482e-9dec-db0334209365

Abstract

Background

Arrhythmogenic ventricular cardiomyopathy (AC) is a genetic progressive disease characterized by fibro-fatty replacement of either ventricles in isolation or in combination. Arrhythmogenic ventricular cardiomyopathy is frequently associated with ventricular tachycardia (VT) having a left bundle branch block (LBBB) morphology and much more rarely with VT having right bundle branch block (RBBB) morphology even when the left ventricle is involved. Cardiac magnetic resonance (CMR) imaging plays a key role in the diagnosis of AC. Sustained VT in AC may occur in the concealed stage of the disease before the manifestation of morphological abnormalities on echocardiogram; however, they almost always are accompanied by structural abnormalities of the ventricles on CMR.

Case summary

A 54-year-old man presented with sustained VT of LBBB configuration consistent with the diagnosis of AC but with no right ventricular (RV) anomalies at repeat CMR. Ten years later, he developed sustained VT with RBBB morphology and structural changes at CMR compatible with RV involvement in the setting of AC. Two years later, he suffered from recurrent identical sustained RBBB-VT with typical CMR signs of left ventricular involvement. Genetic analysis was negative for any known mutation.

Discussion

In the present report, we describe a patient with AC who first exhibited LBBB- and 10 years later RBBB-sustained VT. Contrasting with what is usually observed in patients with AC, documentations of the VT’s arising from either ventricle were found to precede the structural anomalies in the respective cardiac chambers. This case highlights that normal CMR does not exclude underlying AC contrary to the perceptions of many clinicians. In addition, it strongly encourages repeating CMR after 1–2 years when the diagnosis of AC is highly suspected.

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<![CDATA[Game changer? A sporting indication to implant a left atrial appendage closure device in a rugby player with atrial fibrillation: a case report]]> https://www.researchpad.co/article/Nf2cd79d6-2340-49a1-9b6c-1fa564661d51

Abstract

Background

Caring for athletes with cardiac disease requires an approach that caters to the specific needs of the athlete.

Case summary

A 27-year-old professional rugby player was admitted with decompensated heart failure and atrial fibrillation (AF). Transthoracic echocardiogram showed features in keeping with a dilated cardiomyopathy with severe left ventricular (LV) systolic impairment. He made good progress on evidence-based heart failure medication and his LV systolic function returned to normal. He failed to maintain sinus rhythm with cardioversion and remained in persistent AF. He then suffered a transient ischaemic attack despite appropriate anticoagulation. At 1-year follow-up, he was asymptomatic and against medical advice continued to play competitive rugby whilst taking rivaroxaban. He subsequently underwent implantation with a percutaneous left atrial appendage occlusion device, allowing him to discontinue anticoagulation, reduce his bleeding risk and resume his career, whilst simultaneously lowering the thromboembolic risk.

Discussion

Counselling should include different management options aimed at minimizing the risks to athletes if they to return to competitive sports. Left atrial appendage occlusion devices are a suitable AF-related stroke prevention strategy in athletes competing in full-contact sports.

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<![CDATA[Response to Mechanical Stress Is Mediated by the TRPA Channel Painless in the Drosophila Heart]]> https://www.researchpad.co/article/5989db1bab0ee8fa60bce1e3

Mechanotransduction modulates cellular functions as diverse as migration, proliferation, differentiation, and apoptosis. It is crucial for organ development and homeostasis and leads to pathologies when defective. However, despite considerable efforts made in the past, the molecular basis of mechanotransduction remains poorly understood. Here, we have investigated the genetic basis of mechanotransduction in Drosophila. We show that the fly heart senses and responds to mechanical forces by regulating cardiac activity. In particular, pauses in heart activity are observed under acute mechanical constraints in vivo. We further confirm by a variety of in situ tests that these cardiac arrests constitute the biological force-induced response. In order to identify molecular components of the mechanotransduction pathway, we carried out a genetic screen based on the dependence of cardiac activity upon mechanical constraints and identified Painless, a TRPA channel. We observe a clear absence of in vivo cardiac arrest following inactivation of painless and further demonstrate that painless is autonomously required in the heart to mediate the response to mechanical stress. Furthermore, direct activation of Painless is sufficient to produce pauses in heartbeat, mimicking the pressure-induced response. Painless thus constitutes part of a mechanosensitive pathway that adjusts cardiac muscle activity to mechanical constraints. This constitutes the first in vivo demonstration that a TRPA channel can mediate cardiac mechanotransduction. Furthermore, by establishing a high-throughput system to identify the molecular players involved in mechanotransduction in the cardiovascular system, our study paves the way for understanding the mechanisms underlying a mechanotransduction pathway.

