Comparison with other studies
The literature on sex differences in the severity of covid-19 has largely focused on admissions to hospital and the intensive care unit, and death, universally showing a reduced risk in female individuals.9 25 26 A meta-analysis of 70 studies of 2 751 115 patients with covid-19 (those admitted to hospital as well as those in the community) and 214 361 deaths found that female sex was associated with a 28% lower odds of dying from covid-19.9 In patients with covid-19 who required admission to the intensive care unit and vital organ support, female participants were still 37% less likely than male participants to die in the intensive care unit, independent of age, severity of the acute critical illness, lifestyle factors, and comorbidities.26 In our study, female participants had a 35% lower odds of death than male participants while in hospital. Whether this difference between the sexes is the same or greater than would be expected in the general population, where male individuals have a shorter life expectancy, is unclear. For comparison, in the Global Burden of Disease Study, the age-standardised rate for all cause mortality in 2019 was 616 per 100 000 female individuals compared with 874 per 100 000 male individuals, corresponding to a female-to-male relative risk of about 0.70 (http://ghdx.healthdata.org/gbd-results-tool). For infections of the lower respiratory tract, the rate was 30 per 100 000 female individuals compared with 40 per 100 000 male individuals (relative risk 0.75). The difference in mortality between the sexes in our study was therefore greater than that for all cause mortality and other lower respiratory infections, but differences in the methodology between the studies need to be considered. In a study based on country level mortality data, where the magnitude of sex differences in age standardised covid-19 mortality was directly compared with that for all cause mortality and other common causes of death, a considerably greater sex difference for covid-19 was found.25 A better understanding of the extent to which reduced mortality in female individuals with covid-19 differs from already known sex differences in the non-COVID-19 setting is needed.
Cardiovascular complications during covid-19 were reported early in the pandemic, and sex differences in cardiovascular disease in general are known,10 27–29 but few studies have assessed sex differences across a range of cardiovascular complications associated with covid-19. Those studies that have reported sex differences are small,30 have described few cardiovascular events,16 or focused on one cardiovascular subtype,31 32 and have reported inconsistent findings showing either a lower risk of cardiovascular complications in female individuals or no difference between the sexes.16 30 33 We found that female sex was associated with a lower risk of any cardiovascular complication, any arrhythmia, supraventricular tachycardia, cardiac ischaemia, and pulmonary embolism, even after adjusting for pre-existing cardiovascular disease and risk factors for cardiovascular disease. Whether the advantage in female individuals and its magnitude is unique to covid-19 or whether similar patterns exist for other respiratory illnesses is unclear. In general, however, female individuals have been shown to have a lower age adjusted incidence of cardiovascular outcomes than male individuals, including atrial fibrillation34 and myocardial infarction.10
Pre-existing cardiovascular disease has also been repeatedly shown to be associated with worse covid-19 outcomes.6 8 35 In cardiovascular epidemiology, although female individuals generally have a lower risk of acute coronary syndrome and all cause mortality than male individuals, this advantage is considerably reduced after myocardial infarction.10 We investigated whether a similar interaction existed between pre-existing cardiovascular disease and sex for covid-19 disease (ie, whether pre-existing cardiovascular disease reduced the difference in the severity of covid-19 between the sexes). With coronary calcification as a marker of the risk of cardiovascular disease, previous research from Italy found that the protective effect in female individuals disappeared in those with moderate-to-severe coronary calcification, suggesting that a similar phenomenon might exist for covid-19.16 Grouped by pre-existing cardiovascular disease, in this study we found that the point estimate for the female-to-male odds ratio was smaller (indicating a greater advantage in female individuals) in people with no pre-existing cardiovascular disease than in those with cardiovascular disease for all outcomes except cardiac ischaemia. Although none of the ratio of odds ratios was significant, the consistency with which point estimates were reduced in those with pre-existing cardiovascular disease warrants further investigation.
