Slava Polonsky - Academia.edu (original) (raw)
Papers by Slava Polonsky
Heart Rhythm, May 1, 2023
Journal of the American College of Cardiology, Nov 1, 2021
The effectiveness of implantable cardioverter-defibrillators (ICDs) on reducing mortality has not... more The effectiveness of implantable cardioverter-defibrillators (ICDs) on reducing mortality has not been well studied in patients with long QT syndrome (LQTS). This study aimed to assess the survival benefits of ICDs in the overall LQTS population and in subgroups defined by ICD indications. This study included 3,035 patients (597 with ICD) from the Rochester LQTS Registry with a QTc ≥470 milliseconds or confirmed LQTS mutation. Using multivariable Cox proportional hazards models, the risk of all-cause mortality, all-cause mortality before age 50 years, and sudden cardiac death (SCD) were estimated as functions of time-dependent ICD therapy. Indication subgroups examined included patients with: 1) nonfatal cardiac arrest; 2) syncope while on beta-blockers; and 3) a QTc ≥500 milliseconds and syncope while off beta-blockers. During the 118,837 person-years of follow-up, 389 patients died (137 before age 50 years, and 116 experienced SCD). In the entire population, patients with ICDs had a lower risk of death (HR: 0.54; 95% CI: 0.34-0.86), death before age 50 years (HR: 0.29; 95% CI: 0.14-0.61), and SCD (HR: 0.22; 95% CI: 0.09-0.55) than patients without ICDs did. Patients with ICDs also had a lower risk of mortality among the 3 indication subgroups (HR: 0.14; 95% CI: 0.06-0.34; HR: 0.27; 95% CI: 0.10-0.72; and HR: 0.42; 95% CI: 0.19-0.96, respectively). ICD therapy was associated with a lower risk of all-cause mortality, all-cause mortality before age 50 years, and SCD in the LQTS population, as wells as with a lower risk of all-cause mortality in indication subgroups. This study provides evidence supporting ICD implantation in patients with high-risk LQTS.
JAMA Cardiology, Aug 1, 2023
ImportanceSyncope is the most powerful predictor for subsequent life-threatening events (LTEs) in... more ImportanceSyncope is the most powerful predictor for subsequent life-threatening events (LTEs) in patients with congenital long QT syndrome (LQTS). Whether distinct syncope triggers are associated with differential subsequent risk of LTEs is unknown.ObjectiveTo evaluate the association between adrenergic (AD)– and nonadrenergic (non–AD)-triggered syncopal events and the risk of subsequent LTEs in patients with LQT types 1 to 3 (LQT1-3).Design, Setting, and ParticipantsThis retrospective cohort study included data from 5 international LQTS registries (Rochester, New York; the Mayo Clinic, Rochester, Minnesota; Israel, the Netherlands, and Japan). The study population comprised 2938 patients with genetically confirmed LQT1, LQT2, or LQT3 stemming from a single LQTS-causative variant. Patients were enrolled from July 1979 to July 2021.ExposuresSyncope by AD and non-AD triggers.Main Outcomes and MeasuresThe primary end point was the first occurrence of an LTE. Multivariate Cox regression was used to determine the association of AD- or non–AD-triggered syncope on the risk of subsequent LTE by genotype. Separate analysis was performed in patients with β-blockers.ResultsA total of 2938 patients were included (mean [SD] age at enrollment, 29 [7] years; 1645 [56%] female). In 1331 patients with LQT1, a first syncope occurred in 365 (27%) and was induced mostly with AD triggers (243 [67%]). Syncope preceded 43 subsequent LTEs (68%). Syncopal episodes associated with AD triggers were associated with the highest risk of subsequent LTE (hazard ratio [HR], 7.61; 95% CI, 4.18-14.20; P < .001), whereas the risk associated with syncopal events due to non-AD triggers was statistically nonsignificant (HR, 1.50; 95% CI, 0.21-4.77; P = .97). In 1106 patients with LQT2, a first syncope occurred in 283 (26%) and was associated with AD and non-AD triggers in 106 (37%) and 177 (63%), respectively. Syncope preceded 55 LTEs (56%). Both AD- and non–AD-triggered syncope were associated with a greater than 3-fold increased risk of subsequent LTE (HR, 3.07; 95% CI, 1.66-5.67; P ≤ .001 and HR, 3.45, 95% CI, 1.96-6.06; P ≤ .001, respectively). In contrast, in 501 patients with LQT3, LTE was preceded by a syncopal episode in 7 (12%). In patients with LQT1 and LQT2, treatment with β-blockers following a syncopal event was associated with a significant reduction in the risk of subsequent LTEs. The rate of breakthrough events during treatment with β-blockers was significantly higher among those treated with selective agents vs nonselective agents.Conclusion and RelevanceIn this study, trigger-specific syncope in LQTS patients was associated with differential risk of subsequent LTE and response to β-blocker therapy.