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<![CDATA[Acute Effects of Sex Steroid Hormones on Susceptibility to Cardiac Arrhythmias: A Simulation Study]]> https://www.researchpad.co/article/5989d9e1ab0ee8fa60b697a3

Acute effects of sex steroid hormones likely contribute to the observation that post-pubescent males have shorter QT intervals than females. However, the specific role for hormones in modulating cardiac electrophysiological parameters and arrhythmia vulnerability is unclear. Here we use a computational modeling approach to incorporate experimentally measured effects of physiological concentrations of testosterone, estrogen and progesterone on cardiac ion channel targets. We then study the hormone effects on ventricular cell and tissue dynamics comprised of Faber-Rudy computational models. The “female” model predicts changes in action potential duration (APD) at different stages of the menstrual cycle that are consistent with clinically observed QT interval fluctuations. The “male” model predicts shortening of APD and QT interval at physiological testosterone concentrations. The model suggests increased susceptibility to drug-induced arrhythmia when estradiol levels are high, while testosterone and progesterone are apparently protective. Simulations predict the effects of sex steroid hormones on clinically observed QT intervals and reveal mechanisms of estrogen-mediated susceptibility to prolongation of QT interval. The simulations also indicate that acute effects of estrogen are not alone sufficient to cause arrhythmia triggers and explain the increased risk of females to Torsades de Pointes. Our results suggest that acute effects of sex steroid hormones on cardiac ion channels are sufficient to account for some aspects of gender specific susceptibility to long-QT linked arrhythmias.

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<![CDATA[Dilated Cardiomyopathy with Increased SR Ca2+ Loading Preceded by a Hypercontractile State and Diastolic Failure in the α1CTG Mouse]]> https://www.researchpad.co/article/5989da01ab0ee8fa60b74317

Mice over-expressing the α1−subunit (pore) of the L-type Ca2+ channel (α1CTG) by 4months (mo) of age exhibit an enlarged heart, hypertrophied myocytes, increased Ca2+ current and Ca2+ transient amplitude, but a normal SR Ca2+ load. With advancing age (8–11 mo), some mice demonstrate advanced hypertrophy but are not in congestive heart failure (NFTG), while others evolve to frank dilated congestive heart failure (FTG). We demonstrate that older NFTG myocytes exhibit a hypercontractile state over a wide range of stimulation frequencies, but maintain a normal SR Ca2+ load compared to age matched non-transgenic (NTG) myocytes. However, at high stimulation rates (2–4 Hz) signs of diastolic contractile failure appear in NFTG cells. The evolution of frank congestive failure in FTG is accompanied by a further increase in heart mass and myocyte size, and phospholamban and ryanodine receptor protein levels and phosphorylation become reduced. In FTG, the SR Ca2+ load increases and Ca2+ release following excitation, increases further. An enhanced NCX function in FTG, as reflected by an accelerated relaxation of the caffeine-induced Ca2+ transient, is insufficient to maintain a normal diastolic Ca2+ during high rates of stimulation. Although a high SR Ca2+ release following excitation is maintained, the hypercontractile state is not maintained at high rates of stimulation, and signs of both systolic and diastolic contractile failure appear. Thus, the dilated cardiomyopathy that evolves in this mouse model exhibits signs of both systolic and diastolic failure, but not a deficient SR Ca2+ loading or release, as occurs in some other cardiomyopathic models.

