Increase In QRS Duration Research Articles

Abstract P373: Cardiac Depolarization and Repolarization Changes with Mental Stress are Associated with Mental Stress- Induced Ischemia

Introduction: QRS duration and frontal QRS/T angle are simple and easily available electrocardiographic measures of cardiac depolarization and repolarization that predict cardiovascular disease (CVD) events and mortality. Such measures may be indicative of cardiac structural disease, ischemia, or primary conduction abnormalities. Mental stress-induced myocardial ischemia (MSI) is also associated with increased CVD risk, but the underlying mechanisms are unknown. We hypothesized that MSI is associated with stress-induced abnormalities in cardiac depolarization and repolarization, QRS duration and frontal QRS/T angle. Methods: We compared QRS duration & frontal QRS/T angle during mental stress between coronary artery disease (CAD) patients who were MSI positive (MSI+) and CAD patients who were MSI negative (MSI-). For each MSI+ case (n=22), one or two MSI- controls were matched for age, gender and race- ethnicity (n=41). QRS duration and frontal QRS/T angle were automatically computed by a 12-lead ECG (GE MAC 5000). QRS/T angle was calculated as absolute minimal difference between the frontal R and T axes in patients with QRS duration < 120 ms (n= 50). Mental stress was induced via speech stressor, and nuclear 99m-Tc-sestamibi gated Single-Photon Emission Computed Tomography (SPECT) was used to assess MSI. Results: Mean age was 65 years, 20 patients were black, and 55 were males. The two groups were similar in terms of demographics and past medical history. Both MSI+ and MSI- groups had similar QRS duration at baseline, but MSI+ patients had an adjusted 3.1 ms higher increase in QRS duration with mental stress than MSI- patients (95% CI: 0.5 to 5.7), after adjusting for CVD risk factors, hemodynamic changes during mental stress (blood pressure, heart rate), and baseline QRS duration. MSI+ patients had an adjusted 28.2 degrees larger QRS/T angle at baseline (95% CI: 2.5 to 53.9) compared to MSI- patients, but did not differ with regards to change in QRS/T angle with mental stress. However, among those with normal baseline conduction (QRS<100 ms, n=36), MSI+ patients had an adjusted 17.8 degrees larger change in QRS/T angle with mental stress compared to MSI- patients (95% CI: 3.1 to 32.4). In patients with mildly abnormal conduction (QRS duration between 100 and 119 ms, n=14), no differences were found, p=0.059 for QRS duration x MSI interaction. Conclusion: CAD patients exhibit changes in cardiac depolarization and repolarization during acute mental stress. Those with MSI have greater baseline QRS/T angle and larger changes in QRS/T angle and QRS duration with mental stress. These findings may help to explain the pathophysiology linking mental stress and CVD, as well as the increased risk in patients with MSI.

Cardiac Resynchronization Therapy in Patients With Heart Failure and a QRS Complex <120 Milliseconds

Background— Although the benefits of cardiac resynchronization therapy are well established in selected patients with heart failure and a prolonged QRS duration, salutary effects in patients with narrow QRS complexes remain to be demonstrated. Methods and Results— The Evaluation of Resynchronization Therapy for Heart Failure (LESSER-EARTH) trial is a randomized, double-blind, 12-center study that was designed to compare the effects of active and inactive cardiac resynchronization therapy in patients with severe left ventricular dysfunction and a QRS duration <120 milliseconds. The trial was interrupted prematurely by the Data Safety and Monitoring Board because of futility and safety concerns after 85 patients were randomized. Changes in exercise duration after 12 months were no different in patients with and without active cardiac resynchronization therapy (−0.7 minutes [95% confidence interval (CI), −2.9 to 1.5] versus 0.8 minutes [95% CI, −1.2 to 2.9]; P =0.31]. Similarly, no significant differences were observed in left ventricular end-systolic volumes (−6.4 mL [95% CI, −18.8 to 5.9] versus 3.1 mL [95% CI, −9.2 to 15.5]; P =0.28) and ejection fraction (3.3% [95% CI, 0.7–6.0] versus 2.1% [95% CI, −0.5 to 4.8]; P =0.52). Moreover, cardiac resynchronization therapy was associated with a significant reduction in the 6-minute walk distance (−11.3 m [95% CI, −31.7 to 9.7] versus 25.3 m [95% CI, 6.1–44.5]; P =0.01), an increase in QRS duration (40.2 milliseconds [95% CI, 34.2–46.2] versus 3.4 milliseconds [95% CI, 0.6–6.2]; P <0.0001), and a nonsignificant trend toward an increase in heart failure–related hospitalizations (15 hospitalizations in 5 patients versus 4 hospitalizations in 4 patients). Conclusions— In patients with a left ventricular ejection fraction ≤35%, symptoms of heart failure, and a QRS duration <120 milliseconds, cardiac resynchronization therapy did not improve clinical outcomes or left ventricular remodeling and was associated with potential harm. Clinical Trial Registration URL: http://www.clinicaltrials.gov . Unique identifier: NCT00900549.

