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2.  ECG Quantification of Myocardial Scar and Risk Stratification in MADIT-II 
Low left ventricular ejection fraction (LVEF) increases risk for both sudden cardiac death (SCD) and for heart failure (HF) death; however, implantable cardioverter-defibrillators (ICDs) reduce the incidence of SCD, not HF death. Distinguishing individuals at risk for HF death (non-SCD) vs. SCD could improve ICD patient selection.
This study evaluated whether electrocardiogram (ECG) quantification of myocardial infarction (MI) could discriminate risk for SCD vs. non-SCD.
Selvester QRS scoring was performed on 995 MADIT-II trial subjects’ ECGs to quantify MI size. MIs were categorized as small (0–3 QRS points), medium (4–7) or large (≥8). Mortality, SCD and non-SCD rates in the conventional medical therapy (CMT) arm and mortality and ventricular tachycardia/fibrillation (VT/VF) rates in the ICD arm were analyzed by QRS score group. Both arms were analyzed to determine ICD efficacy by QRS score group.
In the CMT arm, mortality, SCD and non-SCD rates were similar across QRS score groups (p=0.73. p=0.92 and p=0.77). The ICD arm showed similar rates of mortality (p=0.17) and VT/VF (p=0.24) across QRS score groups. ICD arm mortality was lower than CMT arm mortality across QRS score groups with greatest benefit in the large scar group.
Recently, QRS score was shown to be predictive of VT/VF in the SCD-HeFT population consisting of both ischemic and non-ischemic HF and having a maximum LVEF of 35% vs. 30% for MADIT-II. Our study found that QRS score did not add prognostic value in the MADIT-II population exhibiting relatively more severe cardiac dysfunction.
PMCID: PMC3779916  PMID: 24047486
Sudden death; heart failure; implantable cardioverter-defibrillator; electrocardiography; electrophysiology; tachyarrhythmias
3.  Inhalation of ultrafine carbon particles alters heart rate and heart rate variability in people with type 2 diabetes 
Diabetes may confer an increased risk for the cardiovascular health effects of particulate air pollution, but few human clinical studies of air pollution have included people with diabetes. Ultrafine particles (UFP, ≤100 nm in diameter) have been hypothesized to be an important component of particulate air pollution with regard to cardiovascular health effects.
17 never-smoker subjects 30–60 years of age, with stable type 2 diabetes but otherwise healthy, inhaled either filtered air (0–10 particles/cm3) or elemental carbon UFP (~107 particles/cm3, ~50 ug/m3, count median diameter 32 nm) by mouthpiece, for 2 hours at rest, in a double-blind, randomized, crossover study design. A digital 12-lead electrocardiogram (ECG) was recorded continuously for 48 hours, beginning 1 hour prior to exposure.
Analysis of 5-minute segments of the ECG during quiet rest showed reduced high-frequency heart rate variability with UFP relative to air exposure (p = 0.014), paralleled by non-significant reductions in time-domain heart rate variability parameters. In the analysis of longer durations of the ECG, we found that UFP exposure increased the heart rate relative to air exposure. During the 21- to 45-hour interval after exposure, the average heart rate increased approximately 8 beats per minute with UFP, compared to 5 beats per minute with air (p = 0.045). There were no UFP effects on cardiac rhythm or repolarization.
Inhalation of elemental carbon ultrafine particles alters heart rate and heart rate variability in people with type 2 diabetes. Our findings suggest that effects may occur and persist hours after a single 2-hour exposure.
PMCID: PMC4110706  PMID: 25028096
Air pollution; Ultrafine particles; Diabetes; Heart rate; Heart rate variability; Human; Cardiac
4.  Happiness and Stress Alter Susceptibility to Cardiac Events in Long QT Syndrome 
We sought to determine whether the circumstances preceding an arrhythmic event differed from those preceding a prior control occasion in patients with Long QT Syndrome (LQTS), a well-characterized genetically-based disorder that puts affected individuals at risk for sudden cardiac death.
38 patients (89% female) with LQTS completed a “case-crossover interview” in which each patient served as his/her own control by reporting on circumstances preceding an arrhythmic event (syncope, aborted cardiac arrest or defibrillator discharge) and preceding a control occasion (the next-to-last birthday). On average the interview was conducted 17 months after the cardiac event and control occasion.
During the 24-hour period preceding the cardiac event compared to the day before the control occasion, psychological stress was elevated, peak happiness was reduced, and peak exertion was not significantly different. Rated for the 6-month intervals preceding the event and control occasions, none of these three variables was significantly associated with events.
Happiness is associated with a reduction in the 24-hour risk of cardiac events in patients with LQTS, with stress having an opposite effect. To our knowledge this is the first report indicating that positive emotion may have a protective effect on life-threatening ventricular arrhythmias. This study lends further support to the role of emotions in influencing cardiac events in arrhythmia-prone patients.
PMCID: PMC4029944  PMID: 19419405
Happiness; Long QT Syndrome; Resilience; Stress; Sudden Cardiac Death
5.  Long QT Syndrome in African-Americans 
We evaluated the risk factors and clinical course of Long QT syndrome (LQTS) in African-American patients.
The study involved 41 African-Americans and 3,456 Caucasians with a QTc ≥ 450 ms from the U.S. portion of the International LQTS Registry. Data included information about the medical history and clinical course of the LQTS patients with end points relating to the occurrence of syncope, aborted cardiac arrest, or LQTS- related sudden cardiac death from birth through age 40 years. The statistical analyses involved Kaplan-Meier time to event graphs and Cox regression models for multivariable risk factor evaluation.