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<![CDATA[Common Genetic Variation Near the Phospholamban Gene Is Associated with Cardiac Repolarisation: Meta-Analysis of Three Genome-Wide Association Studies]]> https://www.researchpad.co/article/5989da08ab0ee8fa60b7665b

To identify loci affecting the electrocardiographic QT interval, a measure of cardiac repolarisation associated with risk of ventricular arrhythmias and sudden cardiac death, we conducted a meta-analysis of three genome-wide association studies (GWAS) including 3,558 subjects from the TwinsUK and BRIGHT cohorts in the UK and the DCCT/EDIC cohort from North America. Five loci were significantly associated with QT interval at P<1×10−6. To validate these findings we performed an in silico comparison with data from two QT consortia: QTSCD (n = 15,842) and QTGEN (n = 13,685). Analysis confirmed the association between common variants near NOS1AP (P = 1.4×10−83) and the phospholamban (PLN) gene (P = 1.9×10−29). The most associated SNP near NOS1AP (rs12143842) explains 0.82% variance; the SNP near PLN (rs11153730) explains 0.74% variance of QT interval duration. We found no evidence for interaction between these two SNPs (P = 0.99). PLN is a key regulator of cardiac diastolic function and is involved in regulating intracellular calcium cycling, it has only recently been identified as a susceptibility locus for QT interval. These data offer further mechanistic insights into genetic influence on the QT interval which may predispose to life threatening arrhythmias and sudden cardiac death.

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<![CDATA[Functional Interactions between KCNE1 C-Terminus and the KCNQ1 Channel]]> https://www.researchpad.co/article/5989da10ab0ee8fa60b7945f

The KCNE1 gene product (minK protein) associates with the cardiac KvLQT1 potassium channel (encoded by KCNQ1) to create the cardiac slowly activating delayed rectifier, IKs. Mutations throughout both genes are linked to the hereditary cardiac arrhythmias in the Long QT Syndrome (LQTS). KCNE1 exerts its specific regulation of KCNQ1 activation via interactions between membrane-spanning segments of the two proteins. Less detailed attention has been focused on the role of the KCNE1 C-terminus in regulating channel behavior. We analyzed the effects of an LQT5 point mutation (D76N) and the truncation of the entire C-terminus (Δ70) on channel regulation, assembly and interaction. Both mutations significantly shifted voltage dependence of activation in the depolarizing direction and decreased IKs current density. They also accelerated rates of channel deactivation but notably, did not affect activation kinetics. Truncation of the C-terminus reduced the apparent affinity of KCNE1 for KCNQ1, resulting in impaired channel formation and presentation of KCNQ1/KCNE1 complexes to the surface. Complete saturation of KCNQ1 channels with KCNE1-Δ70 could be achieved by relative over-expression of the KCNE subunit. Rate-dependent facilitation of K+ conductance, a key property of IKs that enables action potential shortening at higher heart rates, was defective for both KCNE1 C-terminal mutations, and may contribute to the clinical phenotype of arrhythmias triggered by heart rate elevations during exercise in LQTS mutations. These results support several roles for KCNE1 C-terminus interaction with KCNQ1: regulation of channel assembly, open-state destabilization, and kinetics of channel deactivation.

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<![CDATA[Genome-Wide Association Studies of the PR Interval in African Americans]]> https://www.researchpad.co/article/5989daedab0ee8fa60bbfc37