Wenxin Keli Suppresses Ventricular Triggered Arrhythmias via Selective Inhibition of Late Sodium Current

Wenxin Keli is a popular Chinese herb extract that approximately five million Asians are currently taking for the treatment of a variety of ventricular arrhythmias. However, its electrophysiological mechanisms remain poorly understood. The concentration-dependent electrophysiological effects of Wenxin Keli were evaluated in the isolated rabbit left ventricular myocytes and wedge preparation. Wenxin Keli selectively inhibited late sodium current (INa) with an IC50 of 3.8 ± 0.4 mg/mL, which was significantly lower than the IC50 of 10.6 ± 0.9 mg/mL (n = 6, P < 0.05) for the fast INa. Wenxin Keli produced a small but statistically significant QT prolongation at 0.3 mg/mL, but shortened the QT and Tp-e interval at concentrations ≥ 1 mg/mL. Wenxin Keli increased QRS duration by 10.1% from 34.8 ± 1.0 ms to 38.3 ± 1.1 ms (n = 6, P < 0.01) at 3 mg/mL at a basic cycle length of 2,000 ms. However, its effect on the QRS duration exhibited weak use-dependency, that is, QRS remained less changed at increased pacing rates than other classic sodium channel blockers, such as flecainide, quinidine, and lidocaine. On the other hand, Wenxin Keli at 1-3 mg/mL markedly reduced dofetilide-induced QT and Tp-e prolongation by attenuation of its reverse use-dependence and abolished dofetilide-induced early afterdepolarization (EAD) in four of four left ventricular wedge preparations. It also suppressed digoxin-induced delayed after depolarization (DAD) and ventricular tachycardias without changing the positive staircase pattern in contractility at 1-3 mg/mL in a separate experimental series (four of four). Wenxin Keli suppressed EADs, DADs, and triggered ventricular arrhythmias via selective inhibition of late INa.

Acute effects of right ventricular pacing on cardiac haemodynamics and transvalvular impedance

To assess the acute side-effects of right ventricular (RV) stimulation applied in apex and mid-septum, in order to establish the optimal lead location in clinical practice. During pacemaker implantation, the ventricular lead was temporarily fixed in the apex and then moved to mid-septum. In both positions, surface and endocardial electrograms and transvalvular impedance (32 cases), left ventricular (LV) pressure (23), and transthoracic echocardiography (10) were acquired with intrinsic activity and VDD pacing. A larger increase in QRS duration was noticed with apical than septal pacing (65±25 vs. 45±29 ms; P<10(-4)). The proportion of cases where RV stimulation affected the transvalvular impedance waveform was higher with apical lead location (56% vs. 20%; P<0.02). VDD pacing at either site reduced the maximum dP/dt by 6% with respect to intrinsic AV conduction (IAVC; P<0.005). The maximum pressure drop taking place in 100 ms was reduced by 6 and 8%, respectively, with apical and septal pacing (P<0.01 vs. IAVC). Apical VDD decreased mitral annulus velocity in early diastole (E') from 7.5±1.4 to 5.9±0.9 cm/s (P<0.02) and prolonged the E-wave deceleration time (DT) from 156±33 to 199±54 ms (P<0.02), while septal pacing induced non-significant modifications in E' and DT. Ventricular stimulation acutely impairs LV systolic and diastolic performance, independent of the pacing site. Septal lead location preserves RV contraction mechanics and reduces the electrical interventricular delay.

QRS Duration and Mechanical Dyssynchrony Correlations with Right Ventricular Function after Fontan Procedure

In studies of adult patients, increased QRS duration and mechanical dyssynchrony have been associated with decreased ventricular function. The aim of this study was to test the hypothesis that similar findings would be present in a population of patients with hypoplastic left heart syndrome (HLHS) after the Fontan procedure. A retrospective cross-sectional study was conducted. All patients with HLHS after the Fontan procedure were eligible. QRS duration was measured using 12-lead electrocardiography. Echocardiographic measurements of mechanical dyssynchrony included Doppler tissue imaging (DTI) QRS to onset of s' wave difference between the left ventricle and the right ventricle, time to peak strain, time to peak systolic strain rate (SRs), the standard deviation of time to peak strain rate (modified Yu strain), and the standard deviation of time to peak SRs (modified Yu SRs). Right ventricular (RV) functional measurements included DTI s' wave, DTI RV myocardial performance index, global strain, global SRs, and RV fractional area change. Pearson's correlations were performed between the variables. Thirty-one echocardiographic studies were performed on 26 patients. The median age was 5.3 years (range, 2.5-15.4 years). QRS duration was correlated significantly with global SRs (r=0.42). Time to peak SRs was correlated significantly with DTI s' wave (r=-0.48) and global SRs (r=0.37). Modified Yu SRs was correlated significantly with global strain (r=0.35) and RV fractional area change (r=-0.35). Both QRS duration and mechanical dyssynchrony were correlated with RV function, albeit weakly. The clinical significance of these findings is intriguing, but only larger studies will determine if these measurements are reliable in guiding treatment options for this complex patient population.