Annals of Noninvasive Electrocardiology, Aug 11, 2023
BackgroundCongenital Long QT Syndrome (LQTS) is a hereditary arrhythmic disorder. We aimed to ass... more BackgroundCongenital Long QT Syndrome (LQTS) is a hereditary arrhythmic disorder. We aimed to assess the performance of current genetic variant annotation scores among LQTS patients and their predictive impact.MethodsWe evaluated 2025 patients with unique mutations for LQT1–LQT3. A patient‐specific score was calculated for each of four established genetic variant annotation algorithms: CADD, SIFT, REVEL, and PolyPhen‐2. The scores were tested for the identification of LQTS and their predictive performance for cardiac events (CE) and life‐threatening events (LTE) and then compared with the predictive performance of LQTS categorization based on mutation location/function. Score performance was tested using Harrell's C‐index.ResultsA total of 917 subjects were classified as LQT1, 838 as LQT2, and 270 as LQT3. The identification of a pathogenic variant occurred in 99% with CADD, 92% with SIFT, 100% with REVEL, and 86% with PolyPhen‐2. However, none of the genetic scores correlated with the risk of CE (Harrell's C‐index: CADD = 0.50, SIFT = 0.51, REVEL = 0.50, and PolyPhen‐2 = 0.52) or LTE (Harrell's C‐index: CADD = 0.50, SIFT = 0.53, REVEL = 0.54, and PolyPhen‐2 = 0.52). In contrast, high‐risk mutation categorization based on location/function was a powerful independent predictor of CE (HR = 1.88; p < .001) and LTE (HR = 1.89, p < .001).ConclusionIn congenital LQTS patients, well‐established algorithms (CADD, SIFT, REVEL, and PolyPhen‐2) were able to identify the majority of the causal variants as pathogenic. However, the scores did not predict clinical outcomes. These results indicate that mutation location/functional assays are essential for accurate interpretation of the risk associated with LQTS mutations.
Heart Rhythm, May 1, 2022
Circulation: Arrhythmia and Electrophysiology
Circulation, 2016
Introduction: Predicting episodes of ventricular tachyarrhythmia (VT) and especially fast VT even... more Introduction: Predicting episodes of ventricular tachyarrhythmia (VT) and especially fast VT events in arrhythmogenic right ventricular cardiomyopathy (ARVC) patients could be useful for identifica...
Circulation, 2017
Introduction: The association between antidepressant drugs (ADs) and the risk of arrhythmic event... more Introduction: The association between antidepressant drugs (ADs) and the risk of arrhythmic events has not been studied in patients with Long QT Syndrome (LQTS), who are at an increased risk of ven...
Journal of Molecular and Cellular Cardiology, Nov 1, 2016
In-silico models of human cardiac electrophysiology are now being considered for prediction of ca... more In-silico models of human cardiac electrophysiology are now being considered for prediction of cardiotoxicity as part of the preclinical assessment phase of all new drugs. We ask the question whether any of the available models are actually fit for this purpose. We tested three models of the human ventricular action potential, the O'hara-Rudy (ORD11), the Grandi-Bers (GB10) and the Ten Tusscher (TT06) models. We extracted clinical QT data for LQTS1 and LQTS2 patients with nonsense mutations that would be predicted to cause 50% loss of function in I Ks and I Kr respectively. We also obtained clinical QT data for LQTS3 patients. We then used a global optimization approach to improve the existing in silico models so that they reproduced all three clinical data sets more closely. We also examined the effects of adrenergic stimulation in the different LQTS subsets. All models, in their original form, produce markedly different and unrealistic predictions of QT prolongation for LQTS1, 2 and 3. After global optimization of the maximum conductances for membrane channels, all models have similar current densities during the action potential, despite differences in kinetic properties of the channels in the different models, and more closely reproduce the prolongation of repolarization seen in all LQTS subtypes. In-silico models of cardiac electrophysiology have the potential to be tremendously useful in complementing traditional preclinical drug testing studies. However, our results demonstrate they should be carefully validated and optimized to clinical data before they can be used for this purpose. COPYRIGHT STATEMENT. This is the author's version of a work that was accepted for publication. Changes introduced as a result of publishing processes such as copy-editing and formatting may not be reflected in this work. For a definitive version of this work please refer to the published source. This is the peer reviewed author's version of the following article: Mann, et al., (2016) Convergence of models of human ventricular myocyte electrophysiology after global optimization to recapitulate clinical long QT phenotypes. Journal of Molecular and Cellular Cardiology, 100. pp.25-34 which has been published in final form at http://dx.doi.org/10.1016/j.yjmcc.2016.09.011. This article may be used for noncommercial purposes in accordance with a Creative Commons Attribution Non-Commercial No Derivatives License https:// creativecommons.org/licenses/by-nc-nd/3.0/ Highlights: LQTS causes action potential prolongation by genetically heterogeneous mechanisms. Current in silico models cannot reproduce clinical data for major LQTS subtypes. We optimized in silico models to reproduce APD prolongation for LQTS1, 2 &3. Following optimization, models converged to have similar membrane conductance levels. These optimised models are better starting points for assessing drug toxicity.
