Electrocardiographic predictors of sudden cardiac death in patients with left ventricular hypertrophy

Abstract

Background

Left ventricular hypertrophy (LVH) has been associated with increased risk of sudden cardiac death (SCD), and improvements in risk stratification methodology are warranted.

Methods

We evaluated electrocardiographic intervals as potential markers of SCD risk in LVH. Corrected QT, QRS and JT intervals were evaluated in consecutive cases with SCD and LVH from the ongoing Oregon Sudden Unexpected Death study who underwent a 12-lead EKG and echocardiogram prior to and unrelated to the SCD event. Comparisons of age, gender, BMI, LV ejection fraction and EKG intervals together with clinical conditions (hypertension and diabetes) were conducted with geographically matched controls that had coronary artery disease but no history of ventricular arrhythmias or cardiac arrest. LVH was determined using the modified American Society of Echocardiography equation for LV mass. Independent samples t-test, Pearson’s chi square test and multiple logistic regression were used for statistical comparisons.

Results

Of the 109 cases and 49 controls who met study criteria, age, gender and co-morbidities were similar among cases and controls. The mean LV mass index was not significantly different in cases compared to controls. However mean QTc (470.6 ± 53.6ms vs. 440.7 ± 38.7ms; p<0.0001) and QRS duration (113.6 ± 30.0ms vs. 104.9 ± 18.7ms; p=0.03) were significantly higher in cases than controls. In logistic regression analysis, prolonged QTc was the only EKG interval significantly associated with SCD [OR 1.72 (1.23–2.40)].

Conclusion

Prolonged QTc was independently associated with SCD among subjects with LVH and merits further evaluation as a predictor of SCD in LVH.

Sudden cardiac death (SCD) continues to be a major public health problem accounting for 250,000 – 300,000 deaths in the US on a yearly basis^1,2 and constituting 50% of overall cardiovascular mortality.³ Even with advanced first responder systems, the survival rate after a sudden cardiac arrest is less than 5%.⁴ While the use of the implantable defibrillator has contributed to SCD prevention, current risk stratification methods are likely to be inadequate. ^5,6 Improvements in methodology of risk stratification will be critical for effective prevention of SCD.

Left ventricular hypertrophy (LVH) has been associated with SCD. ^7,8 Since it is a relatively common condition with 9–15% prevalence in the overall community ⁹ only a small proportion of overall subjects with LVH will suffer SCD. Mechanisms of ventricular arrhythmogenesis in patients with LVH are likely to be multifactorial ¹⁰ but there is clear evidence of cardiac electrical abnormalities. In experimental models of LVH, ventricular repolarization is abnormal, manifesting as prolonged action potential duration; and myocardial conduction abnormalities have also been described. ^11–14 In subjects with LVH diagnosed by EKG, the QT and QRS intervals have been found to be prolonged. ^15,16 Given the importance of SCD risk stratification and the wide availability of the 12-lead EKG we evaluated EKG markers of abnormal ventricular repolarization and depolarization as potential predictors of SCD in LVH.

Methods

Oregon SUDS is an ongoing study that prospectively identifies all the SCD’s that occurs among the one million residents of Portland, Oregon metropolitan area, from the Emergency medical response system, the medical examiner’s office and local hospitals.¹⁷ SCD was defined as a sudden unexpected pulse-less condition of likely cardiac origin. Survivors of sudden cardiac arrest were also included. Detailed analysis of available medical records, circumstances of cardiac arrest and autopsy data (when available) were performed prior to in-house adjudication of SCD cases. Deaths due to terminal illness such as cancer and known non-cardiac causes like pulmonary embolism, cerebrovascular accidents and drug overdoses were excluded. Since up to 80% of cases of SCD will have associated significant coronary artery disease (CAD),¹⁸ controls with CAD were ascertained from the same geographical location. Coronary artery disease was defined as a ≥50% stenosis of a major coronary artery or history of myocardial infarction (MI), coronary artery bypass grafting, or percutaneous coronary intervention. The analysis was restricted to subjects ≥18 years of age.

Echocardiographic criteria were used to identify cases of LVH. Left ventricular mass (LVM) was calculated from quantitative values on M-mode echocardiograms using the American Society of Echocardiography modified equation, indexed to body surface area (BSA); LV mass = 0.8 × {1.04[(LVIDd + PWTd + SWTd)³ − (LVIDd)³]} + 0.6g (LVIDd – Left ventricular internal dimension in diastole, PWTd - posterior wall thickness at end diastole and SWTd - septal wall thickness in end diastole).¹⁹ LV mass calculated with this method correlates well with measurements made at autopsy.²⁰ LVH was defined as LVM/BSA >134 g/m2 for men and >110 g/m2 for women.^20–22 Analysis was restricted to subjects with LVH, who had QTc and QRS duration measurements available and echocardiogram performed. Subjects with hypertrophic cardiomyopathy were excluded from the analysis. Severe LV dysfunction was defined as a left ventricular ejection fraction less than 35% measured by echocardiogram, MUGA or LV angiogram.

