Arrhythmogenic cardiomyopathy is a genetic heart muscle disorder characterized by fibro-fatty replacement of cardiomyocytes leading to life-threatening ventricular arrhythmias, heart failure, and sudden cardiac death. Mutations in genes encoding cardiac junctional proteins are known to cause about half of cases, while remaining genetic causes are unknown. Using exome sequencing, we identified 2 missense variants (p.H33N and p.H77Y) that were predicted to be damaging in the integrin-linked kinase (ILK) gene in 2 unrelated families. The p.H33N variant was found to be de novo. ILK links integrins and the actin cytoskeleton, and is essential for the maintenance of normal cardiac function. Both of the new variants are located in the ILK ankyrin repeat domain, which binds to the first LIM domain of the adaptor proteins PINCH1 and PINCH2. In silico binding studies proposed that the human variants disrupt the ILK-PINCH complex. Recombinant mutant ILK expressed in H9c2 rat myoblast cells shows aberrant prominent cytoplasmic localization compared to the wild-type. Expression of human wild-type and mutant ILK under the control of the cardiac-specific cmlc2 promotor in zebrafish shows that p.H77Y and p.P70L, a variant previously reported in a dilated cardiomyopathy family, cause cardiac dysfunction and death by about 2-3 weeks of age. Our findings provide genetic and functional evidence that ILK is a cardiomyopathy disease gene and highlight its relevance for diagnosis and genetic counseling of inherited cardiomyopathies.

SummaryImplantable cardiac electronic device lead dislodgment is a relatively common complication and carries significant comorbidities. A potential cause of lead dislodgement includes inadequate anchoring along the lead suture sleeve at thevenous insertion site. We assessed which of the 3 commonly applied knot-tying techniques results in the most effective anchoring of a pacing lead along its suture sleeve, which could be associated with minimized lead motion postimplant.Following controlled traction force measurements, the anchor knot technique offered the greatest amount of lead stability when compared with the simple knot and the looping knot techniques.

OBJECTIVEOral anticoagulation (OAC) reduces stroke risk in patients with atrial fibrillation (AF) or atrial flutter (AFL). However, OAC initiation rates in patients discharged directly from the emergency department (ED) are low. We aimed to address this care gap by implementing a quality improvement intervention.METHODSThe study was performed in four Canadian urban EDs between 2015 and 2016. Patients were included if they had an electrocardiogram (ECG) documenting AF/AFL in the ED, were directly discharged from the ED, and were alive after 90 days. Baseline rates of OAC initiation were determined prior to the intervention. Between June and December 2016, we implemented our intervention in two EDs (ED-intervention), with the remaining sites acting as controls (ED-control). The intervention included a reminder statement prompting OAC initiation according to guideline recommendations, manually added to ECGs with a preliminary interpretation of AF/AFL, along with a decision-support algorithm that included a referral sheet. The primary outcome was the rate of OAC initiation within 90 days of the ED visit.RESULTSPrior to the intervention, 37.2% OAC-naïve patients with ECG-documented AF/AFL were initiated on OAC. Following implementation of the intervention, the rate of OAC initiation increased from 38.6% to 47.5% (absolute increase of 8.5%; 95% CI, 0.3% to 16.7%, p=0.04) among the ED-intervention sites, whereas the rate remained unchanged in ED-control sites (35.3% to 35.9%, p=0.9).CONCLUSIONSImplementation of a quality improvement intervention consisting of a reminder and decision-support tool increased initiation of OAC in high-risk patients. This support package can be readily implemented in other jurisdictions to improve OAC rates for AF/AFL.