Journal of the American College of Cardiology, May 1, 2021
European Heart Journal, Aug 1, 2018
Journal of the American College of Cardiology, May 1, 2021
BACKGROUNDThere are conflicting data on the impact of implantable cardioverter-defibrillator (ICD... more BACKGROUNDThere are conflicting data on the impact of implantable cardioverter-defibrillator (ICD) shocks on subsequent mortality.OBJECTIVESThe aim of this study was to determine whether the arrhythmic substrate leading to ICD therapy or the therapy itself increases mortality.METHODSThe study cohort included 5,516 ICD recipients who were enrolled in 5 landmark ICD trials (MADIT-II, MADIT-RISK, MADIT-CRT, MADIT-RIT, RAID). The authors evaluated the association of device therapy with subsequent mortality in 4 separate time-dependent models: model I, type of ICD therapy; model II, type of arrhythmia for which ICD therapy was delivered; model III, combined assessment of all arrhythmia and therapy types during follow-up; and model IV, incremental risk associated with repeated ICD shocks.RESULTSWhen analyzed by the type of ICD therapy (model I), a first appropriate ICD shock was associated with increased risk of subsequent mortality with or without concomitant occurrence of inappropriate shock during follow-up (hazard ratios [HRs]: 2.78 and 2.31; p < 0.001 and p = 0.12), whereas inappropriate shock alone was not associated with mortality risk (HR: 1.23; p = 0.42). Similarly, ICD therapy for ventricular tachycardia (VT) ≥200 beats/min or ventricular fibrillation (VF) (model II) was associated with increased risk of death with or without concomitant therapy for VT <200 beats/min (HRs: 2.25 and 2.62; both p < 0.001), whereas appropriate therapy for VT <200 beats/min or inappropriate therapy (regardless of etiology) did not reach statistical significance (all p > 0.10). Combined assessment of all therapy and arrhythmia types during follow-up (model III) showed that appropriate ICD shocks for VF, shocks for fast VT (≥200 beats/min) without prior antitachycardia pacing (ATP), as well as shocks for fast VT delivered after failed ATP, were associated with the highest risk of subsequent death (HRs: all >2.8; p < 0.001). Finally, 2 or more ICD appropriate shocks were not associated with incremental risk to the first appropriate ICD shock (model IV).CONCLUSIONThe combined data from 5 landmark ICD trials suggest that the underlying arrhythmic substrate rather than the ICD therapy is the more important determinant of mortality in ICD recipients.
JACC: Clinical Electrophysiology, Jul 1, 2023
Journal of Heart and Lung Transplantation, Apr 1, 2021
Purpose Patients have an increased risk of gastrointestinal bleeding (GIB) and thromboembolic eve... more Purpose Patients have an increased risk of gastrointestinal bleeding (GIB) and thromboembolic events (TE) after left ventricular assist device (LVAD) implantation. We hypothesized that GIB in LVAD recipients leads to low international normalized ratio (INR) values that may predispose to increased risk of TE. Methods This study included 410 patients in the University of Rochester Medical Center LVAD Database who were implanted between 2008 and 2020 (mean age 56 ± 13 years, 80% male, 84% white). Longitudinal data on INR was categorized as therapeutic (2-3), sub-therapeutic ( 3). A TE event was defined as device malfunction, confirmed or suspected pump thrombosis, ischemic stroke, transient ischemic attack, venous thromboembolism, or arterial non-CNS thromboembolism. The primary outcome was recurrent TE. The Anderson-Gill recurrent regression analysis was used to obtain hazard ratios and confidence intervals. Results During median follow-up of 2.07 years 83 (20%) patients had TE. After multivariate adjustment, GIB was associated with a 28% increased likelihood for subsequent sub-therapeutic INR values ( Conclusion Our findings suggest that the occurrence of GIB following LVAD implantation may predispose to increased risk of recurrent TE through sub-therapeutic INR values. INR
European Heart Journal, May 1, 2021
The benefit of prophylactic implantable cardioverter-defibrillator (ICD) is not uniform due to di... more The benefit of prophylactic implantable cardioverter-defibrillator (ICD) is not uniform due to differences in the risk of life-threatening ventricular tachycardia (VT)/ventricular fibrillation (VF) and non-arrhythmic mortality. We aimed to develop an ICD benefit prediction score that integrates the competing risks.
Circulation-arrhythmia and Electrophysiology, May 1, 2018
See Editorial by Killu and Cha BACKGROUND: Although cardiac resynchronization therapy (CRT) is be... more See Editorial by Killu and Cha BACKGROUND: Although cardiac resynchronization therapy (CRT) is beneficial in heart failure patients with left bundle branch block, 30% of these patients do not respond to the therapy. Identifying these patients before implantation of the device is one of the current challenges in clinical cardiology. METHODS: We verified the diagnostic contribution and an optimized computerized approach to measuring ventricular electrical activation delay (VED) from body surface 12-lead ECGs. We applied the method to ECGs acquired before implantation (baseline) in the MADIT-CRT trial (Multicenter Automatic Defibrillator Implantation-Cardiac Resynchronization Therapy). VED values were dichotomized using its quartiles, and we tested the association of VED values with the MADIT-CRT primary end point of heart failure or death. Multivariate Cox proportional models were used to estimate the risk of study end points. In addition, the association between VED values and hemodynamic changes after CRT-D implantation was examined using 1-year follow-up echocardiograms. RESULTS: Our results showed that left bundle branch block patients with baseline VED <31.2 ms had a 35% risk of MADIT-CRT end points, whereas patients with VED ≥31.2 ms had a 14% risk (P<0.001). The hazard ratio for predicting primary end points in patients with low VED was 2.34 (95% confidence interval, 1.53-3.57; P<0.001). Higher VED values were also associated with beneficial hemodynamic changes. These strong VED associations were not found in the right bundle branch block and intraventricular conduction delay cohorts of the MADIT-CRT trial. CONCLUSIONS: Left bundle branch block patients with a high baseline VED value benefited most from CRT, whereas left bundle branch block patients with low VED did not show CRT benefits.