Measurement of QT and QRS Intervals from the 12-Lead EKG

Measurement of these intervals were made in EKGs with sinus rhythm. The standard 12-lead EKG tracing at 10mm/mV amplitude and 25mm/s paper speed was used for analysis and the intervals were measured manually. The most recent EKG available in medical records, before and unrelated to the cardiac arrest was used in cases of SCD. For controls, we used an EKG prior to ascertainment if available; if unavailable, an EKG available following ascertainment was utilized. The end of the T wave was defined as the intersection of the tangent to the down slope of the T–wave and the isoelectric line when not followed by a U wave or if distinct from the following U wave.²³ If a U wave followed the T wave, the T-wave offset was measured as the nadir between the T and U waves. If the T wave amplitude was less than 1.5mm in a particular lead, that lead was excluded from the analysis. The QT interval was measured from the beginning of the earliest onset of the QRS complex to the end of the T wave. After measurements in all precordial and limb leads, the longest QT interval was recorded. The QT interval was corrected for heart rate using Bazett’s formula.²⁴ EKG readers were blinded to all details of subjects. The study was approved by the Institutional Review Boards of Cedars-Sinai Medical Center, Oregon Health and Science University and all participating hospitals and health systems.

Statistical Analysis

Analysis was conducted using SPSS 18 and SAS 9.1 statistical software. Univariate case control comparisons were done using independent-samples t tests and Pearson’s chi-square tests. Multiple logistic regression was used to estimate the odds ratio (OR) for SCD associated with abnormal QTc and QRS duration adjusted for age and gender. Odds ratios for each measurements for an estimated one standard deviation increase in that interval among controls were calculated. A p value of less than 0.05 was considered significant for all the statistical analysis.

Results

Univariate analysis

There were 109 cases and 49 controls that met study criteria. All the controls and 97.3% (106) of the cases had evidence of CAD (p=0.24). The mean age and gender were not significantly different among cases and controls. Systemic hypertension, diabetes, body mass index were not significantly different among cases and controls. Left ventricular dysfunction was not a significant predictor of SCD (Table 1). The mean LV mass index though higher in cases, was not a significant predictor of SCD.

Table 1.

Patient characteristics of subjects with LVH by echocardiographic LV mass criteria (n = 158).

Categories	Cases (n = 109)	Controls (n = 49)	P value*
Age (yr)	70.6 ± 13.9	68.5 ± 13.2	0.38
Male	62 (56.9%)	26 (53.1%)	0.65
BMI	29.2 ± 10.2	31.3 ± 6.7	0.12
Hypertension	90 (82.6%)	40 (81.6%)	0.89
Diabetes	57 (52.3%)	22 (44.9%)	0.39
Severe LV dysfunction§	35 (32.4%)	10 (32.3%)	0.99
Missing||	1	18
LV mass index	161.2 ± 35.1	154.2 ± 30.4	0.22

Results presented as n (%) or mean ±SD

^*p-value from Pearson’s chi-square test for categorical variables and t-test for continuous variables.

^§Severe LV dysfunction was defined as a left ventricular ejection fraction less than 35% measured by echocardiogram, MUGA or LV angiogram.

^||For variables with missing values, proportions and p-values are calculated using the non-missing data as the denominator.

BMI, Body mass index; LV, left ventricle.

EKG predictors

The heart rate was similar in cases and controls and could not identify the high risk subjects (Table 2). The mean QRS duration was significantly higher in cases when compared to controls (113.3 ± 30.0ms vs. 104.9 ± 18.7ms; p=0.03). QTc was significantly higher in cases compared to controls (470.6 ± 53.6ms vs. 440.7 ± 38.7ms; p<0.0001). The mean JTc was also higher in cases than controls though it was not statistically significant (350.2 ± 50.9ms vs. 337.0 ± 37.2ms; p=0.07).

Table 2.

EKG measurements of subjects with LVH by echocardiographic LV mass criteria (n = 158).