Atrial fibrillation and atrial flutter (AF/AFL) are associated with an increased risk of stroke and systemic embolism. However, many patients are not started on guideline-recommended oral anticoagulation (OAC). We determined factors associated with initiation of OAC in eligible patients presenting to emergency departments. This retrospective cohort included patients with electrocardiogram (ECG)-documented AF/AFL presenting to 4 urban emergency departments in 2015. Presenting diagnoses, admission status, and comorbidities were determined by chart review. The primary outcome was OAC prescription within 90 days of ED presentation in guideline-eligible patients not previously on OAC. Of 4948 patients presenting to emergency departments with ECG-documented AF/AFL, we identified 2059 patients with Congestive Heart failure, Age (≥65),Diabetes, and Stroke (CHADS-65) score ≥1 not previously on OAC. Of those patients, 1287 (62.5%) were admitted, and 772 (37.5%) were discharged from the emergency department. Within 90 days of discharge, 663 (32.2%) patients were initiated on OAC. On multivariable analysis, hospitalization (odds ratio [OR] 1.31; 95% confidence interval [CI] 1.05-1.63, P = 0.02), presenting diagnosis of AF/AFL (OR 4.56, 95% CI 3.60-5.79, P < 0.01), and higher CHADS-65 score (OR 1.14 per point, 95% CI 1.04-1.25, P < 0.01) were associated with increased rates of OAC initiation. However, there was no association with individual components of the CHADS-65 score. Guideline-directed OAC is infrequently initiated in eligible patients within 90 days of presenting to emergency departments. The strongest factors associated with OAC initiation rates were hospitalization or having primary presenting diagnoses in emergency departments of AF/AFL after adjusting for other important characteristics. New interventions are required to improve appropriate OAC initiation in patients with AF/AFL.

Our website uses cookies to enhance your experience. By continuing to use our site, or clicking "Continue," you are agreeing to our Cookie Policy | Continue JAMA Internal Medicine HomeNew OnlineCurrent IssueFor Authors Podcast Publications JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry (1919-1959) JN Learning / CMESubscribeJobsInstitutions / LibrariansReprints & Permissions Terms of Use | Privacy Policy | Accessibility Statement 2023 American Medical Association. All Rights Reserved Search All JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Forum Archive JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry Input Search Term Sign In Individual Sign In Sign inCreate an Account Access through your institution Sign In Purchase Options: Buy this article Rent this article Subscribe to the JAMA Internal Medicine journal

Bradyarrhythmia is a common clinical presentation. Although the majority of cases are acquired, genetic screening of families with bradyarrhythmia has led to the discovery of a growing number of causative hereditary mutations. These mutations can interfere with any of the steps required for the occurrence of each cardiac cycle, including generation of an action potential in the sinoatrial node, successful exit of the action potential from the node, propagation of the action potential throughout the atria until the depolarization waves reach the atrioventricular node, and finally transmission of the action potential to the ventricles through the His-Purkinje system. As expected, channelopathies are the predominant culprit for hereditary bradyarrhythmias, because they play a crucial role in action potential generation and propagation. Interestingly, there are an increasing number of genes that encode for various regulatory or structural cellular components that have been linked to hereditary bradyarrhythmias. Furthermore, population-based genetic screening has revealed that age-related conduction defects may in fact be caused by genetic predispositions rather than the simple process of aging. With recent advances in genetic testing and the creation of animal models, not only have we discovered new culprit genes but it has also has become evident that there are still significant gaps in our knowledge of cardiac pathophysiology. In this review, we discuss the clinical presentations of known hereditary bradyarrhythmias and their associated conditions in addition to detailing our current molecular understanding of the mechanisms by which they are manifested.

Our website uses cookies to enhance your experience. By continuing to use our site, or clicking "Continue," you are agreeing to our Cookie Policy | Continue JAMA Internal Medicine HomeNew OnlineCurrent IssueFor Authors Podcast Publications JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry (1919-1959) JN Learning / CMESubscribeJobsInstitutions / LibrariansReprints & Permissions Terms of Use | Privacy Policy | Accessibility Statement 2023 American Medical Association. All Rights Reserved Search All JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Forum Archive JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry Input Search Term Sign In Individual Sign In Sign inCreate an Account Access through your institution Sign In Purchase Options: Buy this article Rent this article Subscribe to the JAMA Internal Medicine journal

Sudden cardiac death secondary to drug-induced long QT syndrome is a major safety concern and has led to withdrawal of several high-profile drugs, such as cisapride and astemizole, from the market. Although these drugs have different chemical structures, they all block the rapid delayed rectifier K+ current ( I Kr) with high potency. The hERG channel (Kv11.1) encoded by the hERG gene is responsible for this current. This channel has a high affinity for wide spectrum of compounds compared with other ion channels mainly because of the presence of unique aromatic amino acids in the S6 domain of hERG.1 This in turn has created a major challenge for development of new drugs.2 In fact, it is now a routine practice in the pharmaceutical industry to screen compounds for their ability to block hERG early in preclinical safety assessments according to the Food and Drug Administration guidelines. This in turn leads to elimination of a large number of potentially beneficial compounds from chemical libraries. See Article by Yu et al Interestingly, screening libraries of compounds for their blocking effect on hERG has resulted in discovery of many hERG activators/modulators. These drugs increase current flow through hERG via various mechanisms that include slowing of deactivation, removal of inactivation, and facilitation of activation.3 In theory, hERG channel activators could have the potential to normalize the QT interval in acquired or congenital long QT syndromes.4 …

