In this cohort study of postmenopausal women with CAD, SCD comprised the majority of cardiac-related deaths during the 6.8 year follow-up period. We found heart failure, reduced kidney function, atrial fibrillation and diabetes as independent risk factors for SCD in both the overall analysis and the echocardiographic subgroup. MI and physical inactivity were additional risk factors for SCD in the original analysis; however, these variables were not independent markers of risk when LVEF was added to the model. In a competing risks analysis, we confirmed that myocardial infarction, heart failure, reduced kidney function and diabetes were associated with SCD in the overall cohort. In developing a risk-stratification approach, we delineated nearly a 10-fold gradient in SCD risk by using the number of risk factors present at baseline. Clinical characteristics were better predictors of SCD risk than LVEF alone, and the combination did better still.
Our study quantifies the risk of SCD events in an ambulatory cohort of women with CAD. During the 6.8 year follow-up period, 136 of the 254 cardiovascular deaths were adjudicated as sudden, making SCD the leading cause of cardiovascular-related mortality among this group. Prior population-based studies have found approximately a 10-fold lower risk of SCD in women.2
Further, the annual rate of SCD among women in HERS is lower than SCD rates observed in populations with an established cardiomyopathy (e.g. participants in the ICD trials). In this context we have identified a group of well-functioning women at intermediate risk of SCD.
Most SCD cases occur in the general population or among individuals without advanced cardiovascular disease.14, 18, 26
With the exception of LVEF, other risk stratification variables are not utilized routinely in clinical practice. Our findings highlight that a simple assessment of clinical risk factors has better predictive value for SCD than LVEF alone. These findings complement prior studies in higher risk populations that suggest an improvement in SCD risk prediction when clinical risk factors are combined with ejection fraction.27, 28
Our final model, which consisted of both LVEF and clinical risk factors, also differentiated between SCD and non-cardiac deaths; however, it did not discriminate between sudden and non-sudden cardiac events. This latter finding remains an area of important investigation and will require the evaluation of unique risk factors associated with cardiac arrhythmias. From the standpoint of clinical relevance, our model improves SCD prediction compared to LVEF alone, which may impact the care of women with CAD given that SCD comprised the majority of cardiac-related deaths.
Among the identified risk factors, the strength of atrial fibrillation as an independent predictor of SCD was surprising. This finding suggests that a history of atrial arrhythmias increases the risk of ventricular tachyarrhythmias, which are the presumed cause of the majority of SCD events, especially in patients with structural heart disease. Electrical remodeling processes in the atria, characterized by shorter action potential duration and refractoriness, underlie the mechanisms implicated in atrial fibrillation.29
Similar changes may also occur in ventricular myocytes and subsequently increase the risk of ventricular tachycardia or ventricular fibrillation in susceptible patients.30
Also, the short-long-short sequences of ventricular conduction in atrial fibrillation may trigger ventricular arrhythmias. Alternatively, atrial fibrillation may be an additional marker of underlying structural heart disease. Regardless of the mechanism, our study indicates a need to evaluate atrial fibrillation further in another risk-based or predictive model for SCD events. This approach may require combining several cohorts of women with CAD.
Exercise and regular physical activity in women have been strongly associated with improved cardiovascular outcomes and lower all-cause mortality.31–34
Our findings suggest a strong association between regular exercise consisting of at least 3 sessions per week and a lower risk of SCD events. Given that very few noninvasive therapies protect against SCD, it is important to evaluate whether regular exercise reduces the incidence of SCD.
Diabetes and impaired glucose tolerance are other well-established risk factors for SCD in both men and women.35
Population-based studies including the Paris Prospective Study and the Honolulu Heart Program, which each enrolled approximately 8,000 men have demonstrated independent associations of diabetes and impaired glucose tolerance with SCD risk.36, 37
Similarly, the Nurses’ Health Study also identified diabetes as one of the strongest clinical risk factors for SCD in women.2
The echocardiographic subgroup analysis confirmed that many of the risk factors identified in the original analysis remained independent predictors of SCD risk after including LVEF. LVEF < 35% is currently considered the most clinically relevant risk factor for SCD risk stratification and identifies patients who may benefit from an implantable cardioverter-defibrillator (ICD).38, 39
Although we did not have LVEF measures in the entire cohort, our subgroup analysis demonstrated that heart failure, reduced kidney function, atrial fibrillation and diabetes remained independent risk factors for SCD after adjustment for LVEF. Prior MI and physical inactivity likely co-segregate with left ventricular function, as the inclusion of LVEF in the subgroup analysis precluded their addition to the model. Finally, although LVEF measures were not standardized in a core, imaging laboratory, their assessment via chart review mimics echocardiographic-based methods of risk stratification in clinical practice. In addition, echocardiograms were not obtained at the outset of the study unlike other predictors of SCD in our study; however, the application of a LVEF measure from earlier time-points also represents clinical practice.
Several limitations of our study should be considered. First, the limited number of SCD events may have resulted in a relatively small number of potential risk factors. In addition, we did not validate our prediction model in other cohorts. Future studies will require collaborations across multiple cohorts to refine further SCD risk discrimination and provide a means for both replication and cross-validation. The majority of women in this analysis were white; therefore, further assessment is required in post-menopausal women of other ethnicities. Left ventricular ejection fraction, a powerful predictor of risk for SCD, was not measured in all the participants of this study. Although we included a separate, subgroup analysis, our findings may be limited given the lower number of SCD events. Finally, the variables identified in our analysis also appeared to be associated with non-sudden cardiac death. This current limitation in risk prediction will require future studies to identify unique predictors of SCD.
In conclusion, SCD comprised the majority of cardiac-related deaths among post-menopausal women with coronary artery disease. We found that in addition to LVEF, MI, heart failure, an eGFR < 40 ml/min, atrial fibrillation, physical inactivity, and diabetes were independently associated with SCD in this large, multicenter sample of women with coronary artery disease. The risk factors served as better predictors of SCD than LVEF alone and enhanced risk discrimination when both were combined. A simple risk stratification based on the number of risk factors predicted a 10-fold gradient in the incidence of SCD. Future projects should focus on combining studies to allow more robust estimates for established risk factors and to identify additional markers that augment the predictive ability of a SCD risk model.