The QTc was 29ms longer in African-Americans than Caucasians. Multivarite Cox analyses with adjustment for decade of birth revealed that the cardiac event rate was similar in African-Americans and Caucasians with LQTS and that β-blockers were equally effective in reducing cardiac events in the two racial groups.
The clinical course of LQTS in African-Americans is similar to that of Caucasians with comparable risk factors and benefit from β-blocker therapy in the two racial groups.
PMCID: PMC4028024  PMID: 20146785
6.  Mutation and Gender Specific Risk in Type-2 Long QT Syndrome 
Men and women with type-2 long QT syndrome (LQT2) exhibit time-dependent differences in the risk for cardiac events. We hypothesized that data regarding the location of the disease-causing mutation in the KCNH2 channel may affect gender-specific risk in LQT2
To risk stratify LQT2 patients for life-threatening cardiac events based on clinical and genetic information.
The risk for life-threatening cardiac events from birth through age 40 (comprising aborted cardiac arrest [ACA] or sudden cardiac death [SCD]) years was assessed among 1,166 LQT2 males (n=490) and females (n=676) by the location of the LQTS-causing mutation in the KCNH2 channel (pre-specified in the primary analysis as pore-loop vs. nonpore-loop).
During follow-up, the cumulative probability of life-threatening cardiac events years was significantly higher among LQT2 women (26%) as compared with men (14%; p<0.001). Multivariate analysis showed that the risk for life-threatening cardiac events was not significantly different between women with and without pore-loop mutations (HR=1.20; p=0.33). In contrast, men with pore-loop mutations displayed a significant >2-fold higher risk of a first ACA or SCD as compared with those with nonpore-loop mutations (HR=2.18; p=0.01). Consistently, women experienced a high rate of life-threatening events regardless of mutation-location (pore-loop: 35%, nonpore-loop: 23%), whereas in men the rate of ACA or SCD was high among those with pore-loop mutations (28%) and relatively low among those with nonpore-loop mutations (8%).
Combined assessment of clinical and mutation-specific data can be used for improved risk stratification for life-threatening cardiac events in type-2 long QT syndrome.
PMCID: PMC4028036  PMID: 21440677
long-QT syndrome; pore-loop mutations; sudden cardiac death; gender
7.  β-Blocker Efficacy in High-Risk Patients with the Congenital Long-QT Syndrome Types 1 and 2 
β-blockers are the mainstay therapy in patients with the congenital long-QT syndrome (LQTS) types 1 and 2. However, limited data exist regarding the efficacy and limitations of this form of medical management within high-risk subsets of these populations.
Methods and Results
Multivariate analysis was carried out to identify age-related gender- and genotype- specific risk factors for cardiac events (comprising syncope, aborted cardiac arrest [ACA] or sudden cardiac death [SCD]) from birth through age 40 years among 971 LQT1 (n=549) and LQT2 (n=422) patients from the International LQTS Registry. Risk factors for cardiac events included the LQT1 genotype (HR=1.49, p=0.003) and male gender (HR=1.31, p=0.04) in the 0-14 years age-group; and the LQT2 genotype (HR=1.67, p<0.001) and female gender (HR=2.58, p<0.001) in the 15-40 years age-group. Gender-genotype subset analysis showed enhanced risk among LQT1 males (HR=1.93, p<0.001) and LQT2 females (HR=3.28, p<0.001) in the 2 respective age-groups. β-blocker therapy was associated with a significant risk-reduction in high-risk patients, including a 67% reduction (p=0.02) in LQT1 males and a 71% reduction (p<0.001) in LQT2 females. Life-threatening events (ACA/SCD) rarely occurred as a presenting symptom among β-blocker-treated patients. However, high-risk patients who experienced syncope during β-blocker therapy had a relatively high rate of subsequent ACA/SCD (>1 event per 100 patient-years).
The present findings suggest that β-blocker therapy should be routinely administered to all high-risk LQT1 and LQT2 patients without contraindications as a first line measure, whereas primary defibrillator therapy should be recommended for those who experience syncope during medical therapy.
PMCID: PMC4005824  PMID: 20233272
long QT syndrome; β-blockers; cardiac events; sudden cardiac death
8.  Risk of Cardiac Events in Patients with Asthma and Long QT Syndrome Treated with β2-agonists 
The American journal of cardiology  2008;102(7):871-874.
The clinical course and risk factors associated with β2-agonist therapy for asthma have not been investigated previously in patients with the Long QT Syndrome (LQTS). The risk of a first LQTS-related cardiac event due to β2-agonist therapy was examined in 3,287 patients enrolled in the International LQTS Registry with QTc≥450msec. The Cox proportional hazards model was used to assess the independent contribution of clinical factors for first cardiac events (syncope, aborted cardiac arrest, or sudden death) from birth through age 40. Time-dependent β2-agonist therapy for asthma was associated with an increased risk for cardiac events (hazard ratio (HR) = 2.00, 95% confidence interval 1.26–3.15, p = 0.003) after adjustment for relevant covariates including time-dependent β-blocker use, sex, QTc, and history of asthma. This risk was augmented within the first year after the initiation of β2-agonist therapy (HR = 3.53; p = 0.006). The combined use of β2-agonist and anti-inflammatory steroids was associated with an elevated risk for cardiac events (HR = 3.66; p < 0.01). β-blocker therapy was associated with a reduction in cardiac events in those using β2-agonists (HR = 0.14; P = 0.05). In conclusion, β2-agonist therapy was associated with an increased risk for cardiac events in asthmatic patients with LQTS, and this risk was diminished in patients receiving β-blockers.