ECG Diagnosis: Flecainide Toxicity

Flecainide acetate is a Vaughn-Williams class IC antiarrhythmic and a sodium channel blocking agent used mainly for the treatment of supraventricular dysrhythmias.1 Adverse cardiac effects include moderate negative inotropic action and depression of all major conduction pathways.2 With increasing concentration, flecainide's action on conduction pathways is manifested on electrocardiogram as an increased PR interval and QRS duration. Toxicity is suggested when a 50% increase in QRS duration (0.18 sec) or 30% prolongation in PR interval (0.26 sec) occurs. The QTc interval can also be prolonged in cases of flecainide overdose.3 Treatment of acute flecainide overdose includes administration of activated charcoal (for patient presenting early in course of ingestion), administration of sodium bicarbonate (reverses action of sodium channel blockade), pressors (eg, dobutamine) for profound hypotension, and transthoracic or transvenous pacing.1,4 Figure 1 12-lead Electrocardiogram from a 46-year-old woman with flecainide toxicity. Figure 2 12-lead Electrocardiogram from same patient obtained 24 hours later.

Response to Letter Regarding Article, “Duration of QRS Complex in Resting Electrocardiogram is a Predictor of Sudden Cardiac Death in Men”

We appreciate the letter from Gnechi-Ruscone and Guazzi regarding our article. 1 We certainly agree with their suggestion of the need for a more detailed evaluation of sudden cardiac death risk related to an increase in QRS duration ranging from 110 to 120 ms. The study by Aro et al1 indeed demonstrated that intraventricular conduction delay was associated with excess mortality risk, including sudden arrhythmic death. In that study, using visual measurements of QRS duration, the threshold of 110 ms rather than the …

Abstract 9473: Prognostic Significance of Temporal Increase in QRS Duration and Morphological Development of QRS Complex

Background: QRS duration and morphology provide an opportunity to derive useful prognostic information. But, prognostic value of temporal increase in QRS duration in relation to the morphological development is yet to be determined. Methods: From among a database containing 359,737 ECGs, digital analysis of 12-lead ECG was performed to select patients whose QRS duration increased from &lt;110 ms to ≥120 ms over time. The long-term prognosis was assessed according to QRS morphology. Hospitalization for heart failure was the primary end point, and the cardiovascular composite events of hospitalization for heart failure, device implantation, or cardiovascular death were the secondary end point. Results: We enrolled 143 patients (100 males; mean age, 58.9±11.1 years). During follow-up (mean, 12.0±5.3 years), QRS duration increased by 46.4±13.8 ms (49.6%), resulting in the development of right bundle branch block (RBBB) in 99 (69.2%) patients and non-RBBB (i.e., left bundle branch block,RBBB with left anterior hemiblock, or intraventricular conduction disturbance) in 44 (30.8%) patients. During a mean follow-up of 16.6±5.3 years, 44(30.3%),15(10.3%), and 6(4.1%) patients resulted in heart failure hospitalization,device implantation, and cardiovascular death, respectively. Cox proportional -hazards model showed that 1) the temporal increment of QRS duration was significantly associated with the primary end point (HR 1.98; 95% CI 1.05-3.80; P=0.04 for QRS duration ≥4 ms/year versus &lt;4 ms/year) and the secondary end point (HR 2.79;95% CI 1.55-5.00; P=0.0001 for QRS duration ≥5 ms/year versus &lt;5 ms/year),2) QRS morphology was significantly associated with the primary end point (HR 3.02;95% CI 1.59-5.73; P=0.0001 for non-RBBB versus RBBB) and the secondary end point (HR 2.82; 95% CI 1.57-3.09; P=0.001 for non-RBBB versus RBBB), and 3) the temporal increment of QRS duration and the QRS morphology of non-RBBB potentiated each other, leading to the higher primary end point rate (HR 7.73; 95% CI 2.90-22.74;P&lt;0.0001) and the higher secondary end point rate (HR 8.25; 95% CI 3.39-19.85; P&lt;0.0001). Conclusion: Newly developed wide QRS complex excluding RBBB played a significant role in heart failure hospitalization and cardiovascular events.

Abstract 9039: Predictors of High Defibrillation Energy Requirements: Results From the NCDR ICD Registry