The PR interval on the electrocardiogram reflects atrial and atrioventricular nodal conduction time. The PR interval is heritable, provides important information about arrhythmia risk, and has been suggested to differ among human races. Genome-wide association (GWA) studies have identified common genetic determinants of the PR interval in individuals of European and Asian ancestry, but there is a general paucity of GWA studies in individuals of African ancestry. We performed GWA studies in African American individuals from four cohorts (n = 6,247) to identify genetic variants associated with PR interval duration. Genotyping was performed using the Affymetrix 6.0 microarray. Imputation was performed for 2.8 million single nucleotide polymorphisms (SNPs) using combined YRI and CEU HapMap phase II panels. We observed a strong signal (rs3922844) within the gene encoding the cardiac sodium channel (SCN5A) with genome-wide significant association (p<2.5×10−8) in two of the four cohorts and in the meta-analysis. The signal explained 2% of PR interval variability in African Americans (beta  = 5.1 msec per minor allele, 95% CI  = 4.1–6.1, p = 3×10−23). This SNP was also associated with PR interval (beta = 2.4 msec per minor allele, 95% CI = 1.8–3.0, p = 3×10−16) in individuals of European ancestry (n = 14,042), but with a smaller effect size (p for heterogeneity <0.001) and variability explained (0.5%). Further meta-analysis of the four cohorts identified genome-wide significant associations with SNPs in SCN10A (rs6798015), MEIS1 (rs10865355), and TBX5 (rs7312625) that were highly correlated with SNPs identified in European and Asian GWA studies. African ancestry was associated with increased PR duration (13.3 msec, p = 0.009) in one but not the other three cohorts. Our findings demonstrate the relevance of common variants to African Americans at four loci previously associated with PR interval in European and Asian samples and identify an association signal at one of these loci that is more strongly associated with PR interval in African Americans than in Europeans.

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<![CDATA[Local Control of Excitation-Contraction Coupling in Human Embryonic Stem Cell-Derived Cardiomyocytes]]> https://www.researchpad.co/article/5989daceab0ee8fa60bb557c

We investigated the mechanisms of excitation-contraction (EC) coupling in human embryonic stem cell-derived cardiomyocytes (hESC-CMs) and fetal ventricular myocytes (hFVMs) using patch-clamp electrophysiology and confocal microscopy. We tested the hypothesis that Ca2+ influx via voltage-gated L-type Ca2+ channels activates Ca2+ release from the sarcoplasmic reticulum (SR) via a local control mechanism in hESC-CMs and hFVMs. Field-stimulated, whole-cell [Ca2+]i transients in hESC-CMs required Ca2+ entry through L-type Ca2+ channels, as evidenced by the elimination of such transients by either removal of extracellular Ca2+ or treatment with diltiazem, an L-type channel inhibitor. Ca2+ release from the SR also contributes to the [Ca2+]i transient in these cells, as evidenced by studies with drugs interfering with either SR Ca2+ release (i.e. ryanodine and caffeine) or reuptake (i.e. thapsigargin and cyclopiazonic acid). As in adult ventricular myocytes, membrane depolarization evoked large L-type Ca2+ currents (ICa) and corresponding whole-cell [Ca2+]i transients in hESC-CMs and hFVMs, and the amplitude of both ICa and the [Ca2+]i transients were finely graded by the magnitude of the depolarization. hESC-CMs exhibit a decreasing EC coupling gain with depolarization to more positive test potentials, “tail” [Ca2+]i transients upon repolarization from extremely positive test potentials, and co-localized ryanodine and sarcolemmal L-type Ca2+ channels, all findings that are consistent with the local control hypothesis. Finally, we recorded Ca2+ sparks in hESC-CMs and hFVMs. Collectively, these data support a model in which tight, local control of SR Ca2+ release by the ICa during EC coupling develops early in human cardiomyocytes.

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<![CDATA[Variable Nav1.5 Protein Expression from the Wild-Type Allele Correlates with the Penetrance of Cardiac Conduction Disease in the Scn5a+/− Mouse Model]]> https://www.researchpad.co/article/5989da1aab0ee8fa60b7c9fa

Background

Loss-of-function mutations in SCN5A, the gene encoding Nav1.5 Na+ channel, are associated with inherited cardiac conduction defects and Brugada syndrome, which both exhibit variable phenotypic penetrance of conduction defects. We investigated the mechanisms of this heterogeneity in a mouse model with heterozygous targeted disruption of Scn5a (Scn5a+/− mice) and compared our results to those obtained in patients with loss-of-function mutations in SCN5A.