PMCID: PMC4005827  PMID: 18805113
9.  Risk Factors for Aborted Cardiac Arrest and Sudden Cardiac Death in Children with the Congenital Long-QT Syndrome 
Circulation  2008;117(17):2184-2191.
The congenital long-QT syndrome (LQTS) is an important cause of sudden cardiac death (SCD) in children without structural heart disease. However, specific risk factors for life-threatening cardiac events in children with this genetic disorder have not been identified
Methods and Results
Cox proportional hazards regression modeling was used to identify risk factors for aborted cardiac arrest (ACA) or SCD in 3,015 LQTS children from the International LQTS Registry who were followed up from age 1 through 12 years. The cumulative probability of the combined end point was significantly higher in males (5%) than in females (1%; p<0.001). Risk factors for ACA or SCD during childhood included QTc duration >500 msec (HR=2.72 [95%CI 1.50 - 4.92]; p=0.001) and prior syncope (recent syncope [<2 years]: HR=6.16 [95%CI 3.41 - 11.15], p<0.001; remote syncope [≥2 years]: HR=2.67 [95% CI 1.22 - 5.85], p=0.01) in males, whereas prior syncope was the only significant risk factor among females (recent syncope: HR=27.82 [95%CI 9.72 - 79.60], p<0.001]; remote syncope: HR=12.04 [95%CI 3.79 - 38.26], p<0.001). β-blocker therapy was associated with a significant 53% reduction in the risk of ACA or SCD (p=0.01).
LQTS males experience a significantly higher rate of fatal or near-fatal cardiac events than females during childhood. A QTc duration >500 msec and a history of prior syncope identify risk in males, whereas prior syncope is the only significant risk factor among females. β-blocker therapy is associated with a significant reduction in the risk of life-threatening cardiac events during childhood.
PMCID: PMC3944375  PMID: 18427136
long-QT syndrome; risk factors; sudden death
10.  Risk of Life Threatening Cardiac Events among Patients with Long QT Syndrome and Multiple Mutations 
Patients with long QT syndrome (LQTS) who harbor multiple mutations (i.e. ≥ 2 mutations in ≥ 1 LQTS-susceptibility gene) may experience increased risk for life-threatening cardiac events.
The present study was designed to compare the clinical course of LQTS patients with multiple mutations to those with a single mutation.
The risk for life-threatening cardiac events (comprising aborted cardiac arrest, implantable defibrillator shock, or sudden cardiac death) from birth through age 40 years, by the presence of multiple vs. single mutations, was assessed among 403 patients from the LQTS Registry.
Patients with multiple mutations (n = 57) exhibited a longer QTc at enrollment compared with those with a single mutation (mean ± SD: 506 ± 72 vs. 480 ± 56 msec, respectively; p = 0.003) and had a higher rate of life threatening cardiac events during follow-up (23% vs. 11%, respectively; p < 0.001). Consistently, multivariate analysis demonstrated that patients with multiple mutations had a 2.3-fold (p = 0.015) increased risk for life threatening cardiac events as compared to patients with a single mutation. The presence of multiple mutations in a single LQTS gene was associated with a 3.2-fold increased risk for life threatening cardiac events (p = 0.010) whereas the risk associated with multiple mutation status involving > 1 LQTS gene was not significantly different from the risk associated with a single mutation (HR 1.7, p = 0.26).
LQTS patients with multiple mutations have a greater risk for life-threatening cardiac events as compared to patients with a single mutation.
PMCID: PMC3690288  PMID: 23174487
Aborted cardiac arrest; Long QT syndrome; Mutation; Risk factor; Sudden cardiac death
11.  Ambient fine particulate air pollution triggers ST-elevation myocardial infarction, but not non-ST elevation myocardial infarction: a case-crossover study 
We and others have shown that increases in particulate air pollutant (PM) concentrations in the previous hours and days have been associated with increased risks of myocardial infarction, but little is known about the relationships between air pollution and specific subsets of myocardial infarction, such as ST-elevation myocardial infarction (STEMI) and non ST-elevation myocardial infarction (NSTEMI).
Using data from acute coronary syndrome patients with STEMI (n = 338) and NSTEMI (n = 339) and case-crossover methods, we estimated the risk of STEMI and NSTEMI associated with increased ambient fine particle (<2.5 um) concentrations, ultrafine particle (10-100 nm) number concentrations, and accumulation mode particle (100-500 nm) number concentrations in the previous few hours and days.
We found a significant 18% increase in the risk of STEMI associated with each 7.1 μg/m3 increase in PM2.5 concentration in the previous hour prior to acute coronary syndrome onset, with smaller, non-significantly increased risks associated with increased fine particle concentrations in the previous 3, 12, and 24 hours. We found no pattern with NSTEMI. Estimates of the risk of STEMI associated with interquartile range increases in ultrafine particle and accumulation mode particle number concentrations in the previous 1 to 96 hours were all greater than 1.0, but not statistically significant. Patients with pre-existing hypertension had a significantly greater risk of STEMI associated with increased fine particle concentration in the previous hour than patients without hypertension.