Andersen- Tawil syndrome (ATS) is caused by mutations in KCNJ2 (Kir2.1). It remains unclear whether dilated cardiomyopathy (DCM) is a primary feature of ATS. We studied a proband with typical physical features of ATS plus DCM and moderate to severe left ventricular dysfunction (left ventricular ejection fraction = 30.5%). Genetic screening revealed a novel mutation in Kir2.1 (c.665T>C, p.L222S). Functional studies showed that this mutation reduced ionic currents in a dominant-negative manner. Suppression of ventricular arrhythmias with bisoprolol led to normalization of left ventricular size and function. We conclude that DCM is likely a secondary phenotype in ATS and is caused by high ventricular arrhythmia burden.

Andersen-Tawil syndrome (ATS) is a rare autosomal dominant multisystem disorder characterized by cardiac arrhythmias, periodic paralysis, and dysmorphic features. Mutations in the KCNJ2, the gene encoding the human inward rectifier potassium channel Kir2.1 (IK1) have been linked to ATS. Currently, it remains unclear whether dilated cardiomyopathy is a primary feature of ATS.

PURPOSE:The objective of this study was to assess whether sex differences exist in plaque burden and plaque subtype as assessed by coronary computed tomography angiography (CCTA).METHODS:The study cohort included 937 consecutive patients who underwent CCTA between 2008 and 2010. Stenosis was quantified using the Society of Cardiovascular Computed Tomography stenosis grading scale and a total stenosis score (TSS) was generated. Plaque morphology (PM) was reported as predominantly calcified (CP), noncalcified (NCP), or mixed (MP) plaque, and CP, NCP, and MP percentages were calculated.RESULTS:On multivariate analysis, men were significantly more likely to have plaque (65.9% of men vs. 44.6% of women, p<0.001), at least one segment with ≥50% stenosis (22.7% of men vs. 10.3% of women, p<0.001) and higher TSS (mean score=2.81 for men vs. 1.58 for women, p<0.001). Sex was the strongest predictor in all models (odds ratio [OR]=2.55, 95% confidence interval [CI] 1.78-3.67, p<0.001 for any plaque; OR=2.48, 95% CI 1.48-4.16, p<0.01 for segments with ≥50% stenosis; β=1.46, 95% CI 0.69-2.22, p<0.001 for TSS). Among patients with coronary plaque present, no significant sex differences in PM were found.CONCLUSIONS:Sex was the strongest risk factor for the presence and extent of plaque. Significant sex differences in PM did not exist.

Purpose: The purpose of this study was to determine whether low-kilovoltage (80 or 100 kV) computed tomography (CT)-guided interventions performed in a community-based hospital are feasible and to compare radiation exposure incurred with conventional 120 kV potential.Materials and Methods: Effective doses (ED) received by patients who underwent CT-guided intervention were analysed before and after a low-dose kilovoltage protocol was instituted in our department. We performed CT-guided procedures of 93 consecutive patients by using conventional 120-kV tube voltage (50 patients) and a low voltage of 80 or 100 kV for the remainder of this cohort. Automatic tube current modulation was enabled to obtain the best image quality. Procedure details were prospectively recorded and included examination site and type, slice width, tube voltage and current, dose length product, volume CT dose index, and size-specific dose estimate. Dose length product was converted to ED to account for radiosensitivity of specific organs. Statistical comparisons with test differences in the ED, volume CT dose index, size-specific dose estimate, and effective diameter (patient size) were made by using the Student t test.Results: All but 6 of the procedures performed at 80 kV were successful, for a success rate of 86%. At lower voltages, the ED was significantly (P < .01) reduced, on average, by 57%, 73%, and 65% for the pelvic, chest, and abdomen procedures, respectively.Conclusion: A low-dose radiation technique by using 80 or 100 kV results in a high technical success rate for pelvic, chest, and abdomen CT-guided interventional procedures, although dramatically decreasing radiation exposure. There was no significant difference in effective diameter (patient size) between the conventional and the low-dose groups, which would suggest that dose reduction was indeed a result of kVp change and not patient size.

Objective: To assess the association between the use of HMG Co A reductase inhibitors (statin medications) and coronary artery plaque morphology (PM) in South Asians (SA) vs. Non South Asians (NSA)...