Circulation, Jul 18, 2023
BACKGROUND: Black Americans have a higher risk of nonischemic cardiomyopathy (NICM) than White Am... more BACKGROUND: Black Americans have a higher risk of nonischemic cardiomyopathy (NICM) than White Americans. We aimed to evaluate differences in the risk of tachyarrhythmias among patients with an implantable cardioverter-defibrillator (ICD). METHODS: The study population comprised 3895 ICD recipients in the United States enrolled in primary prevention ICD trials. Outcome measures included ventricular tachyarrhythmia (VTA), atrial tachyarrhythmia (ATA), ICD therapies, VTA burden (using Andersen-Gill recurrent event analysis), death, and the predicted benefit of the ICD. All events were adjudicated blindly. Outcomes were compared between self-reported Black patients versus White patients with cardiomyopathy (ischemic and NICM). RESULTS: Black patients were more likely to be female (35% versus 22%) and younger (57±12 versus 62±12 years) with a higher frequency of comorbidities. In NICM, Black patients had a higher rate of first VTA, fast VTA, ATA, and appropriate and inappropriate ICD therapy (VTA ≥170 bpm, 32% versus 20%; VTA ≥200 bpm, 22% versus 14%; ATA, 25% versus 12%; appropriate therapy, 30% versus 20%; and inappropriate therapy, 25% versus 11%; P <0.001 for all). Multivariable analysis showed that Black patients with NICM experienced a higher risk of all types of arrhythmia or ICD therapy (VTA ≥170 bpm, hazard ratio [HR] 1.71; VTA ≥200 bpm, HR 1.58; ATA, HR 1.87; appropriate therapy, HR 1.62; inappropriate therapy, HR 1.86; P ≤0.01 for all), higher burden of tachyarrhythmias or therapies (VTA, HR 1.84; appropriate therapy, HR 1.84; P <0.001 for both), and a higher risk of death (HR 1.92; P =0.014). In contrast, in ischemic cardiomyopathy, the risk of all types of tachyarrhythmia, ICD therapy, or death was similar between Black patients and White patients. Both Black patients and White patients derived a significant and similar benefit from ICD implantation. CONCLUSIONS: Among patients with NICM with an ICD for primary prevention, Black patients compared with White patients had a high risk and burden of VTA, ATA, and ICD therapies with a lower survival rate. Nevertheless, the overall benefit of the ICD was maintained and was similar to that of White patients.
European Heart Journal, Aug 1, 2017
Acute coronary syndromes: the full picture / Genetics and cardiac arrhythmias 245 outcomes after ... more Acute coronary syndromes: the full picture / Genetics and cardiac arrhythmias 245 outcomes after complete revascularization depend upon when non-culprit vessel intervention occurs. Methods: A random effects model was employed to determine weighted risk ratios (RR). We searched EMBASE, PubMed, and CENTRAL databases to identify potential publications; only RCTs were included. Results: Nine RCTs (2,419 patients) met the eligibility criteria for comparison of culprit-vessel only treatment versus complete revascularization. In three RCTs (655 patients), complete revascularization was immediate and in six (1,764 patients) complete revascularization was delayed from one day to three weeks after the initial culprit-vessel intervention. For all nine studies, complete revascularization reduced the risk of major adverse cardiac events (MACE) by 40% versus culprit-only therapy (RR = 0.58; 95% confidence intervals (CI) [0.48 to 0.69]; P<0.0001). Furthermore, the need for later repeat revascularization was reduced after complete revascularization by almost 50% versus culprit-only treatment (RR = 0.51; 95% CI [0.43 to 0.62]; P<0.0001). Both analyses appeared robust in that omission of each study in turn produced no material change in overall results. Meta-regression analysis revealed the benefit of complete revascularization decreased as the delay after initial intervention increased; the sooner revascularization was complete the better. For MACE, this regression relationship (P=0.01) indicated that outcomes favored complete revascularization only when the delay was less than 15 days. Similarly, for later repeat revascularization, outcomes favored complete revascularization only when the delay was less than three weeks; although evidence against the null hypothesis was weaker (P=0.08). This interpretation was consistent with the finding that the benefits of complete revascularization were greater in RCTs with immediate complete revascularization than for all nine RCTs; for MACE, RR = 0.44; 95% CI [0.32 to 0.60] and for the risk of repeat revascularization, RR = 0.34; 95% CI [0.23 to 0.51]. Conclusion: Complete revascularization in STEMI cases with multi-vessel disease provides superior MACE and re-intervention benefit over culprit-vessel only therapy. However, these benefits appear time-dependent, questioning the practice of delaying complete revascularization beyond three weeks. These hypothesisgenerating results provide a basis for the rational design of future RCTs.