Methodology/Principal Findings

Based on ECG, 10-week-old Scn5a+/− mice were divided into 2 subgroups, one displaying severe ventricular conduction defects (QRS interval>18 ms) and one a mild phenotype (QRS≤18 ms; QRS in wild-type littermates: 10–18 ms). Phenotypic difference persisted with aging. At 10 weeks, the Na+ channel blocker ajmaline prolonged QRS interval similarly in both groups of Scn5a+/− mice. In contrast, in old mice (>53 weeks), ajmaline effect was larger in the severely affected subgroup. These data matched the clinical observations on patients with SCN5A loss-of-function mutations with either severe or mild conduction defects. Ventricular tachycardia developed in 5/10 old severely affected Scn5a+/− mice but not in mildly affected ones. Correspondingly, symptomatic SCN5A–mutated Brugada patients had more severe conduction defects than asymptomatic patients. Old severely affected Scn5a+/− mice but not mildly affected ones showed extensive cardiac fibrosis. Mildly affected Scn5a+/− mice had similar Nav1.5 mRNA but higher Nav1.5 protein expression, and moderately larger INa current than severely affected Scn5a+/− mice. As a consequence, action potential upstroke velocity was more decreased in severely affected Scn5a+/− mice than in mildly affected ones.

Conclusions

Scn5a+/− mice show similar phenotypic heterogeneity as SCN5A-mutated patients. In Scn5a+/− mice, phenotype severity correlates with wild-type Nav1.5 protein expression.

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<![CDATA[Atrial Natriuretic Peptide Regulates Ca2+ Channel in Early Developmental Cardiomyocytes]]> https://www.researchpad.co/article/5989daf0ab0ee8fa60bc105a

Background

Cardiomyocytes derived from murine embryonic stem (ES) cells possess various membrane currents and signaling cascades link to that of embryonic hearts. The role of atrial natriuretic peptide (ANP) in regulation of membrane potentials and Ca2+ currents has not been investigated in developmental cardiomyocytes.

Methodology/Principal Findings

We investigated the role of ANP in regulating L-type Ca2+ channel current (ICaL) in different developmental stages of cardiomyocytes derived from ES cells. ANP decreased the frequency of action potentials (APs) in early developmental stage (EDS) cardiomyocytes, embryonic bodies (EB) as well as whole embryo hearts. ANP exerted an inhibitory effect on basal ICaL in about 70% EDS cardiomyocytes tested but only in about 30% late developmental stage (LDS) cells. However, after stimulation of ICaL by isoproterenol (ISO) in LDS cells, ANP inhibited the response in about 70% cells. The depression of ICaL induced by ANP was not affected by either Nω, Nitro-L-Arginine methyl ester (L-NAME), a nitric oxide synthetase (NOS) inhibitor, or KT5823, a cGMP-dependent protein kinase (PKG) selective inhibitor, in either EDS and LDS cells; whereas depression of ICaL by ANP was entirely abolished by erythro-9-(2-Hydroxy-3-nonyl) adenine (EHNA), a selective inhibitor of type 2 phosphodiesterase(PDE2) in most cells tested.

Conclusion/Significances

Taken together, these results indicate that ANP induced depression of action potentials and ICaL is due to activation of particulate guanylyl cyclase (GC), cGMP production and cGMP-activation of PDE2 mediated depression of adenosine 3′, 5′–cyclic monophophate (cAMP)–cAMP-dependent protein kinase (PKA) in early cardiomyogenesis.

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<![CDATA[The Role of Cardiac Troponin T Quantity and Function in Cardiac Development and Dilated Cardiomyopathy]]> https://www.researchpad.co/article/5989dac4ab0ee8fa60bb1ac4

Background

Hypertrophic (HCM) and dilated (DCM) cardiomyopathies result from sarcomeric protein mutations, including cardiac troponin T (cTnT, TNNT2). We determined whether TNNT2 mutations cause cardiomyopathies by altering cTnT function or quantity; whether the severity of DCM is related to the ratio of mutant to wildtype cTnT; whether Ca2+ desensitization occurs in DCM; and whether absence of cTnT impairs early embryonic cardiogenesis.