Background: Defibrillation testing is typically performed at the time of ICD implantation to establish effective arrhythmia termination. Despite technological advancements, including biphasic waveforms and higher output devices, an inadequate safety margin for defibrillation may still occur. The NCDR ICD Registry was examined to evaluate predictors of a high defibrillation requirement (DER) using modern day devices. Methods: Patients who underwent defibrillation testing in the NCDR ICD Registry were examined to determine characteristics associated with a high DER. This included 45,686 initial ICD implantation procedures from April 2010 to December 2010 performed at 1261 facilities. Patient characteristics were compared using chi-square tests for categorical variables and unbalanced t-tests for continuous variables. Multivariable logistic regression was used to assess independent predictors of a "high" DER, which was defined as &gt;25 joules. Results: A high DER was noted in 4.1% of patients undergoing testing. Patients with a high DER were more often younger, male, on dialysis, and were more likely to have a higher NYHA functional class, lower LVEF, higher creatinine, and wider QRS. Patients on antiarrhythmic drugs and those with nonischemic heart disease were more likely to have a high DER. Independent predictors of a high DER included younger age, higher NYHA class, and increased QRS duration. A high DER was associated with longer post-procedure length of stay (1.6 ± 2.9 vs. 2.1 ± 3.8 days, p&lt;0.001) as well as any complication or death prior to hospital discharge (2.6% vs. 4.0%, p&lt;0.001). Conclusions: A high DER was observed in 4.1% of patients and was associated with more complications and mortality. Several clinical predictors of a high DER were identified, potentially enabling the identification of patients most likely to benefit from testing. Additional study is needed to determine if testing predicts long-term outcome of patients with modern day devices.

Similarities and differences between electrocardiogram signs of left bundle-branch block and left-ventricular uncoupling

A left bundle-branch block (LBBB) electrocardiogram (ECG) type may be caused by either a block in the left branch of the ventricular conduction system or by uncoupling in the working myocardium. We used a realistic large-scale computer model to evaluate the effects of uncoupling with and without left-sided block and in combination with biventricular pacing. Action potential propagation was simulated using a reaction-diffusion model of the human ventricles. Electrocardiograms and cardiac electrograms were computed from the simulated action potentials by solving the bidomain equations. In all situations, diffuse uncoupling reduced QRS amplitude, prolonged QRS duration, and rotated the QRS axis leftward. Uncoupling by 50% increased QRS duration from 90 to 120 ms with a normal conduction system and from 140 to 190 ms when the left bundle branch was blocked. Biventricular pacing did not change QRS duration but reduced total ventricular activation time. Uncoupling in the working myocardium can mimic left-sided block in the ventricular conduction system and can explain an LBBB ECG pattern with relatively low amplitude. Biventricular pacing improves ventricular activation in true LBBB with or without uncoupling but not in case of 50% uncoupling alone.

Sudden Cardiac Death in Adult Congenital Heart Disease

Sudden cardiac death (SCD) is a major cause of mortality in adults with congenital heart disease (CHD). The aim of this study was to determine the adult CHD population at risk of SCD and the clinical parameters associated with SCD. We performed a multicenter case-control study. Patients who died suddenly as a result of proven or presumed arrhythmia were included (cases). For each case, 2 controls matched on diagnosis, type of surgical intervention, age, and gender were included. From 3 databases including 25 790 adults with CHD, 1189 deaths (5%) were identified, of whom 213 patients (19%) died suddenly. Arrhythmic death occurred in 171 of 1189 patients. The underlying cardiac lesions were mild, moderate, and severe CHD in 12%, 33%, and 55% of the SCD cases, respectively. Clinical variables associated with SCD were supraventricular tachycardia (odds ratio [OR], 3.5; 95% confidence interval [CI], 1.5-7.9; P=0.004), moderate to severe systemic ventricular dysfunction (OR, 3.4; 95% CI, 1.1-10.4; P=0.034), moderate to severe subpulmonary ventricular dysfunction (OR, 3.4; 95% CI, 1.1-10.2; P=0.030), increased QRS duration (OR, 1.34 [per 10-ms increase]; 95% CI, 1.10-1.34; P=0.008), and QT dispersion (OR, 1.22 [per 10-ms increase]; 95% CI, 1.22-1.48; P=0.008). The clinical parameters found to be associated with SCD in adults with a broad spectrum of CHD, including systemic right ventricles, are similar to those in ischemic heart disease. Moreover, even those patients with mild cardiac lesions are potentially at risk for SCD. This highlights the need for further prospective studies as well as vigilant ongoing follow-up of the adult with CHD.

Correlation of Electrocardiographic Changes and Myocardial Fibrosis in Patients With Hypertrophic Cardiomyopathy Detected by Cardiac Magnetic Resonance Imaging

Despite several electrophysiologic and pathologic studies, the cause of electrocardiographic (ECG) changes in patients with hypertrophic cardiomyopathy (HCM) remains unclear. Late gadolinium enhancement (LGE) cardiovascular magnetic resonance (CMR) imaging can detect myocardial fibrosis. We aimed to assess the relationship between ECG findings and LGE in such patients. Myocardial LGE may be associated with ECG changes in HCM. Seventy consecutive patients with HCM (mean age, 55.5 ± 10.7 years; 47 males) underwent CMR and 12-lead ECG. The subjects were divided into 3 groups according to the type of hypertrophy: the asymmetric septal hypertrophy group (ASH group, n = 31), the apical hypertrophy group (AP group, n = 22), and concentric hypertrophy group (CH group, n = 17). The transmural and segmental extent, pattern, and location of myocardial LGE were assessed and analyzed in relation to ECG changes. All of the subjects showed some degree of LGE on CMR. The AP group showed significantly higher prevalence of negative T-wave (P = 0.028) and deep negative T-wave inversion (P = 0.001) than the ASH and CH groups. The total volume of LGE did not show any significant association with ECG changes. LGE detected at the interventricular septum was associated with increased QRS duration (P = 0.009) and was found in 94% of the ASH group, 59% of the AP group, and 77% of the CH group. LGE at the apex of the heart was present in 32% of the ASH group, 73% of the AP group, and 35% of the CH group and was also associated with negative T-wave (P = 0.006) and deep negative T-wave inversion (P = 0.018). Multifocal LGE lesions were associated with increased QRS duration (P = 0.039) as opposed to single nodular or patchy pattern of presence. The location of myocardial LGE in HCM shows significant association with various ECG changes. This may be useful information for initially evaluating subjects with HCM and adds pathophysiological insight into understanding ECG changes in myocardial diseases that cannot be explained otherwise.