Categories	Cases (n = 109)	Controls (n = 49)	P value*
QTc (msec)§	470.6 ± 53.6	440.7 ± 38.7	0.0001
JTc (msec)§	350.2 ± 50.9	337.0 ± 37.2	0.07
QRS (msec)§	113.3 ± 30.0	104.9 ± 18.7	0.03
HR (msec)§	74.6 ± 15.3	73.1 ± 18.0	0.60
Conduction abnormality			0.26
Normal	43 (39.4%)	16 (32.7%)
1st degree	6 (5.5%)	4 (8.2%)
LAFB	4 (3.7%)	1 (2.0%)
IRBBB/ILBBB	1 (0.9%)	1 (2.0%)
IVCD	27 (24.8%)	21 (42.9%)
RBBB	11 (10.1%)	2 (4.1%)
LBBB	16 (14.7%)	3 (6.1%)
Bifascicular block	1 (0.9%)	1 (2.0%)

Results presented as n (%) or mean ±SD

^*p-value from Pearson’s chi-square test for categorical variables and t-test for continuous variables.

^§QRS duration and HR as reported on the EKG recording. QT and JT intervals were manually measured.

JTc, corrected JT interval; LV, left ventricle; HR, heart rate; QRS, QRS complex duration; QTc, corrected QT interval.

Multivariate analysis

Using EKG variable as continuous variables and adjusted for age and gender, QTc was the only EKG predictor that could significantly predict SCD in the logistic regression model. A one standard deviation increase in QTc caused a 1.7 fold increase in odds for SCD [OR 1.72 (1.23 – 2.40)], whereas a one standard deviation increase in QRS duration was not significantly associated with increase in risk [OR 1.15 (0.86 – 1.54)].

Discussion

Main findings

This study was restricted to cases of SCD that underwent 12-lead EKG and echocardiograms prior to the SCD and had LVH by echo criteria and comparisons made with geographically matched controls with the same information that had known CAD. Age, gender, co-morbidities, presence of CAD and LV systolic dysfunction were not significantly different among the cases and controls. The LV mass index failed to predict risk of SCD. Among the EKG parameters, though both QTc and QRS duration were significant predictors of SCD in univariate analysis, only QTc was significant in the logistic regression model.

Left ventricular hypertrophy has been associated with overall cardiovascular mortality as well as SCD.^25,26 In the Framingham study each increment in LV mass of 50g/meter of height was found to be associated with 1.5 fold increase in cardiovascular disease and a 1.7–2.1 fold increase in risk adjusted cardiovascular mortality.^7,27 In the Losartan Intervention for End Point Reduction in Hypertension Study (LIFE), patients who had reduction of left ventricular hypertrophy by EKG criteria during treatment of hypertension had lower rates of sudden death. This effect was found to be independent of the treatment used and blood pressure achieved.²⁸

Morin et al reported that prolonged QRS duration was significantly related to the risk of sudden death in the patients treated aggressively for systemic hypertension after controlling for risk factors for CAD, changes in blood pressure, severity of left ventricular hypertrophy and left bundle branch block in the LIFE study.²⁹ However at present time there is no universally accepted risk stratification model for SCD in LVH. Prolonged QRS duration and QTc are associated with increased risk of SCD, as well as cardiovascular and all cause mortality. Oikarinen et al reported that among patients with LVH diagnosed by EKG in the LIFE study, QRS duration and maximum rate adjusted QT_apex interval were predictive of increased cardiovascular and all-cause mortality.¹⁶ Since echocardiography has a higher sensitivity for the diagnosis of LVH than the EKG, the present findings may potentially be more relevant for clinical purposes. Since a one standard deviation increase in QTc caused a 1.7 fold increase in the odds of SCD [OR 1.72 (1.23 – 2.40)], this parameter warrants further evaluation as a predictor of SCD in LVH. None of the conduction abnormalities measured from the EKG conferred increased SCD risk. However, it has been reported that intraventricular conduction abnormalities complicating acute myocardial infarction can degenerate into higher degree conduction blocks that are known to increase SCD risk. ³⁰

Limitations

The difficulty in locating the T end when the T wave is flat for multiphasic may affect the QTc measurements, but since the reader was blinded to the case control status of the subjects, such an error would have affected the cases and controls equally and is unlikely to lead to any bias on the findings of the study.

Conclusion

Prolonged QTc interval was significantly associated with sudden cardiac death in subjects with echocardiographic LVH determined by calculation of LV mass. These findings have potential implications for clinical risk stratification and merit evaluation in larger, prospective studies.

Table 3.

Multivariate odds ratio estimates of SCD

Categories	OR (95% CI) n = 158
Age	1.01 (0.99 – 1.04)
Male	1.17 (0.55 – 2.46)
QTc (1SD increase)	1.72 (1.23 – 2.40)
QRS (1SD increase)	1.15 (0.86 – 1.54)

QRS, QRS duration; QTc, Corrected QT interval; SCD, Sudden cardiac death.