Methods and Findings

We ablated Tnnt2 to produce heterozygous Tnnt2+/− mice, and crossbreeding produced homozygous null Tnnt2−/− embryos. We also generated transgenic mice overexpressing wildtype (TGWT) or DCM mutant (TGK210Δ) Tnnt2. Crossbreeding produced mice lacking one allele of Tnnt2, but carrying wildtype (Tnnt2+/−/TGWT) or mutant (Tnnt2+/−/TGK210Δ) transgenes. Tnnt2+/− mice relative to wildtype had significantly reduced transcript (0.82±0.06[SD] vs. 1.00±0.12 arbitrary units; p = 0.025), but not protein (1.01±0.20 vs. 1.00±0.13 arbitrary units; p = 0.44). Tnnt2+/− mice had normal hearts (histology, mass, left ventricular end diastolic diameter [LVEDD], fractional shortening [FS]). Moreover, whereas Tnnt2+/−/TGK210Δ mice had severe DCM, TGK210Δ mice had only mild DCM (FS 18±4 vs. 29±7%; p<0.01). The difference in severity of DCM may be attributable to a greater ratio of mutant to wildtype Tnnt2 transcript in Tnnt2+/−/TGK210Δ relative to TGK210Δ mice (2.42±0.08, p = 0.03). Tnnt2+/−/TGK210Δ muscle showed Ca2+ desensitization (pCa50 = 5.34±0.08 vs. 5.58±0.03 at sarcomere length 1.9 µm, p<0.01), but no difference in maximum force generation. Day 9.5 Tnnt2−/− embryos had normally looped hearts, but thin ventricular walls, large pericardial effusions, noncontractile hearts, and severely disorganized sarcomeres.

Conclusions

Absence of one Tnnt2 allele leads to a mild deficit in transcript but not protein, leading to a normal cardiac phenotype. DCM results from abnormal function of a mutant protein, which is associated with myocyte Ca2+ desensitization. The severity of DCM depends on the ratio of mutant to wildtype Tnnt2 transcript. cTnT is essential for sarcomere formation, but normal embryonic heart looping occurs without contractile activity.

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<![CDATA[Beta1-Adrenoceptor Polymorphism Predicts Flecainide Action in Patients with Atrial Fibrillation]]> https://www.researchpad.co/article/5989dafbab0ee8fa60bc48e6

Background

Antiarrhythmic action of flecainide is based on sodium channel blockade. Beta1-adrenoceptor (β1AR) activation induces sodium channel inhibition, too. The aim of the present study was to evaluate the impact of different β1AR genotypes on antiarrhythmic action of flecainide in patients with structural heart disease and atrial fibrillation.

Methodology/Principal Findings

In 145 subjects, 87 with atrial fibrillation, genotyping was performed to identify the individual β1AR Arg389Gly and Ser49Gly polymorphism. Resting heart rate during atrial fibrillation and success of flecainide-induced cardioversion were correlated with β1AR genotype. The overall cardioversion rate with flecainide was 39%. The Arg389Arg genotype was associated with the highest cardioversion rate (55.5%; OR 3.30; 95% CI; 1.34–8.13; p = 0.003) compared to patients with Arg389Gly (29.5%; OR 0.44; 95% CI; 0.18–1.06; p = 0.066) and Gly389Gly (14%; OR 0.24; 95% CI 0.03–2.07; p = 0.17) variants. The single Ser49Gly polymorphism did not influence the conversion rate. In combination, patients with Arg389Gly-Ser49Gly genotype displayed the lowest conversion rate with 20.8% (OR 0.31; 95% CI; 0.10–0.93; p = 0.03). In patients with Arg389Arg variants the heart rate during atrial fibrillation was significantly higher (110±2.7 bpm; p = 0.03 vs. other variants) compared to Arg389Gly (104.8±2.4 bpm) and Gly389Gly (96.9±5.8 bpm) carriers. The Arg389Gly-Ser49Gly genotype was more common in patients with atrial fibrillation compared to patients without atrial fibrillation (27.6% vs. 5.2%; HR 6.98; 95% CI; 1.99–24.46; p<0.001).