Heart Rhythm, May 1, 2023
Journal of the American College of Cardiology, Nov 1, 2021
The effectiveness of implantable cardioverter-defibrillators (ICDs) on reducing mortality has not... more The effectiveness of implantable cardioverter-defibrillators (ICDs) on reducing mortality has not been well studied in patients with long QT syndrome (LQTS). This study aimed to assess the survival benefits of ICDs in the overall LQTS population and in subgroups defined by ICD indications. This study included 3,035 patients (597 with ICD) from the Rochester LQTS Registry with a QTc ≥470 milliseconds or confirmed LQTS mutation. Using multivariable Cox proportional hazards models, the risk of all-cause mortality, all-cause mortality before age 50 years, and sudden cardiac death (SCD) were estimated as functions of time-dependent ICD therapy. Indication subgroups examined included patients with: 1) nonfatal cardiac arrest; 2) syncope while on beta-blockers; and 3) a QTc ≥500 milliseconds and syncope while off beta-blockers. During the 118,837 person-years of follow-up, 389 patients died (137 before age 50 years, and 116 experienced SCD). In the entire population, patients with ICDs had a lower risk of death (HR: 0.54; 95% CI: 0.34-0.86), death before age 50 years (HR: 0.29; 95% CI: 0.14-0.61), and SCD (HR: 0.22; 95% CI: 0.09-0.55) than patients without ICDs did. Patients with ICDs also had a lower risk of mortality among the 3 indication subgroups (HR: 0.14; 95% CI: 0.06-0.34; HR: 0.27; 95% CI: 0.10-0.72; and HR: 0.42; 95% CI: 0.19-0.96, respectively). ICD therapy was associated with a lower risk of all-cause mortality, all-cause mortality before age 50 years, and SCD in the LQTS population, as wells as with a lower risk of all-cause mortality in indication subgroups. This study provides evidence supporting ICD implantation in patients with high-risk LQTS.
JAMA Cardiology, Aug 1, 2023
ImportanceSyncope is the most powerful predictor for subsequent life-threatening events (LTEs) in... more ImportanceSyncope is the most powerful predictor for subsequent life-threatening events (LTEs) in patients with congenital long QT syndrome (LQTS). Whether distinct syncope triggers are associated with differential subsequent risk of LTEs is unknown.ObjectiveTo evaluate the association between adrenergic (AD)– and nonadrenergic (non–AD)-triggered syncopal events and the risk of subsequent LTEs in patients with LQT types 1 to 3 (LQT1-3).Design, Setting, and ParticipantsThis retrospective cohort study included data from 5 international LQTS registries (Rochester, New York; the Mayo Clinic, Rochester, Minnesota; Israel, the Netherlands, and Japan). The study population comprised 2938 patients with genetically confirmed LQT1, LQT2, or LQT3 stemming from a single LQTS-causative variant. Patients were enrolled from July 1979 to July 2021.ExposuresSyncope by AD and non-AD triggers.Main Outcomes and MeasuresThe primary end point was the first occurrence of an LTE. Multivariate Cox regression was used to determine the association of AD- or non–AD-triggered syncope on the risk of subsequent LTE by genotype. Separate analysis was performed in patients with β-blockers.ResultsA total of 2938 patients were included (mean [SD] age at enrollment, 29 [7] years; 1645 [56%] female). In 1331 patients with LQT1, a first syncope occurred in 365 (27%) and was induced mostly with AD triggers (243 [67%]). Syncope preceded 43 subsequent LTEs (68%). Syncopal episodes associated with AD triggers were associated with the highest risk of subsequent LTE (hazard ratio [HR], 7.61; 95% CI, 4.18-14.20; P &lt; .001), whereas the risk associated with syncopal events due to non-AD triggers was statistically nonsignificant (HR, 1.50; 95% CI, 0.21-4.77; P = .97). In 1106 patients with LQT2, a first syncope occurred in 283 (26%) and was associated with AD and non-AD triggers in 106 (37%) and 177 (63%), respectively. Syncope preceded 55 LTEs (56%). Both AD- and non–AD-triggered syncope were associated with a greater than 3-fold increased risk of subsequent LTE (HR, 3.07; 95% CI, 1.66-5.67; P ≤ .001 and HR, 3.45, 95% CI, 1.96-6.06; P ≤ .001, respectively). In contrast, in 501 patients with LQT3, LTE was preceded by a syncopal episode in 7 (12%). In patients with LQT1 and LQT2, treatment with β-blockers following a syncopal event was associated with a significant reduction in the risk of subsequent LTEs. The rate of breakthrough events during treatment with β-blockers was significantly higher among those treated with selective agents vs nonselective agents.Conclusion and RelevanceIn this study, trigger-specific syncope in LQTS patients was associated with differential risk of subsequent LTE and response to β-blocker therapy.
