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Indianapolis, IN, United States

Spoonamore K.G.,Krannert Institute of Cardiology | Ware S.M.,Indiana University
Heart Rhythm | Year: 2016

Sudden cardiac death due to heritable ventricular arrhythmias is an important cause of mortality, especially in young healthy individuals. The identification of the genetic basis of Mendelian diseases associated with arrhythmia has allowed the integration of this information into the diagnosis and clinical management of patients and at-risk family members. The rapid expansion of genetic testing options and the increasing complexity involved in the interpretation of results creates unique opportunities and challenges. There is a need for competency to incorporate genetics into clinical management and to provide appropriate family-based risk assessment and information. In addition, disease-specific genetic knowledge is required to order and correctly interpret and apply genetic testing results. Importantly, genetic diagnosis has a critical role in the risk stratification and clinical management of family members. This review summarizes the approach to genetic counseling and genetic testing for inherited arrhythmias and highlights specific genetic principles that apply to long QT syndrome, short QT syndrome, Brugada syndrome, and catecholaminergic polymorphic ventricular tachycardia. © 2016 Heart Rhythm Society. All rights reserved. Source

Chen Z.,Indiana University | Chen Z.,Krannert Institute of Cardiology
FEBS Journal | Year: 2015

Phospholamban (PLB) inhibits the activity of the cardiac calcium pump SERCA2a. We previously showed that PLB with engineered Cys residues only cross-linked with the Ca2+-free E2 intermediate of SERCA2a. Formation of E2•PLB prevents Ca2+ binding at the high-affinity Ca2+ binding sites, blocking the enzyme kinetic cycle. Here we further studied the synergistic action of PLB and ATP on E2 in terms of prevention of formation of the phosphorylated E2P-like states stabilized by metal fluorides. SERCA2a was co-expressed in insect cell microsomes with PLB mutants of normal or super-inhibitory strength, with cross-linkable mutations at either the cytosolic side (N30C) or the luminal side (V49C) of PLB. For normal-strength PLB mutants, in the absence of nucleotide, metal fluorides totally inhibited both SERCA2a enzyme activity and cross-linking of PLB to SERCA2a at both sites, suggesting that PLB dissociates from SERCA2a in the E2P-like states. However, under the same conditions, super-inhibitory PLB mutants prevented total enzyme inhibition by metal fluorides. Further, the cross-linking of super-inhibitory PLB to SERCA2a was only partially inhibited by metal fluorides, but was drastically restored upon sequential addition of ATP. These results revealed the equilibrium between E2•PLB, E2•ATP, or E2•ATP•PLB states and E2P-like states, suggesting that the synergistic binding of ATP and PLB to SERCA is very strong, sufficient to prevent formation of E2 phosphoenzymes, even when stabilized by metal fluorides. Phospholamban (PLB) inhibits the cardiac calcium pump (SERCA2a) by binding to the calcium-free, E2 state. We showed that the synergistic action of super-inhibitory PLB and ATP reversed metal fluorides inhibition of the enzyme activity and SERCA2a cross-linking to PLB. Thus, the E2•ATP•PLB complex prevents the formation of E2 phosphoenzymes, even when stabilized by metal fluorides. © 2015 FEBS. Source

Chang P.C.,Krannert Institute of Cardiology
Journal of the American Heart Association | Year: 2013

We previously reported that IKAS are heterogeneously upregulated in failing rabbit ventricles and play an important role in arrhythmogenesis. This study goal is to test the hypothesis that subtype 2 of the small-conductance Ca(2+) activated K(+) (SK2) channel and apamin-sensitive K(+) currents (IKAS) are upregulated in failing human ventricles. We studied 12 native hearts from transplant recipients (heart failure [HF] group) and 11 ventricular core biopsies from patients with aortic stenosis and normal systolic function (non-HF group). IKAS and action potential were recorded with patch-clamp techniques, and SK2 protein expression was studied by Western blotting. When measured at 1 μmol/L Ca(2+) concentration, IKAS was 4.22 (median) (25th and 75th percentiles, 2.86 and 6.96) pA/pF for the HF group (n=11) and 0.98 (0.54 and 1.72) pA/pF for the non-HF group (n=8, P=0.008). IKAS was lower in the midmyocardial cells than in the epicardial and the endocardial cells. The Ca(2+) dependency of IKAS in HF myocytes was shifted leftward compared to non-HF myocytes (Kd 314 versus 605 nmol/L). Apamin (100 nmol/L) increased the action potential durations by 1.77% (-0.9% and 7.3%) in non-HF myocytes and by 11.8% (5.7% and 13.9%) in HF myocytes (P=0.02). SK2 protein expression was 3-fold higher in HF than in non-HF. There is heterogeneous upregulation of IKAS densities in failing human ventricles. The midmyocardial layer shows lower IKAS densities than epicardial and endocardial layers of cells. Increase in both Ca(2+) sensitivity and SK2 protein expression contributes to the IKAS upregulation. Source