Conclusions

The β1AR Arg389Arg genotype is associated with increased flecainide potency and higher heart rate during atrial fibrillation. The Arg389Gly-Ser49Gly genotype might be of predictive value for atrial fibrillation.

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<![CDATA[Selective Deletion of the A1 Adenosine Receptor Abolishes Heart-Rate Slowing Effects of Intravascular Adenosine In Vivo]]> https://www.researchpad.co/article/5989da86ab0ee8fa60b9c4c6

Objective

Intravenous adenosine induces temporary bradycardia. This is due to the activation of extracellular adenosine receptors (ARs). While adenosine can signal through any of four ARs (A1AR, A2AAR, A2BAR, A3AR), previous ex vivo studies implicated the A1AR in the heart-rate slowing effects. Here, we used comparative genetic in vivo studies to address the contribution of individual ARs to the heart-rate slowing effects of intravascular adenosine.

Methods and Results

We studied gene-targeted mice for individual ARs to define their in vivo contribution to the heart-rate slowing effects of adenosine. Anesthetized mice were treated with a bolus of intravascular adenosine, followed by measurements of heart-rate and blood pressure via a carotid artery catheter. These studies demonstrated dose-dependent slowing of the heart rate with adenosine treatment in wild-type, A2AAR−/−, A2BAR−/−, or A3AR−/− mice. In contrast, adenosine-dependent slowing of the heart-rate was completely abolished in A1AR−/− mice. Moreover, pre-treatment with a specific A1AR antagonist (DPCPX) attenuated the heart-rate slowing effects of adenosine in wild-type, A2AAR−/−, or A2BAR−/− mice, but did not alter hemodynamic responses of A1AR−/− mice.

Conclusions

The present studies combine pharmacological and genetic in vivo evidence for a selective role of the A1AR in slowing the heart rate during adenosine bolus injection.

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<![CDATA[Caveolae Act as Membrane Reserves Which Limit Mechanosensitive ICl,swell Channel Activation during Swelling in the Rat Ventricular Myocyte]]> https://www.researchpad.co/article/5989dab0ab0ee8fa60bab1af

Background

Many ion channels are preferentially located in caveolae where compartmentalisation/scaffolding with signal transduction components regulates their activity. Channels that are mechanosensitive may be additionally dependent on caveolar control of the mechanical state of the membrane. Here we test which mechanism underlies caveolar-regulation of the mechanosensitive ICl,swell channel in the adult cardiac myocyte.

Methodology/Principal Findings

Rat ventricular myocytes were exposed to solution of 0.02 tonicity (T; until lysis), 0.64T for 10–15 min (swelling), and/or methyl-β-cyclodextrin (MBCD; to disrupt caveolae). MBCD and 0.64T swelling reduced the number of caveolae visualised by electron microscopy by 75 and 50% respectively. MBCD stimulated translocation of caveolin 3 from caveolae-enriched buoyant membrane fractions, but both caveolin 1 and 3 remained in buoyant fractions after swelling. ICl,swell inhibition in control cells decreased time to half-maximal volume (t0.5,vol; 0.64T), consistent with a role for ICl,swell in volume regulation. MBCD-treated cells showed reduced time to lysis (0.02T) and t0.5,vol (0.64T) compared with controls. The negative inotropic response to swelling (an index of ICl,swell activation) was enhanced by MBCD.

Conclusions/Significance

These data show that disrupting caveolae removes essential membrane reserves, which speeds swelling in hyposmotic conditions, and thereby promotes activation of ICl,swell. They illustrate a general principle whereby caveolae as a membrane reserve limit increases in membrane tension during stretch/swelling thereby restricting mechanosensitive channel activation.