Annals of Noninvasive Electrocardiology, Aug 11, 2023
BackgroundCongenital Long QT Syndrome (LQTS) is a hereditary arrhythmic disorder. We aimed to ass... more BackgroundCongenital Long QT Syndrome (LQTS) is a hereditary arrhythmic disorder. We aimed to assess the performance of current genetic variant annotation scores among LQTS patients and their predictive impact.MethodsWe evaluated 2025 patients with unique mutations for LQT1–LQT3. A patient‐specific score was calculated for each of four established genetic variant annotation algorithms: CADD, SIFT, REVEL, and PolyPhen‐2. The scores were tested for the identification of LQTS and their predictive performance for cardiac events (CE) and life‐threatening events (LTE) and then compared with the predictive performance of LQTS categorization based on mutation location/function. Score performance was tested using Harrell's C‐index.ResultsA total of 917 subjects were classified as LQT1, 838 as LQT2, and 270 as LQT3. The identification of a pathogenic variant occurred in 99% with CADD, 92% with SIFT, 100% with REVEL, and 86% with PolyPhen‐2. However, none of the genetic scores correlated with the risk of CE (Harrell's C‐index: CADD = 0.50, SIFT = 0.51, REVEL = 0.50, and PolyPhen‐2 = 0.52) or LTE (Harrell's C‐index: CADD = 0.50, SIFT = 0.53, REVEL = 0.54, and PolyPhen‐2 = 0.52). In contrast, high‐risk mutation categorization based on location/function was a powerful independent predictor of CE (HR = 1.88; p < .001) and LTE (HR = 1.89, p < .001).ConclusionIn congenital LQTS patients, well‐established algorithms (CADD, SIFT, REVEL, and PolyPhen‐2) were able to identify the majority of the causal variants as pathogenic. However, the scores did not predict clinical outcomes. These results indicate that mutation location/functional assays are essential for accurate interpretation of the risk associated with LQTS mutations.
Heart Rhythm, May 1, 2022
Circulation: Arrhythmia and Electrophysiology
Circulation, 2016
Introduction: Predicting episodes of ventricular tachyarrhythmia (VT) and especially fast VT even... more Introduction: Predicting episodes of ventricular tachyarrhythmia (VT) and especially fast VT events in arrhythmogenic right ventricular cardiomyopathy (ARVC) patients could be useful for identifica...
Circulation, 2017
Introduction: The association between antidepressant drugs (ADs) and the risk of arrhythmic event... more Introduction: The association between antidepressant drugs (ADs) and the risk of arrhythmic events has not been studied in patients with Long QT Syndrome (LQTS), who are at an increased risk of ven...
Journal of Molecular and Cellular Cardiology, Nov 1, 2016
In-silico models of human cardiac electrophysiology are now being considered for prediction of ca... more In-silico models of human cardiac electrophysiology are now being considered for prediction of cardiotoxicity as part of the preclinical assessment phase of all new drugs. We ask the question whether any of the available models are actually fit for this purpose. We tested three models of the human ventricular action potential, the O'hara-Rudy (ORD11), the Grandi-Bers (GB10) and the Ten Tusscher (TT06) models. We extracted clinical QT data for LQTS1 and LQTS2 patients with nonsense mutations that would be predicted to cause 50% loss of function in I Ks and I Kr respectively. We also obtained clinical QT data for LQTS3 patients. We then used a global optimization approach to improve the existing in silico models so that they reproduced all three clinical data sets more closely. We also examined the effects of adrenergic stimulation in the different LQTS subsets. All models, in their original form, produce markedly different and unrealistic predictions of QT prolongation for LQTS1, 2 and 3. After global optimization of the maximum conductances for membrane channels, all models have similar current densities during the action potential, despite differences in kinetic properties of the channels in the different models, and more closely reproduce the prolongation of repolarization seen in all LQTS subtypes. In-silico models of cardiac electrophysiology have the potential to be tremendously useful in complementing traditional preclinical drug testing studies. However, our results demonstrate they should be carefully validated and optimized to clinical data before they can be used for this purpose. COPYRIGHT STATEMENT. This is the author's version of a work that was accepted for publication. Changes introduced as a result of publishing processes such as copy-editing and formatting may not be reflected in this work. For a definitive version of this work please refer to the published source. This is the peer reviewed author's version of the following article: Mann, et al., (2016) Convergence of models of human ventricular myocyte electrophysiology after global optimization to recapitulate clinical long QT phenotypes. Journal of Molecular and Cellular Cardiology, 100. pp.25-34 which has been published in final form at http://dx.doi.org/10.1016/j.yjmcc.2016.09.011. This article may be used for noncommercial purposes in accordance with a Creative Commons Attribution Non-Commercial No Derivatives License https:// creativecommons.org/licenses/by-nc-nd/3.0/ Highlights: LQTS causes action potential prolongation by genetically heterogeneous mechanisms. Current in silico models cannot reproduce clinical data for major LQTS subtypes. We optimized in silico models to reproduce APD prolongation for LQTS1, 2 &3. Following optimization, models converged to have similar membrane conductance levels. These optimised models are better starting points for assessing drug toxicity.
