Vascular Aging May Explain Long COVID’s Predominance in Women

COVID-19 infection was associated with accelerated aging of blood vessels, especially in women, the CARTESIAN study showed.

In an international cohort of patients recruited from 2020 to 2022, COVID-negative controls showed an adjusted mean carotid-femoral pulse wave velocity (PWV) of 7.53 m/s, while COVID-positive patients had significantly higher PWV, whether they were hospitalized (+0.37 m/s, P=0.001), admitted to the intensive care unit (ICU; +0.40 m/s, P=0.003), or avoided hospitalization (+0.41 m/s, P<0.001) -- higher measurements of PWV translate to stiffer blood vessels and greater vascular age.

This was specifically the case for women, with PWV increases ranging from +0.55 to +1.09 m/s across the COVID-positive groups, reported Rosa Maria Bruno, MD, PhD, of Université Paris Cité, and colleagues in the European Heart Journal.

“The CARTESIAN study is the first study adequately powered to demonstrate the extent of COVID-19-induced vascular aging and the relationship with disease severity, independent of [cardiovascular] risk factor burden,” the authors wrote. “To our knowledge, this is the first study demonstrating that the association between COVID-19 and vascular aging is modified by sex.”

Older literature had generally shown that men were more susceptible to severe acute COVID, while women were more at risk of long COVID.

Bruno cited several possible explanations for the vascular effects of COVID and the observed sex differences.

“The COVID-19 virus acts on specific receptors in the body, called the angiotensin-converting enzyme 2 receptors, that are present on the lining of the blood vessels,” Bruno said in a press release. “The virus uses these receptors to enter and infect cells. This may result in vascular dysfunction and accelerated vascular aging. Our body’s inflammation and immune responses, which defend against infections, may be also involved.”

“One of the reasons for the difference between women and men could be differences in the function of the immune system,” she noted. “Women mount a more rapid and robust immune response, which can protect them from infection. However, this same response can also increase damage to blood vessels after the initial infection.”

This may be relevant to the persistence of brain fog and other long COVID symptoms commonly reported months or even years after the initial SARS-CoV-2 infection.

Indeed, the CARTESIAN researchers reported that among women, those with persistent COVID symptoms at their 6-month follow-up tended to have higher PWV compared with peers who fully recovered from infection (7.52 vs 7.13 m/s, P<0.001). Meanwhile, men had unchanged PWV whether they had persistent symptoms or not (8.50 vs 8.43 m/s, P=0.563).

“Although the study did not explicitly define post-acute COVID-19 syndrome using the WHO criteria, these results suggest that PWV may serve as a physiological marker of symptom persistence in females, and possibly a prognostic indicator of vascular injury,” wrote Behnood Bikdeli, MD, MS, of Brigham and Women’s Hospital and Harvard Medical School in Boston, and colleagues in an accompanying editorial.

Followed over a longer term, the COVID-recovered participants in CARTESIAN typically had stable or improved PWV after 12 months, while controls had increases in PWV during that time.

“The slight increase in PWV seen in the COVID-19 group could be attributed partly to normal aging, but also to a possible asymptomatic or undiagnosed subsequent COVID-19 infection in these patients,” Bruno and team noted.

Bikdeli’s group pointed out that “although irreparable vascular damage is likely, this may be only partial, with other components related to autonomic dysfunction of vascular tone or residual inflammation improving over time, as seen with reduced PWV.”

CARTESIAN was a prospective cohort study of 2,390 people in 16 countries recruited from 2020 to 2022. The researchers included COVID-negative controls and people with recent COVID infection who were divided into those who were not hospitalized, were hospitalized, and admitted to the ICU.

Across the four groups, mean age was 50, and 49.2% were women. As expected, the hospitalized COVID patients were older, more frequently men, and had a higher burden of cardiovascular risk factors and disease compared with non-hospitalized patients and uninfected controls. Non-hospitalized COVID patients and controls shared a similar baseline cardiovascular risk profile.

Ultimately, 2,094 patients were included in the main outcome analysis at 6 months, of which 1,024 made it to the longer follow-up visit that took place a median 314 days later.

Across the COVID cohorts, the prevalence of long COVID symptoms fell from 46% at 6 months to 37.6% at the later follow-up point.

Meanwhile, the proportion of vaccinated participants rose from 10.4% to 72.2%.

Although vaccination was associated with lower PWV in CARTESIAN, the study authors pointed to intrinsic differences between the vaccinated and nonvaccinated patients that could not be controlled with their observational study design.

Bruno and colleagues also acknowledged the potential survival bias and lack of accounting for early vascular aging pre-dating COVID-19 infection in their study.

The editorialists added that the study was not powered to test for treatment effects of medications such as statins.

“Vascular aging is easy to measure and can be addressed with widely available treatments, such as lifestyle changes, blood pressure-lowering and cholesterol-lowering drugs,” Bruno noted. “For people with accelerated vascular aging, it is important to do whatever possible to reduce the risk of heart attacks and strokes.”