Author

James Chao

Date

May 2009

Document Type

Thesis

Degree Name

M.P.H.

Department

Dept. of Public Health and Preventive Medicine

Institution

Oregon Health & Science University

Abstract

Objective The purpose of this investigation is to determine whether or not unhealthy levels of lipoprotein subfractions, such as LDL and HDL, serve as risk factors for ventricular fibrillation (VF) and ventricular tachycardia (VT). This study uses a cohort of 200 patients from an original dataset obtained from a randomized, double-blind, placebo-controlled trial performed at 6 US medical centers with enrollment from February 1999 until January 2003. This initial 1999-2003 trial aimed to determine whether omega-3 polyunsaturated fatty acids (PUFAs) may have beneficial antiarrhythmic effects in patients with a history of sustained VT or VF. It found that among patients with a recent episode of sustained ventricular arrhythmia and an ICD, fish oil supplementation does not reduce the risk of VT/VF and may be proarrhythmic in some patients.1 Context Clinical studies have shown that the balance between LDL and HDL levels not only determines the level of atherosclerosis in the coronary vasculature, but may also serve to indicate the level of cardiac inflammation. These inflammatory processes may play a role in inducing potentially fatal arrhythmias that can lead to sudden cardiac death (SCD). SCD is a cardiovascular affliction that carries the heaviest burden on the United States public health system, more than any other disease, 2,3,4,5. Over 450,000 people in the U.S. die from sudden cardiac arrest (SCA) each year 1, more than death from stroke 2, lung cancer 3, breast cancer 3, and AIDS 4 combined. The most widely-used therapeutic and preventive modality against SCD is ICD. Recent clinical studies have shown that patients most at risk for the fatal arrhythmias that cause SCD receive the most potential benefit from ICDs if they have a left ventricular ejection fraction less than 35%. However, it is now clear that current indications for ICD implantation are not adequate in that patients at the highest risk for ICDs are not being properly identified to benefit from the lifesaving-prevention that ICDs provide. As a result, a larger emphasis is placed on non-invasive risk stratification measures such as lipoprotein subfraction levels in order to refine criteria for ICD implantation for primary and secondary prevention of SCD. Main Outcome Measures There were two main outcome measures of interest: (1) time to first episode of ICD shock for VF and (2) time to first episode of ICD shock for VT, treated separately. ICD shock for VF and VT served as a proxy for the actual, sensed VF and VT events, which were chosen as the main outcome measures based on their high clinical significance for the induction of SCD and for their different outcomes from fish oil treatment in the original fish oil investigation. Methods The statistical analysis was an intent-to-treat-analysis. The baseline characteristics of patients randomized to receive fish oil vs. placebo were compared using the t-test. Significant differences in lipid subfraction values of total cholesterol, LDL, HDL, triglycerides, and total cholesterol:HDL ratio over time were determined using a mixed-model repeated measures analysis of variance approach. The initial value was used as a covariate to control for any differences at baseline, with the most appropriate covariance structure selected using the Akaike information criterion. Least square-adjusted means were estimated and compared for all analysis of variance effects. All analyses will be performed with SAS software, versions 8 and 9, and STATA 10 software. Primary time to event analyses were performed using the Kaplan-Meier method, and continuous, discrete lipid panel subfractions were subjected to univariate Cox proportional hazards regression and quartiled lipid panel subfractions were subjected to the log-rank test. A Cox proportional hazards model was used to assess the significance of the primary outcome controlling for other baseline characteristics. Variable selection was performed with these baseline characteristics using all possible regression models with the score statistic and stepwise addition of variables. Treatment group was then added to the best model to determine if it was a significant predictor after controlling for significant baseline characteristics. Interactions were tested for significance among the significant variables at the multivariate level. The resulting Cox proportional hazards model was tested for the proportionality assumption by using the Schoenfeld and scaled Schoenfeld residuals. The goodness of fit of the final model was be evaluated using Cox-Snell residuals. Post hoc power analysis showed that this investigation had only 28% power and 68% power to detect a 33% difference in VF rate and VT rate, respectively. Results After adjusting for fish oil treatment allocation group, each 1 mg/dl increase in LDL level was associated with a 2% increase in the hazard ratio of ventricular fibrillation (p = 0.027). An ejection fraction less than 40% (hazard ratio 1.5; 95% CI 1.029 – 2.241) and VT as the qualifying arrhythmia (hazard ratio 2.5; 95% CI: 1.555 – 4.163) were significant independent predictors of time to ICD therapy for VT. When treatment assignment was added to this model, the fish oil group had a hazard ratio of 1.5 (95% CI 1.019 – 2.209). This finding is not unexpected, as the original fish oil RCT found similar results for the combined endpoint of VT/VF and was reported in the original publication. None of the lipoprotein nor nonlipoprotein subfractions were significant predictors of time to first ICD therapy for VT. Conclusion Among patients with a recent episode of sustained ventricular arrhythmia and an ICD, LDL level is a significant predictor for ventricular fibrillation before adjusting for treatment allocation. Neither LDL nor HDL were significant predictors for the risk of VT. Moreover, the significance of ejection fraction as a predictor for ventricular tachycardia point to different pathologic mechanisms between the two ventricular tachyarrhythmias most responsible for sudden cardiac death, information that may be useful when risk stratifying patients for ICD implantation for secondary prevention of sudden cardiac death.

Identifier

doi:10.6083/M4TD9V8R

School

School of Medicine

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