Increased fine particle concentrations in the hour prior to acute coronary syndrome onset were associated with an increased risk of STEMI, but not NSTEMI. Patients with pre-existing hypertension and other cardiovascular disease appeared particularly susceptible. Further investigation into mechanisms by which PM can preferentially trigger STEMI over NSTEMI within this rapid time scale is needed.
PMCID: PMC3891992  PMID: 24382024
Myocardial infarction; Acute coronary syndrome; Epidemiology; Air pollution
12.  Measure of the QT/RR Dynamic Coupling in Patients with the Long QT Syndrome 
The patients with the long QT syndrome type-1 (LQT-1) have an impaired adaptation of the QT interval to heart rate changes. Yet, the description of the dynamic QT/RR coupling in genotyped LQT-1 has never been thoroughly investigated.
We propose a method to model the dynamic QT/RR coupling by defining a transfer function characterizing the relationship between a QT interval and its previous RR intervals measured from ambulatory Holter recordings. Three parameters are used to characterize the QT/RR coupling: a fast gain (GainF), a slow gain (GainL), and a time constant (τ). We investigated the values of these parameters across genders, and in genotyped LQT-1 patients with normal QTc interval duration (QTc<470 ms).
The QT/RR dynamic profiles are significantly different between LQT-1 patients (97) and controls (154): LQT-1 have longer QTc interval (453±35 vs. 384±26 ms, p<0.0001), and an increased dependency of the QT interval to previous RR changes revealed by a larger GainL (0.22±0.06 vs. 0.18±0.07, p<0.0001) and GainF (0.05±0.02 vs. 0.03±0.01, p<0.0001). Importantly, LQT-1 patients have a faster QT dynamic response to previous RR changes described by τ: 122±44 vs. 172±92 beats (p<0.0001). This faster QT dynamic response of the QT-RR dynamic coupling remained in LQT-1 patients with QTc in a normal range (<430 ms).
The measurement of QT/RR dynamic coupling could be used in patients suspected to carry a concealed form of the LQT-1 syndrome, or to provide insights into the types of arrhythmogenic triggers a patient may be prone to.
PMCID: PMC3481196  PMID: 23094878
Long QT syndrome; Dynamic QT/RR coupling; Holter recording; QT adaptation; QT parameters
13.  Predictive Value of Beat-to-Beat QT Variability Index across the Continuum of Left Ventricular Dysfunction: Competing Risks of Non-cardiac or Cardiovascular Death, and Sudden or Non-Sudden Cardiac Death 
The goal of this study was to determine the predictive value of beat-to-beat QT variability in heart failure (HF) patients across the continuum of left ventricular dysfunction.
Methods and Results
Beat-to-beat QT variability index (QTVI), heart rate variance (LogHRV), normalized QT variance (QTVN), and coherence between heart rate variability and QT variability have been measured at rest during sinus rhythm in 533 participants of the Muerte Subita en Insuficiencia Cardiaca (MUSIC) HF study (mean age 63.1±11.7; males 70.6%; LVEF >35% in 254 [48%]) and in 181 healthy participants from the Intercity Digital Electrocardiogram Alliance (IDEAL) database. During a median of 3.7 years of follow-up, 116 patients died, 52 from sudden cardiac death (SCD). In multivariate competing risk analyses, the highest QTVI quartile was associated with cardiovascular death [hazard ratio (HR) 1.67(95%CI 1.14-2.47), P=0.009] and in particular with non-sudden cardiac death [HR 2.91(1.69-5.01), P<0.001]. Elevated QTVI separated 97.5% of healthy individuals from subjects at risk for cardiovascular [HR 1.57(1.04-2.35), P=0.031], and non-sudden cardiac death in multivariate competing risk model [HR 2.58(1.13-3.78), P=0.001]. No interaction between QTVI and LVEF was found. QTVI predicted neither non-cardiac death (P=0.546) nor SCD (P=0.945). Decreased heart rate variability (HRV) rather than increased QT variability was the reason for increased QTVI in this study.
Increased QTVI due to depressed HRV predicts cardiovascular mortality and non-sudden cardiac death, but neither SCD nor excracardiac mortality in HF across the continuum of left ventricular dysfunction. Abnormally augmented QTVI separates 97.5% of healthy individuals from HF patients at risk.
PMCID: PMC3432262  PMID: 22730411
ECG; ejection fraction; heart failure; sudden death; QT variability
14.  Plasminogen Activator Inhibitor-2 Polymorphism Associates with Recurrent Coronary Event Risk in Patients with High HDL and C-Reactive Protein Levels 
PLoS ONE  2013;8(7):e68920.