Journal of the American College of Cardiology, May 1, 2021
European Heart Journal, Aug 1, 2018
Journal of the American College of Cardiology, May 1, 2021
BACKGROUNDThere are conflicting data on the impact of implantable cardioverter-defibrillator (ICD... more BACKGROUNDThere are conflicting data on the impact of implantable cardioverter-defibrillator (ICD) shocks on subsequent mortality.OBJECTIVESThe aim of this study was to determine whether the arrhythmic substrate leading to ICD therapy or the therapy itself increases mortality.METHODSThe study cohort included 5,516 ICD recipients who were enrolled in 5 landmark ICD trials (MADIT-II, MADIT-RISK, MADIT-CRT, MADIT-RIT, RAID). The authors evaluated the association of device therapy with subsequent mortality in 4 separate time-dependent models: model I, type of ICD therapy; model II, type of arrhythmia for which ICD therapy was delivered; model III, combined assessment of all arrhythmia and therapy types during follow-up; and model IV, incremental risk associated with repeated ICD shocks.RESULTSWhen analyzed by the type of ICD therapy (model I), a first appropriate ICD shock was associated with increased risk of subsequent mortality with or without concomitant occurrence of inappropriate shock during follow-up (hazard ratios [HRs]: 2.78 and 2.31; p < 0.001 and p = 0.12), whereas inappropriate shock alone was not associated with mortality risk (HR: 1.23; p = 0.42). Similarly, ICD therapy for ventricular tachycardia (VT) ≥200 beats/min or ventricular fibrillation (VF) (model II) was associated with increased risk of death with or without concomitant therapy for VT <200 beats/min (HRs: 2.25 and 2.62; both p < 0.001), whereas appropriate therapy for VT <200 beats/min or inappropriate therapy (regardless of etiology) did not reach statistical significance (all p > 0.10). Combined assessment of all therapy and arrhythmia types during follow-up (model III) showed that appropriate ICD shocks for VF, shocks for fast VT (≥200 beats/min) without prior antitachycardia pacing (ATP), as well as shocks for fast VT delivered after failed ATP, were associated with the highest risk of subsequent death (HRs: all >2.8; p < 0.001). Finally, 2 or more ICD appropriate shocks were not associated with incremental risk to the first appropriate ICD shock (model IV).CONCLUSIONThe combined data from 5 landmark ICD trials suggest that the underlying arrhythmic substrate rather than the ICD therapy is the more important determinant of mortality in ICD recipients.
JACC: Clinical Electrophysiology, Jul 1, 2023
Journal of Heart and Lung Transplantation, Apr 1, 2021
Purpose Patients have an increased risk of gastrointestinal bleeding (GIB) and thromboembolic eve... more Purpose Patients have an increased risk of gastrointestinal bleeding (GIB) and thromboembolic events (TE) after left ventricular assist device (LVAD) implantation. We hypothesized that GIB in LVAD recipients leads to low international normalized ratio (INR) values that may predispose to increased risk of TE. Methods This study included 410 patients in the University of Rochester Medical Center LVAD Database who were implanted between 2008 and 2020 (mean age 56 ± 13 years, 80% male, 84% white). Longitudinal data on INR was categorized as therapeutic (2-3), sub-therapeutic ( 3). A TE event was defined as device malfunction, confirmed or suspected pump thrombosis, ischemic stroke, transient ischemic attack, venous thromboembolism, or arterial non-CNS thromboembolism. The primary outcome was recurrent TE. The Anderson-Gill recurrent regression analysis was used to obtain hazard ratios and confidence intervals. Results During median follow-up of 2.07 years 83 (20%) patients had TE. After multivariate adjustment, GIB was associated with a 28% increased likelihood for subsequent sub-therapeutic INR values ( Conclusion Our findings suggest that the occurrence of GIB following LVAD implantation may predispose to increased risk of recurrent TE through sub-therapeutic INR values. INR
European Heart Journal, May 1, 2021
The benefit of prophylactic implantable cardioverter-defibrillator (ICD) is not uniform due to di... more The benefit of prophylactic implantable cardioverter-defibrillator (ICD) is not uniform due to differences in the risk of life-threatening ventricular tachycardia (VT)/ventricular fibrillation (VF) and non-arrhythmic mortality. We aimed to develop an ICD benefit prediction score that integrates the competing risks.
Circulation-arrhythmia and Electrophysiology, May 1, 2018
See Editorial by Killu and Cha BACKGROUND: Although cardiac resynchronization therapy (CRT) is be... more See Editorial by Killu and Cha BACKGROUND: Although cardiac resynchronization therapy (CRT) is beneficial in heart failure patients with left bundle branch block, 30% of these patients do not respond to the therapy. Identifying these patients before implantation of the device is one of the current challenges in clinical cardiology. METHODS: We verified the diagnostic contribution and an optimized computerized approach to measuring ventricular electrical activation delay (VED) from body surface 12-lead ECGs. We applied the method to ECGs acquired before implantation (baseline) in the MADIT-CRT trial (Multicenter Automatic Defibrillator Implantation-Cardiac Resynchronization Therapy). VED values were dichotomized using its quartiles, and we tested the association of VED values with the MADIT-CRT primary end point of heart failure or death. Multivariate Cox proportional models were used to estimate the risk of study end points. In addition, the association between VED values and hemodynamic changes after CRT-D implantation was examined using 1-year follow-up echocardiograms. RESULTS: Our results showed that left bundle branch block patients with baseline VED <31.2 ms had a 35% risk of MADIT-CRT end points, whereas patients with VED ≥31.2 ms had a 14% risk (P<0.001). The hazard ratio for predicting primary end points in patients with low VED was 2.34 (95% confidence interval, 1.53-3.57; P<0.001). Higher VED values were also associated with beneficial hemodynamic changes. These strong VED associations were not found in the right bundle branch block and intraventricular conduction delay cohorts of the MADIT-CRT trial. CONCLUSIONS: Left bundle branch block patients with a high baseline VED value benefited most from CRT, whereas left bundle branch block patients with low VED did not show CRT benefits.