Das M.K.,Krannert Institute of Cardiology | Maskoun W.,Krannert Institute of Cardiology | Shen C.,Indiana University | Michael M.A.,Krannert Institute of Cardiology | And 4 more authors.
Heart Rhythm | Year: 2010

Background: Myocardial scar is a substrate for reentrant ventricular arrhythmias and is associated with poor prognosis. Fragmented QRS (fQRS) on 12-lead ECG represents myocardial conduction delays due to myocardial scar in patients with coronary artery disease (CAD). Objective: The purpose of this study was to determine whether fQRS is associated with increased ventricular arrhythmic event and mortality in patients with CAD and nonischemic dilated cardiomyopathy (DCM). Methods: Arrhythmic events and mortality were studied in 361 patients (91% male, age 63.3 ± 11.4 years, mean follow-up 16.6 ± 10.2 months) with CAD and DCM who received an implantable cardioverter-defibrillator for primary or secondary prophylaxis. fQRS included various RSR′ patterns (QRS duration <120 ms), such as ≥1 R prime or notching of the R wave or S wave present on at least two contiguous leads of those representing anterior (V1-V5), lateral (I, aVL, V6), or inferior (II, III, aVF) myocardial segments. Results: fQRS was present in 84 (23%) patients (fQRS group) and absent in 100 (28%) patients (non-fQRS group). Wide QRS (wQRS; QRS duration ≥120 ms) was present in 177 (49%) patients. Kaplan-Meier analysis revealed that event-free survival for an arrhythmic event (implantable cardioverter-defibrillator shock or antitachycardia pacing) was significantly lower in the fQRS group than in the non-fQRS and wQRS groups (P <.001 and P <.019, respectively). fQRS was an independent predictor of an arrhythmic event but not of death. Conclusion: fQRS on 12-lead ECG is a predictor of arrhythmic events in patients with CAD and DCM. fQRS is associated with a significantly decreased time to first arrhythmic event compared with non-fQRS and wQRS. Source

Tisdale J.E.,Purdue University | Tisdale J.E.,Indiana University | Jaynes H.A.,Purdue University | Kingery J.R.,Indiana University | And 6 more authors.
Circulation: Cardiovascular Quality and Outcomes | Year: 2013

Background-Identifying hospitalized patients at risk for QT interval prolongation could lead to interventions to reduce the risk of torsades de pointes. Our objective was to develop and validate a risk score for QT prolongation in hospitalized patients. Methods and Results-In this study, in a single tertiary care institution, consecutive patients (n=900) admitted to cardiac care units comprised the risk score development group. The score was then applied to 300 additional patients in a validation group. Corrected QT (QTc) interval prolongation (defined as QTc>500 ms or an increase of >60 ms from baseline) occurred in 274 (30.4%) and 90 (30.0%) patients in the development group and validation group, respectively. Independent predictors of QTc prolongation included the following: female (odds ratio, 1.5; 95% confidence interval, 1.1-2.0), diagnosis of myocardial infarction (2.4 [1.6-3.9]), septic shock (2.7 [1.5-4.8]), left ventricular dysfunction (2.7 [1.6-5.0]), administration of a QT-prolonging drug (2.8 [2.0-4.0]), ≥2 QT-prolonging drugs (2.6 [1.9-5.6]), or loop diuretic (1.4 [1.0-2.0]), age >68 years (1.3 [1.0-1.9]), serum K+ <3.5 mEq/L (2.1 [1.5-2.9]), and admitting QTc >450 ms (2.3; confidence interval [1.6-3.2]). Risk scores were developed by assigning points based on log odds ratios. Low-, moderate-, and high-risk ranges of 0 to 6, 7 to 10, and 11 to 21 points, respectively, best predicted QTc prolongation (C statistic=0.823). A high-risk score ≥11 was associated with sensitivity=0.74, specificity=0.77, positive predictive value=0.79, and negative predictive value=0.76. In the validation group, the incidences of QTc prolongation were 15% (low risk); 37% (moderate risk); and 73% (high risk). Conclusions-A risk score using easily obtainable clinical variables predicts patients at highest risk for QTc interval prolongation and may be useful in guiding monitoring and treatment decisions. © 2013 American Heart Association, Inc. Source

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