The objective of this work was to investigate whether fibrinolysis plays a role in establishing recurrent coronary event risk in a previously identified group of postinfarction patients. This group of patients was defined as having concurrently high levels of high-density lipoprotein cholesterol (HDL-C) and C-reactive protein (CRP) and was previously demonstrated to be at high-risk for recurrent coronary events. Potential risk associations of a genetic polymorphism of plasminogen activator inhibitor-2 (PAI-2) were probed as well as potential modulatory effects on such risk of a polymorphism of low-density lipoprotein receptor related protein (LRP-1), a scavenger receptor known to be involved in fibrinolysis in the context of cellular internalization of plasminogen activator/plansminogen activator inhibitor complexes. To this end, Cox multivariable modeling was performed as a function of genetic polymorphisms of PAI-2 (SERPINB, rs6095) and LRP-1 (LRP1, rs1800156) as well as a set of clinical parameters, blood biomarkers, and genetic polymorphisms previously demonstrated to be significantly and independently associated with risk in the study population including cholesteryl ester transfer protein (CETP, rs708272), p22phox (CYBA, rs4673), and thrombospondin-4 (THBS4, rs1866389). Risk association was demonstrated for the reference allele of the PAI-2 polymorphism (hazard ratio 0.41 per allele, 95% CI 0.20-0.84, p=0.014) along with continued significant risk associations for the p22phox and thrombospondin-4 polymorphisms. Additionally, further analysis revealed interaction of the LRP-1 and PAI-2 polymorphisms in generating differential risk that was illustrated using Kaplan-Meier survival analysis. We conclude from the study that fibrinolysis likely plays a role in establishing recurrent coronary risk in postinfarction patients with concurrently high levels of HDL-C and CRP as manifested by differential effects on risk by polymorphisms of several genes linked to key actions involved in the fibrinolytic process.
PMCID: PMC3706432  PMID: 23874812
15.  Mutations in Cytoplasmic Loops of the KCNQ1 Channel and the Risk of Life-Threatening Events: Implications for Mutation-Specific Response to Beta-Blocker Therapy in Type-1 Long QT Syndrome 
Circulation  2012;125(16):1988-1996.
β-adrenergic stimulation is the main trigger for cardiac events in type-1 long QT syndrome (LQT1). We evaluated a possible association between ion channel response to β-adrenergic stimulation and clinical response to β-blocker therapy according to mutation location.
Methods and Results
The study sample comprised 860 patients with genetically-confirmed mutations in the KCNQ1 channel. Patients were categorized into carriers of missense mutations located in the cytoplasmic loops (C-loops), membrane spanning domain, C/N-terminus, and non-missense mutations. There were 27 aborted cardiac arrest [ACA] and 78 sudden cardiac death [SCD] events from birth through age 40 years. After multivariable adjustment for clinical factors, the presence of C-loop mutations was associated with the highest risk for ACA or SCD (hazard ratio [95% confidence interval] vs. non-missense mutations = 2.75 [1.29-5.86, P=0.009]). β-blocker therapy was associated with a significantly greater reduction in the risk of ACA or SCD among patients with C-loop mutations than among all other patients (hazard ratios = 0.12 [0.02-0.73, P=0.02] and 0.82 [0.31-2.13, P=0.68], respectively; P-for interaction = 0.04). Cellular expression studies showed that membrane spanning and C-loop mutations produced a similar decrease in current, but only C-loop mutations showed a pronounced reduction in channel activation in response to β-adrenergic stimulation.
Patients with C-loop missense mutations in the KCNQ1 channel exhibit a high-risk for life-threatening events and derive a pronounced benefit from treatment with β-blockers. Reduced channel activation following sympathetic activation can explain the increased clinical risk and response to therapy in patients with C-loop mutations.
PMCID: PMC3690492  PMID: 22456477
beta-blockers; ion channels; long QT syndrome; mutation
16.  Risk of Syncope in Family Members Who Are Genotype Negative for a Family-Associated Long QT Syndrome Mutation 
Current clinical diagnosis of long-QT syndrome (LQTS) includes genetic testing of family members of mutation positive patients. The present study was designed to assess the clinical course of individuals who are found negative for the LQTS-causing mutation in their families.
Methods and Results
Multivariate Cox proportional hazards model was used to assess the risk for cardiac events (comprising syncope, aborted cardiac arrest [ACA], or sudden cardiac death [SCD]) from birth through age 40 years among 1828 subjects from the LQTS Registry who were found negative for their family LQTS-causing mutation. The median QTc of study subjects was 423 msec (interquartile-range: 402–442 msec). The cumulative probability of a first syncope through age 40 years was 15%. However, only 2 patients (0.1%) experienced ACA and none died suddenly during follow-up. Independent risk factors for syncope in genotype negative subjects included female gender (HR 1.60, p = 0.002), prolonged QTc (HR = 1.63 per 100 msec increment, p = 0.02), family history of ACA or SCD (HR = 1.89, p = 0.002), and LQT2 vs. LQT1 family mutation (HR = 1.41, p = 0.03). Subgroup analysis showed that the presence of the K897T polymorphism in the LQT2 gene in an affected family was associated with an 11-fold (p = 0.001) increase in the risk of recurrent syncope in genotype negative subjects.
Our findings suggest that cardiac events among genotype-negative family members of LQTS patients are dominated by nonfatal syncopal episodes without occurrence of sudden cardiac death. The risk for nonfatal events in this population may be mediated by the presence of common polymorphisms in LQTS genes.
PMCID: PMC3690290  PMID: 21831960
gene mutation; genetic polymorphisms; long-QT syndrome; sudden cardiac death arrhythmia; syncope
17.  ECG Marker of Adverse Electrical Remodeling Post-Myocardial Infarction Predicts Outcomes in MADIT II Study 
PLoS ONE  2012;7(12):e51812.
Post-myocardial infarction (MI) structural remodeling is characterized by left ventricular dilatation, fibrosis, and hypertrophy of the non-infarcted myocardium.
The goal of our study was to quantify post-MI electrical remodeling by measuring the sum absolute QRST integral (SAI QRST). We hypothesized that adverse electrical remodeling predicts outcomes in MADIT II study participants.