Detecting drug-induced prolongation of the QRS complex: New insights for cardiac safety assessment

BackgroundDrugs slowing the conduction of the cardiac action potential and prolonging QRS complex duration by blocking the sodium current (INa) may carry pro-arrhythmic risks. Due to the frequency-dependent block of INa, this study assesses whether activity-related spontaneous increases in heart rate (HR) occurring during standard dog telemetry studies can be used to optimise the detection of class I antiarrhythmic-induced QRS prolongation. MethodsTelemetered dogs were orally dosed with quinidine (class Ia), mexiletine (class Ib) or flecainide (class Ic). QRS duration was determined standardly (5 beats averaged at rest) but also prior to and at the plateau of each acute increase in HR (3 beats averaged at steady state), and averaged over 1h period from 1h pre-dose to 5h post-dose. ResultsCompared to time-matched vehicle, at rest, only quinidine and flecainide induced increases in QRS duration (Emax 13% and 20% respectively, P<0.01–0.001) whereas mexiletine had no effect. Importantly, the increase in QRS duration was enhanced at peak HR with an additional effect of +0.7±0.5ms (quinidine, NS), +1.8±0.8ms (mexiletine, P<0.05) and +2.8±0.8ms (flecainide, P<0.01) (calculated as QRS at basal HR-QRS at high HR). ConclusionElectrocardiogram recordings during elevated HR, not considered during routine analysis optimised for detecting QT prolongation, can be used to sensitise the detection of QRS prolongation. This could prove useful when borderline QRS effects are detected. Analysing during acute increases in HR could also be useful for detecting drug-induced effects on other aspects of cardiac function.

