Indianapolis, IN, United States
Indianapolis, IN, United States

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Bhakta D.,Krannert Institute of Cardiology | Shen C.,Indiana University | Kron J.,Oregon Health And Science University | Epstein A.E.,University of Pennsylvania | And 2 more authors.
Journal of Cardiovascular Electrophysiology | Year: 2011

Introduction: We assessed implant rates, indications, characteristics, and outcomes in patients with the neuromuscular disease, myotonic dystrophy type 1 (DM1) receiving a pacemaker or an implantable cardioverter-defibrillator (ICD). Methods and Results: Device use was evaluated in a prospective, multicenter registry of 406 genetically confirmed adult patients followed for 9.5 ± 3.2 years. Forty-six (11.3%) had or received a pacemaker and 21 (5.2%) received an ICD. Devices were primarily implanted for asymptomatic conduction abnormalities and left ventricular (LV) systolic dysfunction. However, 7 (15.2%) pacemakers were implanted for third-degree atrioventricular block and 6 (28.6%) ICDs were implanted for ventricular tachyarrhythmias (ventricular tachycardia [VT] or fibrillation [VF]). Patients receiving devices were older and more frequently had heart failure, LV systolic dysfunction, atrial tachyarrhythmias, and ECG conduction abnormalities compared to nondevice patients. Five (10.9%) pacemaker patients underwent upgrade to an ICD, 3 for LV systolic dysfunction, 1 for VT/VF, and 1 for progressive conduction disease. Seventeen (27.4%) of the 62 patients with devices were pacemaker-dependent at last follow-up. Three (14.3%) ICD patients had appropriate therapies. Twenty-four (52.2%) pacemaker patients died including 13 of respiratory failure and 7 of sudden death. Seven (33.3%) ICD patients died including 2 of respiratory failure and 3 of sudden death. The patients with ICDs and sudden death all had LV systolic dysfunction and 1 death was documented due to inappropriate therapies. Conclusions: DM1 patients commonly receive antiarrhythmia devices. The risk of VT/VF and sudden death suggests that ICDs rather than pacemakers should be considered for these patients. © 2011 Wiley Periodicals, Inc.


Sirenko S.,U.S. National Institute on Aging | Maltsev V.A.,U.S. National Institute on Aging | Maltseva L.A.,U.S. National Institute on Aging | Yang D.,U.S. National Institute on Aging | And 4 more authors.
Journal of Molecular and Cellular Cardiology | Year: 2014

Basal phosphorylation of sarcoplasmic reticulum (SR) Ca2+ proteins is high in sinoatrial nodal cells (SANC), which generate partially synchronized, spontaneous, rhythmic, diastolic local Ca2+ releases (LCRs), but low in ventricular myocytes (VM), which exhibit rare diastolic, stochastic SR-generated Ca2+ sparks. We tested the hypothesis that in a physiologic Ca2+ milieu, and independent of increased Ca2+ influx, an increase in basal phosphorylation of SR Ca2+ cycling proteins will convert stochastic Ca2+ sparks into periodic, high-power Ca2+ signals of the type that drives SANC normal automaticity. We measured phosphorylation of SR-associated proteins, phospholamban (PLB) and ryanodine receptors (RyR), and spontaneous local Ca2+ release characteristics (LCR) in permeabilized single, rabbit VM in physiologic [Ca2+], prior to and during inhibition of protein phosphatase (PP) and phosphodiesterase (PDE), or addition of exogenous cAMP, or in the presence of an antibody (2D12), that specifically inhibits binding of the PLB to SERCA-2. In the absence of the aforementioned perturbations, VM could only generate stochastic local Ca2+ releases of low power and low amplitude, as assessed by confocal Ca2+ imaging and spectral analysis. When the kinetics of Ca2+ pumping into the SR were increased by an increase in PLB phosphorylation (via PDE and PP inhibition or addition of cAMP) or by 2D12, self-organized, "clock-like" local Ca2+ releases, partially synchronized in space and time (Ca2+ wavelets), emerged, and the ensemble of these rhythmic local Ca2+ wavelets generated a periodic high-amplitude Ca2+ signal. Thus, a Ca2+ clock is not specific to pacemaker cells, but can also be unleashed in VM when SR Ca2+ cycling increases and spontaneous local Ca2+ release becomes partially synchronized. This unleashed Ca2+ clock that emerges in a physiological Ca2+ milieu in VM has two faces, however: it can provoke ventricular arrhythmias; or if harnessed, can be an important feature of novel bio-pacemaker designs. © 2013.