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<![CDATA[Chaotic Signatures of Heart Rate Variability and Its Power Spectrum in Health, Aging and Heart Failure]]> https://www.researchpad.co/article/5989dabdab0ee8fa60baf545

A paradox regarding the classic power spectral analysis of heart rate variability (HRV) is whether the characteristic high- (HF) and low-frequency (LF) spectral peaks represent stochastic or chaotic phenomena. Resolution of this fundamental issue is key to unraveling the mechanisms of HRV, which is critical to its proper use as a noninvasive marker for cardiac mortality risk assessment and stratification in congestive heart failure (CHF) and other cardiac dysfunctions. However, conventional techniques of nonlinear time series analysis generally lack sufficient sensitivity, specificity and robustness to discriminate chaos from random noise, much less quantify the chaos level. Here, we apply a ‘litmus test’ for heartbeat chaos based on a novel noise titration assay which affords a robust, specific, time-resolved and quantitative measure of the relative chaos level. Noise titration of running short-segment Holter tachograms from healthy subjects revealed circadian-dependent (or sleep/wake-dependent) heartbeat chaos that was linked to the HF component (respiratory sinus arrhythmia). The relative ‘HF chaos’ levels were similar in young and elderly subjects despite proportional age-related decreases in HF and LF power. In contrast, the near-regular heartbeat in CHF patients was primarily nonchaotic except punctuated by undetected ectopic beats and other abnormal beats, causing transient chaos. Such profound circadian-, age- and CHF-dependent changes in the chaotic and spectral characteristics of HRV were accompanied by little changes in approximate entropy, a measure of signal irregularity. The salient chaotic signatures of HRV in these subject groups reveal distinct autonomic, cardiac, respiratory and circadian/sleep-wake mechanisms that distinguish health and aging from CHF.

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<![CDATA[The Persistent Sodium Current Blocker Riluzole Is Antiarrhythmic and Anti-Ischaemic in a Pig Model of Acute Myocardial Infarction]]> https://www.researchpad.co/article/5989da09ab0ee8fa60b76bf2

Background

The potential of the cardiac persistent sodium current as a target for protection of the myocardium from ischaemia and reperfusion injury is gaining increasing interest. We have investigated the anti-ischaemic and antiarrhythmic effects of riluzole, a selective INaP blocker, in an open chest pig model of infarction.

Methods and Principal Findings

The left anterior descending coronary artery (LAD) was ligated in 27 anesthetised pigs (landrace or large white, either sex, 20–35 kg) which had received riluzole (8 mg/kg IP; n = 6), lidocaine (2.5–12 mg/kg bolus plus 0.05–0.24 mg/kg/min; n = 11) or vehicle (n = 10) 50 min prior. Arrhythmias could be delineated into phase 1a (0 to 20 min), phase 1b (20 to 50 min) and phase 2 (from 50 min to termination at 180 min) and were classified as premature ventricular contractions (PVCs), non-sustained ventricular tachycardia (VT) or ventricular fibrillation (VF) (spontaneously reverting within 15 s) or sustained VT or VF (ie. requiring cardioversion at 15 s). Riluzole reduced the average number of all arrhythmias in Phase 2 (PVCs from 484+/−119 to 32+/−13; non sustained arrhythmias from 8.9+/−4.4 to 0.7+/−0.5; sustained arrhythmias from 3.9+/−2.2 to 0.5+/−0.4); lidocaine reduced the average number of non-sustained and sustained arrhythmias (to 0.4+/−0.3 and 0.4+/−0.3 respectively) but not PVCs (to 390+/−234). Riluzole and lidocaine reduced the average number of sustained arrhythmias in phase 1b (from 1.8+/−0.4 to 0.17+/−0.13 (p<0.02) and to 0.55+/−0.26 (p = ns) respectively). Neither lidocaine or riluzole changed the ECG intervals: there was no statistical significance between groups at time zero (just before ligation) for any ECG measure. During the course of the 3 hour period of the ischaemia R-R, and P-R intervals shortened slightly in control and riluzole groups (not significantly different from each other) but not in the lidocaine group (significantly different from control). QRS and QTc did not change appreciably in any group Riluzole reduced the degree of histopathological tissue damage across the infarct zone considerably more than did lidocaine.

Conclusions

At the doses used, riluzole was at least as effective as lidocaine at reducing the number of episodes of ischaemic VT or VF in pigs, and much more effective at reducing the number of PVCs. We propose that this is related to the ability of riluzole to block cardiac persistent sodium current.

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