062 ECG Predictors of Adverse Outcomes in Patients With Atrial Fibrillation: A Combined Affirm and AF-CHF Sub-Study

BackgroundWhile resting ECG parameters have been shown to independently predict adverse cardiovascular outcomes in various populations with and without cardiovascular disease, the prognostic value of these findings have not been specifically addressed in patients with atrial fibrillation.MethodsWe conducted a combined post hoc analysis on all 5436 patients with a history of non-permanent atrial fibrillation randomized to rhythm- versus rate-control therapy in AFFIRM and AF-CHF trials. A total of 7159 baseline ECGs (4848 in atrial fibrillation and 2311 in sinus rhythm) were analyzed to assess the predictive value of the PR interval, QRS duration, and QT intervals on hospitalizations and mortality. Univariate and stepwise multivariate Cox regression models were created for the following outcomes: cardiovascular mortality, all-cause mortality, arrhythmic death, time to first hospitalization, and time to first cardiovascular hospitalization. Separate analyses were performed in atrial fibrillation and in sinus rhythm.ResultsIncreased QRS duration (≥120 msec) was significantly and independently associated with all-cause mortality (HR 1.38; p<0.0001), cardiovascular death (HR 1.50; p<0.0001), arrhythmic death (HR 1.86; p=0.0001), any hospitalisation (HR 1.12; p=0.02), and cardiovascular hospitalisation (HR 1.24; p=0.0002). Increased PR interval (>200 msec) was significantly and independently associated with cardiovascular (HR 1.55; p=0.01), and arrhythmic mortality (HR 2.05; p=0.005). Prolonged QTc (440 msec) predicted cardiovascular hospitalisation (HR 1.23; p=0.04) and arrhythmic mortality (men; HR 1.42; p=0.03). Uncorrected QT interval and rate of change in QRS duration were not predictive of adverse outcomes.ConclusionSimple parameters on baseline ECG significantly and independently predict adverse cardiovascular outcomes in patients with a history of atrial fibrillation. BackgroundWhile resting ECG parameters have been shown to independently predict adverse cardiovascular outcomes in various populations with and without cardiovascular disease, the prognostic value of these findings have not been specifically addressed in patients with atrial fibrillation. While resting ECG parameters have been shown to independently predict adverse cardiovascular outcomes in various populations with and without cardiovascular disease, the prognostic value of these findings have not been specifically addressed in patients with atrial fibrillation. MethodsWe conducted a combined post hoc analysis on all 5436 patients with a history of non-permanent atrial fibrillation randomized to rhythm- versus rate-control therapy in AFFIRM and AF-CHF trials. A total of 7159 baseline ECGs (4848 in atrial fibrillation and 2311 in sinus rhythm) were analyzed to assess the predictive value of the PR interval, QRS duration, and QT intervals on hospitalizations and mortality. Univariate and stepwise multivariate Cox regression models were created for the following outcomes: cardiovascular mortality, all-cause mortality, arrhythmic death, time to first hospitalization, and time to first cardiovascular hospitalization. Separate analyses were performed in atrial fibrillation and in sinus rhythm. We conducted a combined post hoc analysis on all 5436 patients with a history of non-permanent atrial fibrillation randomized to rhythm- versus rate-control therapy in AFFIRM and AF-CHF trials. A total of 7159 baseline ECGs (4848 in atrial fibrillation and 2311 in sinus rhythm) were analyzed to assess the predictive value of the PR interval, QRS duration, and QT intervals on hospitalizations and mortality. Univariate and stepwise multivariate Cox regression models were created for the following outcomes: cardiovascular mortality, all-cause mortality, arrhythmic death, time to first hospitalization, and time to first cardiovascular hospitalization. Separate analyses were performed in atrial fibrillation and in sinus rhythm. ResultsIncreased QRS duration (≥120 msec) was significantly and independently associated with all-cause mortality (HR 1.38; p<0.0001), cardiovascular death (HR 1.50; p<0.0001), arrhythmic death (HR 1.86; p=0.0001), any hospitalisation (HR 1.12; p=0.02), and cardiovascular hospitalisation (HR 1.24; p=0.0002). Increased PR interval (>200 msec) was significantly and independently associated with cardiovascular (HR 1.55; p=0.01), and arrhythmic mortality (HR 2.05; p=0.005). Prolonged QTc (440 msec) predicted cardiovascular hospitalisation (HR 1.23; p=0.04) and arrhythmic mortality (men; HR 1.42; p=0.03). Uncorrected QT interval and rate of change in QRS duration were not predictive of adverse outcomes. Increased QRS duration (≥120 msec) was significantly and independently associated with all-cause mortality (HR 1.38; p<0.0001), cardiovascular death (HR 1.50; p<0.0001), arrhythmic death (HR 1.86; p=0.0001), any hospitalisation (HR 1.12; p=0.02), and cardiovascular hospitalisation (HR 1.24; p=0.0002). Increased PR interval (>200 msec) was significantly and independently associated with cardiovascular (HR 1.55; p=0.01), and arrhythmic mortality (HR 2.05; p=0.005). Prolonged QTc (440 msec) predicted cardiovascular hospitalisation (HR 1.23; p=0.04) and arrhythmic mortality (men; HR 1.42; p=0.03). Uncorrected QT interval and rate of change in QRS duration were not predictive of adverse outcomes. ConclusionSimple parameters on baseline ECG significantly and independently predict adverse cardiovascular outcomes in patients with a history of atrial fibrillation. Simple parameters on baseline ECG significantly and independently predict adverse cardiovascular outcomes in patients with a history of atrial fibrillation.

Effect of QRS Duration and Morphology on Cardiac Resynchronization Therapy Outcomes in Mild Heart Failure

Background— Cardiac resynchronization therapy (CRT) decreases mortality, improves functional status, and induces reverse left ventricular remodeling in selected populations with heart failure. We aimed to assess the impact of baseline QRS duration and morphology and the change in QRS duration with pacing on CRT outcomes in mild heart failure. Methods and Results— Resynchronization Reverses Remodeling in Systolic Left Ventricular Dysfunction (REVERSE) was a multicenter randomized trial of CRT among 610 patients with mild heart failure. Baseline and CRT-paced QRS durations and baseline QRS morphology were evaluated by blinded core laboratories. The mean baseline QRS duration was 151±23 milliseconds, and 60.5% of subjects had left bundle-branch block (LBBB). Patients with LBBB experienced a 25.3-mL/m 2 mean reduction in left ventricular end-systolic volume index ( P &lt;0.0001), whereas non-LBBB patients had smaller decreases (6.7 mL/m 2 ; P =0.18). Baseline QRS duration was also a strong predictor of change in left ventricular end-systolic volume index with monotonic increases as QRS duration prolonged. Similarly, the clinical composite score improved with CRT for LBBB subjects (odds ratio, 0.530; P =0.0034) but not for non-LBBB subjects (odds ratio, 0.724; P =0.21). The association between clinical composite score and QRS duration was highly significant (odds ratio, 0.831 for each 10-millisecond increase in QRS duration; P &lt;0.0001), with improved response at longer QRS durations. The change in QRS duration with CRT pacing was not an independent predictor of any outcomes after correction for baseline variables. Conclusion— REVERSE demonstrated that LBBB and QRS prolongation are markers of reverse remodeling and clinical benefit with CRT in mild heart failure. Clinical Trial Registration— URL: http://www.clinicaltrials.gov . Unique identifier: NCT00271154.

