By Dr. Anthony C. Pearson, MD, FACC
Sudden cardiac death (SCD) has been defined by the Association for European Cardiovascular Pathology as "a natural, unexpected fatal event occurring within one hour from the onset of symptoms in an apparently healthy subject or in one whose disease was not so severe as to predict an abrupt outcome." More recently, the World Health Organization has defined SCD as "sudden unexpected death either within one hour of symptom onset (event witnessed) or within 24 hours of having been observed alive and symptom-free (unwitnessed)."
SCD is the most common natural cause of death in most developed Western countries, being responsible for more than 300,000 deaths per year in the US, according to the Association for European Cardiovascular Pathology guidelines. The majority of SCD cases are men, but multiple studies in the last 30 years have highlighted major gender-related differences in etiology.
Sudden Cardiac Death in Women vs. Men
For both men and women, the most common underlying risk factor for SCD is significant coronary artery disease (CAD).
A 2001 study in Circulation found that SCD was three times more common in men compared to women. Early studies like this implied major differences in the pathophysiology and presentation of SCD depending on gender, with the classic underlying cardiac pathology of left ventricle (LV) dysfunction and CAD being less likely in women.
In addition, the Oregon Sudden Unexpected Death Study (SUDS), an ongoing prospective investigation in the Portland, Oregon area published in the Journal of the American College of Cardiology, found that women were more likely to have SCD as the first CAD-associated event.
Given this heterogeneity of causes, predictors of SCD risk in women are more difficult to identify and prevent. However, recent studies have identified ECG predictors that may be more specific for women and yield insights into the mechanisms of SCD.
A study published in Circulation looked at all cases of SCD in American adults aged 35 and older in 1998. In the study, 456,076 cardiac deaths, or 63% of all cardiac deaths, were defined as SCD, with 74% of decedents being between the ages of 35 and 44. CAD was listed as the cause of death in 62%.
Between 1989 and 1998, SCD rates increased from 56.3% to 63.9% of all cardiac deaths. Age-adjusted SCD rates, however, declined overall, dropping 11.7% in men and 5.8% in women, except in women aged 35 to 44 years, for whom age-specific SCD rates increased by 21%.
The reasons for these gender-related differences are unclear. The authors of the study speculated that the findings may be tied to multiple factors, including lower awareness of risk in women, more atypical symptoms in women, and less aggressive treatment for women compared to men.
Possible Gender-Related ECG Repolarization Abnormalities
Several investigators have looked at ECG markers of repolarization as a predictor of myocardial vulnerability and arrhythmic death.
In the SUDS study, women were significantly less likely than men to have severe LV dysfunction as a precursor to SCA. Sudden cardiac arrest (SCA) was defined as a sudden unexpected pulseless condition occurring within one hour of symptom-onset (witnessed events) or within 24 hours of when the patient was last observed to be alive and symptom-free (unwitnessed).
Of the 1,568 SCA cases, 36% were women. Women were older than men. There were no significant gender differences in multiple key risk factors, including obesity, dyslipidemia, history of COPD/asthma, left ventricular hypertrophy (LVH), and history of MI. In addition, there was a significantly lower likelihood of women having an established diagnosis of CAD prior to SCA.
Although clinically derived factors did not differentiate men from women, analysis of the 12-lead ECG identified significant predictors. The ECG-derived corrected QT interval (QTc) was longer in women who experienced SCA than it was in men who experienced SCA, but after correction for age, gender differences were no longer significant. VF/VT was more commonly the presenting arrhythmia in men, whereas PEA/asystole was more common among women.
A novel cumulative ECG risk score was developed in the Oregon SUDS study and was found to be predictive of SCD, particularly in subjects with LVEF >35%. However, the Oregon SUDS ECG predictor score did not find any interaction with gender in a study published in the European Heart Journal. Further research on gender-related ECG risk factors is needed to clarify these conflicting findings.
Significant ECG Findings in Comparison to Autopsy
The Fingesture study of SCD published in Circulation in 2019 provides insight into current SCD gender differences. Performed between 1998 and 2017, the study looked at 5,869 WHO-defined SCD victims undergoing autopsy in Northern Finland, where autopsy rates are high due to government mandates in cases of unexplained sudden death.
Standard 12-lead ECGs obtained on average two years prior to death were available for review in the cases of 1,101 subjects, of which 78.9% were male and 21.1% were female. The women were older and had higher BMI and abdominal fat. SCD in women was more likely to be unwitnessed, indoors, and unassociated with exercise than SCD in men.
During autopsy, ischemic heart disease was believed to be the cause of SCD in men more often than in women (75.7% versus 71.7% of cases, respectively). The prevalence of myocardial fibrosis was 2.6% in men versus 5.2% in women.
Multiple ECG parameters differed between men and women. Men were twice as likely to have Q waves than women and had significantly higher frequencies of QT prolongation and QRS prolongation. Women, on the other hand, had a significantly higher rate of LVH (Cornell), at 17.9% versus 10.6%.
Overall, 28% of women in the nonischemic SCD group had normal ECGs compared to 16% of men. This suggests that ECG risk markers may not perform as well for women as they do for men, especially in non-ischemic cases.
Prolonged QT interval was associated with SCD in both men and women, but prevalence was significantly higher in men than in women.
The value of LVH as an ECG marker of ischemic SCD seems to be greater for women than for men, as 22.8% of women had LVH-associated findings on prior ECGs, compared to only 10.2% of men. In nonischemic SCD cases, LVH with repolarization abnormalities was more common in women than in men (10.2% of cases versus 4.6%).
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Sudden Cardiac Death in Women and Out-of-Hospital Cardiac Arrest Outcomes
Another perspective on SCD in women comes from an analysis of out-of-hospital cardiac arrest (OHCA) data in the Netherlands. The paper, which was published in the European Heart Journal, identified 5,717 EMS-treated patients with OHCA, 28% of whom were women. Compared to men, women were less likely to receive bystander-initiated CPR (67.9% versus 72.7%), even in the subset that was witnessed.
Overall survival to hospital discharge was significantly lower for resuscitated women (12.5% versus 20.1%). The overall lower survival rate was driven primarily by much lower survival from hospital admission to discharge in women versus men. This lower survival rate for women seems to be primarily explained by their substantially lower rate of having a shockable initial rhythm (SIR), which is known to be the strongest predictor of survival after OHCA.
Possible explanations for this marked difference include:
- Women being less aware of the possibility of OHCA.
- Women being less likely to recognize "sentinel" complaints, a factor which could be related to less typical symptoms of MI in women.
- Women with SCD being more likely to be widowed and living alone.
- Women having a lower prevalence of structural heart disease, which reduces the chance of identifying risk.
- Gender-related biological factors occurring at a myocyte membrane level during acute MI.
In summary, although the prevalence of SCD in women is one-third to one-half the rate in men, and major clinical risk factors are similar for both genders, substantial differences exist in outcomes and predictors.
The 12-lead ECG plays an important role in risk stratification for SCD in general, but its full predictive power is often not leveraged in cases where the patient is a woman, as women are more likely to have normal prior ECGs than men. Emerging evidence suggests that LVH with and without repolarization may be a useful predictor. Much is still left to be learned about gender-related differences in SCD between women and men.
Dr. Anthony C. Pearson, MD, FACC is a Professor of Medicine at the St. Louis University School of Medicine Division of Cardiology and specializes in general and noninvasive cardiology.
The opinions, beliefs, and viewpoints expressed in this article are solely those of the author and do not necessarily reflect the opinions, beliefs, and viewpoints of GE Healthcare. The author is a paid consultant for GE Healthcare and was compensated for creation of this article.