Baseline orthogonal ECGs of 750 MADIT II study participants (448 [59.7%] ICD arm) were analyzed. SAI QRST was measured as the arithmetic sum of absolute QRST integrals over all three orthogonal ECG leads. The primary endpoint was defined as sudden cardiac death (SCD) or sustained ventricular tachycardia (VT)/ventricular fibrillation (VF) with appropriate ICD therapies. All-cause mortality served as a secondary endpoint.
Adverse electrical remodeling in post-MI patients was characterized by wide QRS, increased magnitudes of spatial QRS and T vectors, J-point deviation, and QTc prolongation. In multivariable Cox regression analysis after adjustment for age, QRS duration, atrial fibrillation, New York Heart Association heart failure class and blood urea nitrogen, SAI QRST predicted SCD/VT/VF (HR 1.33 per 100 mV*ms (95%CI 1.11–1.59); P = 0.002), and all-cause death (HR 1.27 per 100 mV*ms (95%CI 1.03–1.55), P = 0.022) in both arms. No interaction with therapy arm and bundle branch block (BBB) status was found.
In MADIT II patients, increased SAI QRST is associated with increased risk of sustained VT/VF with appropriate ICD therapies and all-cause death in both ICD and in conventional medical therapy arms, and in patients with and without BBB. Further studies of SAI QRST are warranted.
PMCID: PMC3522579  PMID: 23251630
18.  Clinical Implications for Patients with Long QT Syndrome Who Experience a Cardiac Event During Infancy 
This study was designed to evaluate the clinical and prognostic aspects of long QT syndrome-related cardiac events that occur in the first year of life (infancy).
The clinical implications for patients with long QT syndrome who experience cardiac events in infancy have not been studied previously.
The study population of 3,323 patients with QTc ≥ 450 ms enrolled in the International LQTS Registry involved 20 patients with sudden cardiac death (SCD), 16 patients with aborted cardiac arrest (ACA), 34 patients with syncope, and 3,253 patients who were asymptomatic during the first year of life.
The risk factors for a cardiac event among 212 patients who had an ECG recorded in the first year of life included QTc≥500ms, heart rate ≤100bpm, and female sex. ACA before age 1 year was associated with a hazard ratio of 23.4 (p<0.01) for ACA or SCD during age 1-10 years. During the 10-year follow-up after infancy, beta-blocker therapy was associated with a significant reduction in ACA/SCD only in those with a syncopal episode within 2 years before ACA/SCD, but not for those who survived ACA in infancy.
Patients with LQTS who experience ACA during the first year of life are at very high-risk for subsequent ACA or death during their next 10 years of life, and beta-blockers may not be effective in preventing fatal or near fatal cardiac events in this small but high-risk subset.
PMCID: PMC3517782  PMID: 19695463
Long QT Syndrome; Genetics; Infants; Risk Stratification
19.  Are Ambient Ultrafine, Accumulation Mode, and Fine Particles Associated with Adverse Cardiac Responses in Patients Undergoing Cardiac Rehabilitation? 
Environmental Health Perspectives  2012;120(8):1162-1169.
Background: Mechanisms underlying previously reported air pollution and cardiovascular (CV) morbidity associations remain poorly understood.
Objectives: We examined associations between markers of pathways thought to underlie these air pollution and CV associations and ambient particle concentrations in postinfarction patients.
Methods: We studied 76 patients, from June 2006 to November 2009, who participated in a 10-week cardiac rehabilitation program following a recent (within 3 months) myocardial infarction or unstable angina. Ambient ultrafine particle (UFP; 10–100 nm), accumulation mode particle (AMP; 100–500 nm), and fine particle concentrations (PM2.5; ≤ 2.5 μm in aerodynamic diameter) were monitored continuously. Continuous Holter electrocardiogram (ECG) recordings were made before and during supervised, graded, twice weekly, exercise sessions. A venous blood sample was collected and blood pressure was measured before sessions.
Results: Using mixed effects models, we observed adverse changes in rMSSD [square root of the mean of the sum of the squared differences between adjacent normal-to-normal (NN) intervals], SDNN (standard deviation of all NN beat intervals), TpTe (time from peak to end of T-wave), heart rate turbulence, systolic and diastolic blood pressures, C-reactive protein, and fibrinogen associated with interquartile range increases in UFP, AMP, and PM2.5 at 1 or more lag times within the previous 5 days. Exposures were not associated with MeanNN, heart-rate–corrected QT interval duration (QTc), deceleration capacity, and white blood cell count was not associated with UFP, AMP, and PM2.5 at any lag time.
Conclusions: In cardiac rehabilitation patients, particles were associated with subclinical decreases in parasympathetic modulation, prolongation of late repolarization duration, increased blood pressure, and systemic inflammation. It is possible that such changes could increase the risk of CV events in this susceptible population.
PMCID: PMC3440073  PMID: 22542955
air pollution; cardiac rehabilitation; fibrinogen; heart rate variability; repolarization
20.  T-Wave Morphology Abnormalities In benign, potent and arrhythmogenic Ikr inhibition 
There is a consensus on the limited value of QT/QTc prolongation as a surrogate marker of drug cardiotoxicity and as a risk stratifier in inherited LQTS patients.
We investigated the interest of repolarization morphology in the acquired and the inherited LQTS.