Hoang A.,Krannert Institute of Cardiology | Shen C.,Indiana University | Zheng J.,Indiana University | Taylor S.,Indiana University | And 4 more authors.
Heart Rhythm | Year: 2014

Background Utilization rates (URs) for implantable cardioverter- defibrillators (ICDs) for primary prevention of sudden cardiac death (PPSCD) are lacking in the community. Objective The purpose of this study was to establish the ICD UR in central Indiana. Methods A query run on 2 hospitals in a health information exchange database in Indianapolis identified patients between 2011 and 2012 with left ventricular ejection fraction (EF) <0.35. ICD eligibility and utilization were determined from chart review. Results We identified 1863 patients with at least 1 low EF study. Two cohorts were analyzed: 1672 patients without and 191 patients with International Classification of Diseases, Ninth Revision, Clinical Modification procedure code 37.94 for ICD placement. We manually reviewed a stratified (by hospital) random sample of 300 patients from the no-ICD procedure code cohort and found that 48 (16%) had no ICD but had class I indications for ICD. Eight of 300 (2.7%) actually had ICD implantation for PPSCD. Review of all 191 patients in the ICD procedure code cohort identified 70 with ICD implantation for PPSCD. The ICD UR (ratio between patients with ICD for PPSCD and all with indication) was 38% overall (95% confidence interval [CI] 28%-49%). URs were 48% for males (95% CI 34%-61%), 21% for females (95% CI 16%-26%, P =.0002 vs males), 40% for whites (95% CI 27%-53%), and 37% for blacks (95% CI 28%-46%, P =.66 vs whites). Conclusion ICD UR is 38% among patients meeting class I indications, suggesting further opportunities for improving guideline compliance. This study also illustrates limitations in calculating ICD UR using large electronic repositories without hands-on chart review. © 2014 Heart Rhythm Society.


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.


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.


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.


Dandamudi G.,Geisinger Heart Institute | Mokabberi R.,Geisinger Heart Institute | Assal C.,Geisinger Heart Institute | Das M.K.,Krannert Institute of Cardiology | And 4 more authors.
Heart Rhythm | Year: 2010

Background: Various diagnostic maneuvers have been proposed to help differentiate orthodromic reciprocating tachycardia (ORT) from atrioventricular nodal reentrant tachycardia (AVNRT) prior to ablation. However, not all criteria are applicable in every situation as each has limitations. Objective: The purpose of this study was to determine whether the behavior of tachycardia during onset of right ventricular (RV) pacing would help differentiate ORT from AVNRT. Methods: We retrospectively reviewed 72 cases (42 typical AVNRT, 7 atypical AVNRT, 15 left free-wall pathways, 6 septal pathways, 2 right free-wall pathways). We assessed the number of beats required to accelerate the tachycardia cycle length (TCL) to the paced cycle length (PCL) once a fully RV paced complex was achieved during supraventricular tachycardia. Results: In the AVNRT group, delta cycle length (DCL = PCL-TCL) was 29 ± 16 ms compared to 29 ± 10 ms in ORT group (P = NS). In the AVNRT group, the average number of fully RV paced beats required to reset the tachycardia was 3.7 ± 1.1 compared to 1 ± 0 in the ORT group (P <.0001). Using a cutoff >1 beat yielded both positive and negative predictive values of 100% for diagnosing AVNRT versus ORT. During entrainment attempts, AVNRT terminated 51% of the time and ORT terminated 65% of the time but still allowed application of the new criterion. Conclusion: Assessing timing and type of response of supraventricular tachycardia to RV pacing can help differentiate ORT from AVNRT with high certainty and prevent the need for other pacing maneuvers and measurements. © 2010 Heart Rhythm Society.


Chen P.-S.,Krannert Institute of Cardiology | Joung B.,Yonsei University | Shinohara T.,Krannert Institute of Cardiology | Das M.,Krannert Institute of Cardiology | And 2 more authors.
Circulation Journal | Year: 2010

During a normal lifetime, the heart may beat over 2 billion times, but the mechanisms by which the heart beats are initiated remain a subject of intense investigation. Since the discovery of a pacemaker current (If ) in 1978, multiple studies have shown that rhythmic changes in membrane voltage (the "membrane voltage clock") underlie the mechanisms of automaticity. The If is a depolarization current activated during hyperpolarization. Therefore, when the cardiac cells recover, the If is activated and slowly depolarizes the cell membrane, leading to the onset of action potential. Recent studies, however, suggest that increased intracellular Ca (Cai) induced by spontaneous rhythmic sarcoplasmic reticulum Ca release (the "calcium clock") is also jointly responsible for the initiation of the heart beat. Elevated Cai activates another ionic current (the sodium-calcium exchanger current or INCX), leading to spontaneous phase 4 depolarization. Under normal conditions, both clocks are needed to initiate the heart beat. Malfunction of the clocks is associated with sinus node dysfunction in heart failure and atrial fibrillation. More studies are needed to determine how both clocks work together to initiate heart beat under normal and disease conditions.


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.


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.

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