Cardiovascular risk in heavy smoking females: an overlooked red flag

Background Women are generally considered at low risk for cardiovascular diseases. In the past, this led to gender bias and udertreatment of female patients. Moreover, the prevalence of female heavy smokers was low compared to men, while it has increased worldwide in recent years. This is considered a public health concern, since some studies suggest that, compared with men, women may be more susceptible to smoking-related morbidity and mortality (1), but even scores and models use to evaluate stable patients often underestimate the cardiovascular risk in this cathegory. In our project, we evaluated the rate of cardiovascular events in heavy smoking females, with atypical chest pain and negative functional tests, compared to men. Methods Between 2010 and 2023 we evaluated 4,790 outpatients aged >35 years old (average 64±9, women 55%) for the presence of stable chest pain. We excluded 367 patients who had ECG changes compatible with recent ischemia, history of myocardial infarction or any other major cardiovascular events, evidence of heart failure, left ventricular dysfunction, or cardiomyopathies. In the other 4423 cases we applied the traditional classification of typical, atypical angina and non-anginal pain. At least one functional test was performed in all patients to exclude the presence of coronary ischemia. In the end, we had 3998 patients with atypical chest pain and negative functional tests. Of these, 4% were heavy smokers. According to the diagnostic algorithm and RF-CL path of ESC guidelines on chronic coronary syndromes (2), if we assessed the risk of coronary obstructive disease in female heavy smokers< 70 years old, this would be low or very low. The median follow-up was two years. Results Table 1 shows the events at two years in current heavy smokers (≥ 20 cigarettes per day) aged <70 years. Heavy female smokers with atypical chest pain and negative functional tests had a 12% risk of fatal events (p=0,02 using exact Fisher test). Conclusions in our analysis, female heavy smokers < 70 years old with atypical chest pain had an extreme high risk of fatal events, despite negative results of functional tests. Despite that, their risk is still underestimated, both by patients and physicians. More efforts should be make to understand if this is due to gender biases in the evaluation of patients, worse performances of functional tests in women, or if women are effectively more susceptible to smoking-related morbidity and mortality.