We analyzed two retrospective ECG datasets from healthy on/off moxifloxacin, and from genotyped KCNH2 patients. We measured QT, RR and T peak to T end intervals, early (ERD) and late repolarization duration, T-roundness, T-amplitude, left (αL) and right slopes of T-waves. We designed multivariate logistic models to predict the presence of the KCNH2 mutation or moxifloxacin while adjusting for the level of QTc prolongation and the level of heart-rate in LQT2 patients. Independent learning and validation sets were used. A list of 4,874 ECGs from 411 healthy individuals, 293 ECGs from 143 LQT2 carriers and 150 non-carrier family members were analyzed.
In the moxifloxacin model, ERD was associated with the presence of the drug (OR=1.15 per ms increase, CI:1.04-1.26, p=0.0001) after adjustment for QTc. The model for the LQT2 revealed that left slope was associated with the presence of the KCNH2 mutation (OR=0.38 per 1.5microV/ms decrease, CI:0.23-0.64, p=0.0002). Only T-roundness complemented QTc in the model investigating cardiac events in LQT2.
These observations demonstrate that the phenotypic expression of KCNH2 mutations and the effect of IKr-inhibitory drug on the surface ECG are specific. Future research should investigate if this phenomenon is linked to different level/form of loss functions of Ikr channels, and if they could result in different arrhythmogenic mechanisms.
PMCID: PMC3145317  PMID: 21315844
Electrocardiogram; long QT syndrome; moxifloxacin; thorough QT studies; KCNH2
21.  Risk of Recurrent Cardiac Events after Onset of Menopause in Women with Congenital Long-QT Syndrome Types 1 and 2 
Circulation  2011;123(24):2784-2791.
Women with congenital long-QT syndrome (LQTS) experience increased risk for cardiac events after the onset of adolescence, that is more pronounced among carriers of the LQT2 genotype. We hypothesized that the hormonal changes associated with menopause may affect clinical risk in this population.
Methods and Results
We used a repeated events analysis to evaluate the risk for recurrent syncope during the menopause-transition and post-menopausal periods (5-years before and after the age at onset of menopause, respectively) among 282 LQT1 (n=151) and LQT2 (n=131) women enrolled in the LQTS Registry. Multivariate analysis showed that the risk for recurrent syncope (n=150) among LQT2 women was significantly increased during both menopause-transition (HR = 3.38 [p = 0.005]) and the post-menopausal period (HR = 8.10 [p < 0.001]) as compared with the reproductive period. The risk increase was evident among women who did or did not receive estrogen therapy. In contrast, among LQT1 women the onset of menopause was associated with a reduction in the risk for recurrent syncope (HR = 0.19 [p = 0.05]; p-value for genotype-by-menopause interaction = 0.02). Only 22 women (8%) experienced aborted cardiac arrest (ACA) or sudden cardiac death (SCD) during follow-up. The frequency of ACA/SCD showed a similar genotype-specific association with the onset of menopause.
The onset of menopause is associated with a significant increase in the risk of cardiac events (dominated by recurrent episodes of syncope) in LQT2 women, suggesting that careful follow-up and continued long-term therapy are warranted in this population.
PMCID: PMC3155756  PMID: 21632495
long-QT syndrome; women; estrogen; testosterone
22.  Combined assessment of sex- and mutation-specific information for risk stratification in type 1 long QT syndrome 
Heart Rhythm  2012;9(6):892-898.
Men and women with type 1 long QT syndrome (LQT1) exhibit time-dependent differences in the risk for cardiac events.
We hypothesized that sex-specific risk for LQT1 is related to the location and function of the disease-causing mutation in the KCNQ1 gene.
The risk for life-threatening cardiac events (comprising aborted cardiac arrest [ACA] or sudden cardiac death [SCD]) from birth through age 40 years was assessed among 1051 individuals with LQT1 (450 men and 601 women) by the location and function of the LQT1-causing mutation (prespecified as mutations in the intracellular domains linking the membrane-spanning segments [ie, S2–S3 and S4–S5 cytoplasmic loops] involved in adrenergic channel regulation vs other mutations).
Multivariate analysis showed that during childhood (age group: 0–13 years) men had >2-fold (P < .003) increased risk for ACA/SCD than did women, whereas after the onset of adolescence the risk for ACA/SCD was similar between men and women (hazard ratio = 0.89 [P = .64]). The presence of cytoplasmic-loop mutations was associated with a 2.7-fold (P < .001) increased risk for ACA/SCD among women, but it did not affect the risk among men (hazard ratio 1.37; P = .26). Time-dependent syncope was associated with a more pronounced risk-increase among men than among women (hazard ratio 4.73 [P < .001] and 2.43 [P = .02], respectively), whereas a prolonged corrected QT interval (≥500 ms) was associated with a higher risk among women than among men.
Our findings suggest that the combined assessment of clinical and mutation location/functional data can be used to identify sex-specific risk factors for life-threatening events for patients with LQT1.
PMCID: PMC3358462  PMID: 22293141
Cytoplasmic-loop mutations; Sex; Long QT syndrome; Sudden cardiac death
23.  Physicians’ Knowledge and Attitudes Regarding Implantable Cardioverter- Defibrillators 
Cardiology Journal  2010;17(3):267-273.
Information is limited regarding the knowledge and attitudes of physicians typically involved in the referral of patients for implantable cardioverter defibrillator (ICD) implantation.