BACKGROUND:The R582C mutation is one of many Long-QT Syndrome type 2 (LQT2)-causing mutations localized to the human ether-a-go-go related gene (hERG) channel's S5-P linker subdomain, yet its specific mechanism of dysfunction has not been examined.OBJECTIVE:This study sought to characterize the biophysical properties of the congenital LQT2-causing mutation, R582C, and utilize this mutation to provide the first report of voltage-dependent fluorescence from the S5-P linker.METHODS:Properties of the R582C channels were characterized by heterologous expression in both HEK293 cells and Xenopus oocytes using a combination of patch-clamp, 2-electrode voltage-clamp, immunoblot assay, and voltage-clamp fluorimetry.RESULTS:Expression of hERG R582C was found to be deficient in HEK293 cells, yet was amenable to rescue by incubation at reduced temperature or by treatment with dofetilide. Rescued channels expressed at levels comparable to wild type (WT) channels. Kinetic differences result in decreased outward repolarizing current evoked by an action potential clamp protocol. Voltage-clamp fluorimetry experiments utilized the introduced cysteine to covalently attach a fluorescent probe (tetramethylrhodamine-5-maleimide) to the S5-P linker to directly observe conformational changes occurring due to inactivation.CONCLUSION:The major mechanism underlying pathogenicity of the R582C mutation is a trafficking deficiency, although channels also exhibit kinetic deficiencies, perhaps reflecting the position of the mutation in the pore turret. Voltage clamp fluorescence signals from R582C channels provide evidence that the hERG turret undergoes distinct conformational changes during inactivation.

Human ether-a-go-go related gene (hERG) channel gating is associated with slow activation, yet the mechanistic basis for this is unclear. Here, we examine the effects of mutation of a unique glycine residue (G546) in the S4-55 linker on voltage sensor movement and its coupling to pore gating. Substitution of G546 with residues possessing different physicochemical properties shifted activation gating by similar to-50 mV (with the exception of G546C). With the activation shift taken into account, the time constant of activation was also accelerated, suggesting a stabilization of the closed state by similar to 1.6-4.3 kcal/mol (the energy equivalent of one to two hydrogen bonds). Predictions of the a-helical content of the 54-S5 linker suggest that the presence of G546 in wild-type hERG provides flexibility to the helix. Deactivation gating was affected differentially by the G546 substitutions. G546V induced a pronounced slow component of closing that was voltage-independent. Fluorescence measurements of voltage sensor movement in G546V revealed a slow component of voltage sensor return that was uncoupled from charge movement, suggesting a direct effect of the mutation on voltage sensor movement. These data suggest that G546 plays a critical role in channel gating and that hERG channel closing involves at least two independently modifiable reconfigurations of the voltage sensor.

Objectives: To assess the predictive value of traditional cardiac risk factors (CRFs) for coronary artery disease (CAD) burden and plaque morphology (PM) as reported by Coronary CT Angiography (CCT...

hERG channel gating is associated with relatively slow voltage sensor movement that limits the rate of channel opening and closing. The mechanistic basis underlying the constraints upon sensor movement in these channels is unclear. Here, we have used voltage clamp fluorimetry (VCF) to study the effects of mutations within the S4-S5 linker on voltage sensor movement and its coupling to the pore. Mutations at G546 had two separable effects on activation and deactivation gating. Substitution of G546 with residues possessing different physico-chemical properties all (with the exception of G546C) shifted activation gating by ∼30mV in the hyperpolarizing direction. With the activation shift taken into account, the time constant of ionic current activation was also accelerated. In addition, a number of G546 mutants affected deactivation gating, although the effects of different mutations varied. In the most dramatic case, the G546V mutation induced biphasic deactivation with a pronounced slow component that was voltage-independent. Deletion of the N-terminus accelerated the fast component, but the slow component remained pronounced, suggesting that the slow component was not mediated by altered interaction with the N-terminus. VCF measurements of voltage sensor movement in G546V channels revealed fast and slow components of fluorescence change associated with deactivation, suggesting that the slow component of ionic current deactivation is due to slow voltage sensor return that is uncoupled from charge movement. Taken together, these data suggest: 1) reduced flexibility of the S4-S5 linker helix reduces constraints on voltage sensor movement during activation gating; 2) normal hERG channel closing involves at least two reconfigurations of the voltage sensor that are rate-limiting for pore closure.