Duration of QRS Complex in Resting Electrocardiogram Is a Predictor of Sudden Cardiac Death in Men

Previous studies indicate that increased QRS duration in ECG is related to the risk of all-cause death. However, the association of QRS duration with the risk of sudden cardiac death (SCD) is not well documented in large population-based studies. Our aim was to examine the relation of QRS duration with SCD in a population-based sample of men. This prospective study was based on a cohort of 2049 men aged 42 to 60 years at baseline with a 19-year follow-up, during which a total of 156 SCDs occurred. As a continuous variable, each 10-ms increase in QRS duration was associated with a 27% higher risk for SCD (relative risk, 1.27; 95% confidence interval, 1.14-1.40; P<0.001). Subjects with QRS duration of >110 ms (highest quintile) had a 2.50-fold risk for SCD (relative risk, 2.50; 95% confidence interval, 1.38-4.55; P=0.002) compared with those with QRS duration of <96 ms (lowest quintile), after adjustment for established key demographic and clinical risk factors (age, alcohol consumption, previous myocardial infarction, smoking, serum low- and high-density lipoprotein cholesterol, C-reactive protein, type 2 diabetes mellitus, body mass index, systolic blood pressure, and cardiorespiratory fitness). In addition to QRS duration, smoking, previous myocardial infarction, type 2 diabetes mellitus, cardiorespiratory fitness, body mass index, systolic blood pressure, and C-reactive protein were independently associated with the risk of SCD. QRS duration is an independent predictor of the risk of SCD and may have utility in estimating SCD risk in the general population.

Contemporary and future trends in cardiac resynchronization therapy to enhance response

The rationale for cardiac resynchronization therapy (CRT), expectations in terms of patient benefit, patient selection for CRT, selection of a CRT pacemaker (CRT-P) vs CRT plus implantable cardioverter-defibrillator (CRT-D) platform, and studies evaluating device programming to enhance benefit from CRT are reviewed. The notion of an "optimal" left ventricular (LV) pacing site, the rationale for identifying and avoiding LV pacing in regions of scar, the use of anatomic, hemodynamic, and electrical parameters to identify an optimal LV pacing site, and the potential utility of multisite LV pacing to enhance benefit from CRT are discussed. Finally, the advantages and disadvantages of the various methods for LV lead delivery are reviewed.

Analysis of the Potential Effect of Ponatinib on the QTc Interval in Patients with Refractory Hematologic Malignancies

Abstract 4441 Background:Ponatinib, an oral multiple tyrosine kinase inhibitor (TKI), is a potent pan-BCR-ABL inhibitor. Preliminary anti-leukemia activity of ponatinib was observed in patients with refractory chronic myeloid leukemia (CML) and advanced hematologic malignancies in a phase 1 study. Due to the QT prolongation noted with other TKIs, the effect of ponatinib on ECGs was examined in this population. Methods:This ongoing phase 1, open-label, dose-escalation, multicenter trial was designed to evaluate the safety of oral ponatinib administered to patients with advanced hematologic malignancies who failed available therapies. Patients received ponatinib orally once daily (2 mg to 60 mg) over at least 1 cycle (28 days) of study treatment unless an unacceptable toxicity or disease progression occurred. Inclusion criteria required screening QTc < 450 ms and prohibited concomitant use of medications known to prolong QTc. For the last 3 cohorts (30 mg, 45 mg and 60 mg), 12-lead ECGs (supine) were recorded using GE MAC1200 ECG recorders at the following time-points: C1D1 pre-dose (triplicate); C1D15 pre-dose (single); C2D1 pre-dose (triplicate); C2D1 2-hour post-dose (triplicate); C2D1 4-hour post-dose (triplicate); C2D1 6-hour post-dose (triplicate). Matching plasma ponatinib concentration data were also obtained at these time-points. This analysis of the cardiac safety of ponatinib only included patients who had replicate ECGs at baseline and a minimum of 1 additional on-treatment time-point with matching plasma ponatinib concentration data. The primary assessment was Fridericia corrected QT (QTcF). Results:A total of 81 patients were enrolled in the phase 1 study; 39 patients who received 30 mg or more of ponatinib daily were included in this analysis. There was no significant effect on cardiac repolarization as measured by the lack of a significant change in QTcF at all doses. Mean QTcF change from baseline was −10.9, −3.6, and −5.9 ms for the 30 mg, 45 mg and 60 mg cohorts, respectively. In addition, the pharmacokinetic-pharmacodynamic models show the slope of the relationship for QTcF versus plasma ponatinib concentration was negative, indicating no exposure-effect relationship, with an estimated QTcF mean change of −6.4 (upper confidence interval −0.9) ms at Cmax for the 60 mg group. ECG data revealed no significant change in heart rate (+3.5, −3.3, and +1.0 bpm for 30 mg, 45 mg and 60 mg cohorts, respectively). There was no signal of any effect on atrioventricular conduction as measured by the PR interval duration (mean change: −0.4, −3.6, and −0.7 ms, respectively). There was a slight, dose responsive, non-clinically significant increase in QRS duration (mean change: −0.8, +1.3, and +3.6 ms, respectively) that may be due to variability secondary to the limited sample size. There were 2 subjects with new atrial fibrillation and new T wave inversion. These morphological changes likely reflect the patient population being studied rather than any potential drug effect. Adverse event (AE) reports from the trial had 3 patients with ECG QT prolonged (2 mg, 4 mg and 45 mg) documented as a treatment-related AE; 2 were grade 3 (4 mg and 45 mg). On review, all 3 patients were found to have baseline (C1D1) prolongation of QTc or were on concomitant medications associated with QTc prolongation. There were no clinical consequences of the ECG findings in these patients. Conclusion:This analysis of the QTc intervals of patients who received ponatinib 30 mg or higher in the phase 1 clinical trial revealed there was no significant effect of ponatinib on cardiac repolarization. Disclosures:Sonnichsen:ARIAD: Consultancy. Dorer:ARIAD: Employment. Cortes:Novartis: Consultancy, Research Funding; BMS: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; Ariad: Consultancy, Research Funding. Talpaz:ARIAD: Research Funding. Deininger:BMS: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; ARIAD: Consultancy, Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees; Celgene: Research Funding; Genzyme: Research Funding. Shah:Bristol-Myers Squibb: Consultancy, Research Funding; Novartis: Consultancy; Ariad: Consultancy, Research Funding. Kantarjian:Novartis: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; BMS: Consultancy, Research Funding; ARIAD: Research Funding. Bixby:Novartis: Speakers Bureau; BMS: Speakers Bureau; GSK: Speakers Bureau. Mauro:ARIAD: Research Funding. Flinn:ARIAD: Research Funding. Litwin:ARIAD: Consultancy. Turner:ARIAD: Employment, Equity Ownership. Haluska:ARIAD: Employment, Equity Ownership.