Circulation, Jul 18, 2023
BACKGROUND: Black Americans have a higher risk of nonischemic cardiomyopathy (NICM) than White Am... more BACKGROUND: Black Americans have a higher risk of nonischemic cardiomyopathy (NICM) than White Americans. We aimed to evaluate differences in the risk of tachyarrhythmias among patients with an implantable cardioverter-defibrillator (ICD). METHODS: The study population comprised 3895 ICD recipients in the United States enrolled in primary prevention ICD trials. Outcome measures included ventricular tachyarrhythmia (VTA), atrial tachyarrhythmia (ATA), ICD therapies, VTA burden (using Andersen-Gill recurrent event analysis), death, and the predicted benefit of the ICD. All events were adjudicated blindly. Outcomes were compared between self-reported Black patients versus White patients with cardiomyopathy (ischemic and NICM). RESULTS: Black patients were more likely to be female (35% versus 22%) and younger (57±12 versus 62±12 years) with a higher frequency of comorbidities. In NICM, Black patients had a higher rate of first VTA, fast VTA, ATA, and appropriate and inappropriate ICD therapy (VTA ≥170 bpm, 32% versus 20%; VTA ≥200 bpm, 22% versus 14%; ATA, 25% versus 12%; appropriate therapy, 30% versus 20%; and inappropriate therapy, 25% versus 11%; P <0.001 for all). Multivariable analysis showed that Black patients with NICM experienced a higher risk of all types of arrhythmia or ICD therapy (VTA ≥170 bpm, hazard ratio [HR] 1.71; VTA ≥200 bpm, HR 1.58; ATA, HR 1.87; appropriate therapy, HR 1.62; inappropriate therapy, HR 1.86; P ≤0.01 for all), higher burden of tachyarrhythmias or therapies (VTA, HR 1.84; appropriate therapy, HR 1.84; P <0.001 for both), and a higher risk of death (HR 1.92; P =0.014). In contrast, in ischemic cardiomyopathy, the risk of all types of tachyarrhythmia, ICD therapy, or death was similar between Black patients and White patients. Both Black patients and White patients derived a significant and similar benefit from ICD implantation. CONCLUSIONS: Among patients with NICM with an ICD for primary prevention, Black patients compared with White patients had a high risk and burden of VTA, ATA, and ICD therapies with a lower survival rate. Nevertheless, the overall benefit of the ICD was maintained and was similar to that of White patients.
European Heart Journal, Aug 1, 2017
Acute coronary syndromes: the full picture / Genetics and cardiac arrhythmias 245 outcomes after ... more Acute coronary syndromes: the full picture / Genetics and cardiac arrhythmias 245 outcomes after complete revascularization depend upon when non-culprit vessel intervention occurs. Methods: A random effects model was employed to determine weighted risk ratios (RR). We searched EMBASE, PubMed, and CENTRAL databases to identify potential publications; only RCTs were included. Results: Nine RCTs (2,419 patients) met the eligibility criteria for comparison of culprit-vessel only treatment versus complete revascularization. In three RCTs (655 patients), complete revascularization was immediate and in six (1,764 patients) complete revascularization was delayed from one day to three weeks after the initial culprit-vessel intervention. For all nine studies, complete revascularization reduced the risk of major adverse cardiac events (MACE) by 40% versus culprit-only therapy (RR = 0.58; 95% confidence intervals (CI) [0.48 to 0.69]; P<0.0001). Furthermore, the need for later repeat revascularization was reduced after complete revascularization by almost 50% versus culprit-only treatment (RR = 0.51; 95% CI [0.43 to 0.62]; P<0.0001). Both analyses appeared robust in that omission of each study in turn produced no material change in overall results. Meta-regression analysis revealed the benefit of complete revascularization decreased as the delay after initial intervention increased; the sooner revascularization was complete the better. For MACE, this regression relationship (P=0.01) indicated that outcomes favored complete revascularization only when the delay was less than 15 days. Similarly, for later repeat revascularization, outcomes favored complete revascularization only when the delay was less than three weeks; although evidence against the null hypothesis was weaker (P=0.08). This interpretation was consistent with the finding that the benefits of complete revascularization were greater in RCTs with immediate complete revascularization than for all nine RCTs; for MACE, RR = 0.44; 95% CI [0.32 to 0.60] and for the risk of repeat revascularization, RR = 0.34; 95% CI [0.23 to 0.51]. Conclusion: Complete revascularization in STEMI cases with multi-vessel disease provides superior MACE and re-intervention benefit over culprit-vessel only therapy. However, these benefits appear time-dependent, questioning the practice of delaying complete revascularization beyond three weeks. These hypothesisgenerating results provide a basis for the rational design of future RCTs.