We conducted a survey of primary care physicians and cardiologists at the University of Rochester Medical Center and the Unity Health System Rochester, NY from December 2008 to February 2009. The survey collected information regarding knowledge and attitudes of physicians towards ICD therapy.
Of the 332 surveys distributed, 110 (33%) were returned. Over-all 94 (87%) physicians reported referring patients for ICD implantation. Eighteen (17%) physicians reported unawareness of guidelines for ICD use. Sixty-four (59%) physicians recommended ICD in patients with ischemic cardiomyopathy and left ventricular ejection fraction (LVEF) ≤ 35%. Sixty-five (62%) physicians use ≤ 35% as LVEF criteria for ICD referral in patients with non-ischemic cardiomyopathy. Cardiologists were more familiar than primary care physicians with LVEF criteria for implantation of ICD in patients with ischemic and non-ischemic cardiomyopathy (p value 0.005 and 0.002 respectively). Twenty-nine (27%) participants were unsure regarding benefits of ICDs in eligible women and Blacks. Eighty two (76%) physicians believed that an ICD could benefit patients ≥70 years whereas only 53 (49%) indicated that an ICD would benefit patients ≥ 80 years of age. A lack of familiarity with current clinical guidelines regarding ICD implantation exists. Primary care physicians are less aware of clinical guidelines than are cardiologists. This finding highlights the need to improve the dissemination of guidelines to primary care physicians in an effort to improve ICD utilization.
PMCID: PMC3337764  PMID: 20535717
Implantable cardioverter defibrillator; Physician’s Knowledge; Gender and Racial Disparities
24.  Clinical Aspects of Type-1 Long-QT Syndrome by Location, Coding Type, and Biophysical Function of Mutations Involving the KCNQ1 Gene 
Circulation  2007;115(19):2481-2489.
Type-1 long-QT syndrome (LQTS) is caused by loss-of-function mutations in the KCNQ1-encoded IKs cardiac potassium channel. We evaluated the effect of location, coding type, and biophysical function of KCNQ1 mutations on the clinical phenotype of this disorder.
Methods and Results
We investigated the clinical course in 600 patients with 77 different KCNQ1 mutations in 101 proband-identified families derived from the US portion of the International LQTS Registry (n=425), the Netherlands’ LQTS Registry (n=93), and the Japanese LQTS Registry (n=82). The Cox proportional hazards survivorship model was used to evaluate the independent contribution of clinical and genetic factors to the first occurrence of time-dependent cardiac events from birth through age 40 years. The clinical characteristics, distribution of mutations, and overall outcome event rates were similar in patients enrolled from the 3 geographic regions. Biophysical function of the mutations was categorized according to dominant-negative (>50%) or haploinsufficiency (≤50%) reduction in cardiac repolarizing IKs potassium channel current. Patients with transmembrane versus C-terminus mutations (hazard ratio, 2.06; P<0.001) and those with mutations having dominant-negative versus haploinsufficiency ion channel effects (hazard ratio, 2.26; P<0.001) were at increased risk for cardiac events, and these genetic risks were independent of traditional clinical risk factors.
This genotype–phenotype study indicates that in type-1 LQTS, mutations located in the transmembrane portion of the ion channel protein and the degree of ion channel dysfunction caused by the mutations are important independent risk factors influencing the clinical course of this disorder.
PMCID: PMC3332528  PMID: 17470695
electrocardiography; genetics; long-QT syndrome
25.  Risk for Life-Threatening Cardiac Events in Patients With Genotype-Confirmed Long-QT Syndrome and Normal-Range Corrected QT Intervals 
This study was designed to assess the clinical course and to identify risk factors for life-threatening events in patients with long-QT syndrome (LQTS) with normal corrected QT (QTc) intervals.
Current data regarding the outcome of patients with concealed LQTS are limited.
Clinical and genetic risk factors for aborted cardiac arrest (ACA) or sudden cardiac death (SCD) from birth through age 40 years were examined in 3,386 genotyped subjects from 7 multinational LQTS registries, categorized as LQTS with normal-range QTc (≤440 ms [n = 469]), LQTS with prolonged QTc interval (>440 ms [n = 1,392]), and unaffected family members (genotyped negative with ≤440 ms [n = 1,525]).
The cumulative probability of ACA or SCD in patients with LQTS with normal-range QTc intervals (4%) was significantly lower than in those with prolonged QTc intervals (15%) (p < 0.001) but higher than in unaffected family members (0.4%) (p < 0.001). Risk factors ACA or SCD in patients with normal-range QTc intervals included mutation characteristics (transmembrane-missense vs. nontransmembrane or nonmissense mutations: hazard ratio: 6.32; p = 0.006) and the LQTS genotypes (LQTS type 1:LQTS type 2, hazard ratio: 9.88; p = 0.03; LQTS type 3:LQTS type 2, hazard ratio: 8.04; p = 0.07), whereas clinical factors, including sex and QTc duration, were associated with a significant increase in the risk for ACA or SCD only in patients with prolonged QTc intervals (female age >13 years, hazard ratio: 1.90; p = 0.002; QTc duration, 8% risk increase per 10-ms increment; p = 0.002).
Genotype-confirmed patients with concealed LQTS make up about 25% of the at-risk LQTS population. Genetic data, including information regarding mutation characteristics and the LQTS genotype, identify increased risk for ACA or SCD in this overall lower risk LQTS subgroup.
PMCID: PMC3332533  PMID: 21185501
corrected QT interval; long-QT syndrome; sudden cardiac death

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