Association of QRS duration and survival in dogs with dilated cardiomyopathy: A retrospective study of 266 clinical cases

Objective The purpose of this study was to investigate the prognostic value of QRS duration in dogs with dilated cardiomyopathy (DCM) by studying its relationship with survival time. Methods The medical records of dogs diagnosed with DCM were retrospectively searched for good quality ECG tracings. The QRS duration was measured from the ECG tracing and two different models were used: binary variable (dogs were divided into 2 groups based on a QRS duration of <60 ms or ≥60 ms) and continuous variable. The survival times were analysed by the Kaplan-Meier method and Cox’s proportional hazard model. Results 266 dogs met the inclusion and exclusion criteria. A QRS duration ≥60 ms was associated with a reduced survival time compared to those with a QRS duration <60 ms (Hazard Ratio of 1.34, 95% CI 1.05–1.71, P = 0.02). When considered as a continuous variable the Hazard Ratio was 1.015 for each increase in QRS duration of 1 ms (95% CI 1.006–1.024, p = 0.001).Dogs with a QRS duration < 60 ms had a median survival time (IQ range) of 25 weeks (97-65) and dogs with a QRS duration ≥60 ms had a median survival time (IQ range) of 13 weeks (3–34). Conclusion The measurement of QRS duration is relatively simple to perform from a surface ECG recording. A duration ≥60 ms is associated with shorter survival times in dogs with DCM, which may provide practitioners with additional prognostic information.

Assessment of Left Ventricular Mechanical Dyssynchrony Using Real Time Three-Dimensional Echocardiography: A Comparative Study to Doppler Tissue Imaging

To assess left ventricular mechanical dyssynchrony (LVMD) using real time three-dimensional echocardiography (RT3DE) and comparing it with the different dyssynchrony indices derived from Doppler tissue imaging (DTI) for the same patient. The study included 60 consecutive patients who were considered candidates for CRT, i.e., having ejection fraction ≤35%, NYHA class III or ambulatory class IV, QRS duration ≥120 msec, on optimal pharmacological therapy. Apical RT3DE full volumes were obtained and analyzed to generate the systolic dyssynchrony index (SDI-16), which is the standard deviation of the time to minimal systolic volume of the 16 segments of LV. Color-coded DTI was performed for the three standard apical views with estimation of the mechanical dyssynchrony index (12 Ts-SD), which is the standard deviation of the time to peak systolic velocity at 12 segments of LV. SDI-16 was 10.96 ± 3.9% (cutoff value: 8.3%), while Ts-SD was 38 ± 10.2 msec (cutoff value: 32.6 msec). The concordance rate for both indices was 75%; however, there was no correlation between both indices (r = 0.14, P = 0.3). SDI-16 showed good correlation with QRS duration (r = 0.45, P < 0.001) and inverse correlation with left ventricular ejection fraction (LVEF) calculated by RT3DE (r =-0.37, P = 0.004), while 12 Ts-SD index showed no correlation with QRS duration (r =-0.0082, P = 0.51) or 2D LVEF (r =-0.26, P = 0.84). RT3DE can quantify LVMD by providing the SDI-16 and it may prove to be more useful than DTI as it shows increasing dyssynchrony with increased QRS duration and decreased LVEF.