Several candidate mechanisms to explain the sex differences in covid-19 have been suggested, with numerous reviews on the topic published.14 36–38 For example, differences between the sexes in the expression and activity of angiotensin converting enzyme 2 (ACE2), the SARS-CoV-2 receptor, and a key regulator of the renin-angiotensin system could feasibly have a role in directly influencing susceptibility to the SARS-CoV-2 virus in organs where ACE2 is expressed (including the heart),39 or in determining the extent of dysregulation of the renin-angiotensin system after ACE2 loss at the cell surface induced by SARS-CoV-2 infection.14 37 38 Although the relation between SARS-CoV-2, ACE2, and the renin-angiotensin system, and sex (and age) has yet to be fully elucidated, the evidence so far, from both covid-19 and cardiovascular disease in general, indicates that sex differences in both of these mechanisms are likely to be to the detriment of male individuals.37 39 Conversely, female individuals have been shown to have rapid and more effective innate and adaptive immune responses than male individuals, with male individuals more likely to develop systemic inflammation and the cytokine storm associated with worse covid-19 outcomes.36–38
Although our findings cannot clarify the plausibility and relative contribution of these various pathways to the differences in cardiovascular complications of covid-19 seen between the sexes, the persistence of the female advantage in those with pre-existing cardiovascular disease suggests that the pathophysiological mechanisms of covid-19 itself might differentially affect the sexes (rather than being an indication of general sex differences in the risk of cardiovascular disease). This finding is further supported by the absence of a difference in the risk of heart failure or stroke between the sexes in our study, in contrast with what is known for the general population29 40 Furthermore, although evidence from the non-covid-19 setting indicates that the lower risk of cardiovascular disease in female individuals might be lost or diminished after the menopause,11 41–43 we found clear sex differences in the risk of cardiovascular disease associated with covid-19 even though the median age of our cohort was 68 years. This finding has implications for future studies investigating the role of sex hormones in sex differences in covid-19.38
The complication profile of covid-19 was similar between the sexes. For example, although serious cardiac complications, such as myocarditis, pericarditis, endocarditis, and acute coronary syndrome, were rare in both sexes (≤0.5% for all), arrhythmia was the most common complication in both sexes. This finding suggests that similar treatment approaches to limiting the effect of covid-19 on cardiovascular health might be appropriate in both sexes. Female and male individuals have been reported to have different long term outcomes after myocarditis, cardiac arrest, and thrombotic events, independent of covid-19.44 Research is therefore needed to understand whether sex differences in the effect of covid-19 on cardiovascular health are worsened, reduced, or even reversed over time. Research is especially important given the findings from a large US study that found that patients who survived covid-19 had an increased risk of incident cardiovascular disease 12 months after infection, compared with those with no history of covid-19.45
Because our study involved patients who were admitted to hospital, which typically accounts for <10% of all confirmed patients with covid-19 disease,46 we assessed whether male participants arrived in more ill heath than female participants and so, once admitted to hospital, are more likely to have cardiovascular complications or die. We found no clinically meaningful sex differences in any of the measurements of vital signs or laboratory values at admission. This result is in line with previous findings showing persistent sex differences even after adjusting for the Acute Physiology and Chronic Health Evaluation II (APACHE II) score, indicating the severity of acute illness.26 Previous research, however, has shown that the association between peak levels of C reactive protein and adverse outcomes in covid-19 is stronger in male individuals.47 The higher risk of severe disease in male individuals among patients admitted to hospital for covid-19 might also be explained by their later presentation to hospital than female individuals. In this study, median time from symptom onset to admission was four days in female individuals and five days in male individuals; whether this difference is enough to affect the risk of cardiovascular complications and death from covid-19 during hospital admission is unclear.
Strengths and limitations of this study
The strengths of our study include the large number of participants, which allowed us to examine sex differences for a range of cardiovascular outcomes. Our findings were limited to patients with covid-19 who were admitted to hospital, however, and therefore sex differences, if any, in the cardiovascular health of patients who recover from covid-19 without requiring admission to hospital is unclear. We also could not assess whether sex differences exist in cardiovascular complications or deaths that occurred outside of the hospital setting or in the long term outcomes of covid-19. Although the age distribution of our cohort was wide, with >30% of patients aged >75 years, generalising our findings to those who are very old or younger adults with cardiovascular complications associated with covid-19 is difficult. Furthermore, we acknowledge that the binary distinction between white and non-white ethnic groups did not capture the full spectrum of ethnic diversity in the population. Although other categories were captured in the registry (Asian, black, Latin American, and mixed ethnic groups), the percentage of participants was small. Therefore, for statistical reasons, and because the primary objective of the study was to examine sex differences, we chose to combine these groups. In the CAPACITY-COVID registry, pre-existing cardiovascular disease was derived from patients’ electronic health records and so misclassification of this exposure is possible. Central determination of complications did not exist.
Finally, the ever changing landscape of the covid-19 pandemic needs to be considered, in terms of the dominant variants in circulation, availability of effective treatments to minimise the effect of the disease on the body, and rates of vaccination, all of which could alter the relation between sex, covid-19, and cardiovascular disease. Data used in this study were collected between March 2020 and May 2021, when the dominant SARS-CoV-2 lineages in Europe were D614G followed by the alpha variant.18–21 Also, no vaccinations were available until December 2020, after which vaccination rates increased rapidly, with 60% and 40% of the population in the UK and the Netherlands, respectively, receiving their first dose by June 2021.20 22 23 Our findings therefore relate to when the direct effect of covid-19 was greatest. Nevertheless, we believe our findings have implications for our overall understanding of sex differences in health and disease, and show the importance of considering sex and gender differences across all aspects of human health.48