COVID-19 and vascular ageing: an accelerated yet partially reversible clock?

This editorial refers to ‘Accelerated vascular ageing after COVID-19 infection: the CARTESIAN study’, by R.M. Bruno et al., https://doi.org/10.1093/eurheartj/ehaf430. Although the acute threat of the COVID-19 (coronavirus disease 2019) pandemic has waned, a new challenge emerged in its aftermath: post-acute COVID-19 syndrome.1 Defined by the World Health Organization (WHO) as symptoms appearing 3 months post-infection and lasting at least 2 months, studies suggest that up to 40% of initial COVID-19 survivors develop this syndrome.2 While its manifestations are diverse, the most concerning are cardiovascular sequelae, ranging from dysautonomia and microvascular vasospastic conditions to myocardial infarction and venous thromboembolism.3 Vascular injury—marked by endothelial dysfunction, inflammation, and coagulation abnormalities—is a key mechanism driving these complications. Yet important questions remain. Can we objectively measure markers of vascular damage? Do they vary with disease severity? Who is at greatest risk? And will they persist? Several prior studies have examined arterial stiffness, specifically via carotid–femoral pulse wave velocity (PWV), in patients with acute and post-acute COVID-19.4 PWV, the speed at which the pressure wave travels through the arteries, is a non-invasive measure of aortic stiffness that improves risk prediction for cardiovascular events beyond traditional risk factors, and serves as a surrogate for vascular ageing.5 PWV increases with ageing and increased blood pressure, and higher PWV is associated with worse cardiovascular outcomes.6 Pooled analyses show higher PWV in individuals with acute COVID-19 and also post-acute COVID-19 syndrome.4 However, the prior studies were limited by small sample sizes (largest n = 140), lack of stratification by disease severity, and absence of sex-specific data—despite the concern that post-acute COVID-19 sequelae may be more frequent in female than in male adults. The CARTESIAN study (Covid-19 effects on ARTErial StIffness and vascular AgeiNg), published in this issue of the European Heart Journal,7 offers critical insight in this regard. This large, multicentre, prospective cohort study enrolled 2390 participants from 34 centres to investigate whether arterial stiffness, as measured by PWV, persisted in individuals with recent COVID-19 infection. Importantly, the study population was not restricted to individuals who met formal criteria for post-acute COVID-19 syndrome, and therefore included both asymptomatic and symptomatic survivors. Participants were divided into four groups: COVID-19-negative controls (n = 391), and COVID-19-positive individuals who were non-hospitalized (n = 828), hospitalized in general wards (n = 729), or admitted to intensive care units (ICUs) (n = 146). At a mean follow-up of 6 months post-infection, all COVID-19-positive groups exhibited significantly higher adjusted PWV compared with controls. The adjusted absolute difference in PWV was +0.41, +0.37, and +0.40 m/s for the non-hospitalized, hospitalized, and ICU groups, respectively, in consideration of the adjusted control PWV of 7.53 m/s. Notably, despite the initial hypothesis that vascular ageing would increase proportionally with COVID-19 severity, no clear linear or graded trend was observed across the three COVID-19-positive severity groups in the overall cohort. However, sex-stratified analyses revealed striking differences: females across all COVID-19-positive groups had significantly elevated PWV, with the highest increase (+1.09 m/s) observed in those requiring ICU admission. In contrast, no significant differences were found between males with and without COVID-19 infection. A formal sex-by-group interaction was significant in non-hospitalized and ICU groups, prompting stratified analyses, although additional interaction tests (e.g. symptom persistence × sex) were not reported. Persistent symptoms were present in 42% of COVID-19-positive participants at 6 months. Among females, those with persistent symptoms had significantly higher PWV than those without (adjusted difference +0.39 m/s), while no such difference was observed in males. 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. The study did not have sufficient power to test for treatment effects of medications such as statins.8 This study has several notable strengths. It utilizes PWV, a validated and reproducible surrogate for vascular ageing,5 and evaluates vascular function across the full spectrum of COVID-19 severity. The inclusion of an international, multicentre sample with near-equal sex distribution improves generalizability. Robust hierarchical mixed models accounted for clustering by device type to test PWV and recruitment setting, and country income level. The availability of 12 month follow-up data for 1024 participants allows for exploration of temporal trends: interestingly, while PWV progressed in controls, a decline was observed in many patients with COVID-19. In a small subset of participants who converted from COVID-19-negative to COVID-19-positive status between visits, PWV increased significantly, adding further support for reversibility and potential causality. This may reflect a transient increase in vascular tone driven by endothelial injury, systemic inflammation, autonomic imbalance with sympathetic overdrive, and acute illness. 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. In addition to answering important questions, CARTESIAN raises new ones. How should these sex-stratified findings and those showing a greater likelihood of post-acute COVID-19 in females be reconciled with greater risk of COVID-19-associated death in males?9,10 There could be potential explanations such as hormonal influences, social determinants of health, or a potential survivor bias, wherein males who were more severely affected and potentially more prone to vascular ageing may have died during the acute phase, leaving a survivor cohort that may not fully reflect the true burden of vascular sequelae in males. The sex-specific findings raise important mechanistic questions as well. Could the cardiac response to increased aortic stiffness—and, therefore, increased systolic pressure—differ by sex? Oestrogen is known to influence vascular tone and endothelial function, but less is known about sex differences in myocardial response to wave reflection and afterload stress. It is conceivable that females exhibit a more maladaptive myocardial or neurohormonal response to COVID-19-induced arterial stiffness. Furthermore, from a clinical perspective, the magnitude of differences in PWV across groups was modest—arguably at the threshold of detectability for the devices used—which warrant further correlative investigations in terms of its predictive utility for longer term symptoms or outcomes. Why a clear graded effect on PWV was not observed in all study participants needs further exploration, as well (Graphical Abstract). The CARTESIAN study delivers an important message to clinicians, researchers, and health policymakers: COVID-19’s vascular legacy is real, measurable, and with a plausible likelihood of sex-specific findings. For clinicians, routine cardiovascular risk stratification in patients with post-acute COVID-19 syndrome—especially females—should be emphasized. Although CARTESIAN was not a comparative effectiveness study with actionable results, at least further attention can be directed toward traditional risk factor modification, as well as patient education about the expected disease trajectory. For researchers, the findings demand mechanistic studies into sex differences in post-viral endothelial function and immune response. The CARTESIAN study makes the case that COVID-19 has aged our arteries, especially for female adults. The question is whether we can find modifiable targets to prevent this in future surges of infection, and mitigate adverse outcomes in those afflicted with COVID-19-induced vascular ageing. Outside the submitted work, B.B. was supported by a Career Development Award from the American Heart Association and VIVA Physicians (#938814), the Scott Schoen and Nancy Adams IGNITE Award, and the Mary Ann Tynan Research Scientist award from the Mary Horrigan Connors Center for Women’s Health and Gender Biology at Brigham and Women’s Hospital. He reports that he was a consulting expert, on behalf of the plaintiff, for litigation related to two specific brand models of IVC filters. He has not been involved in the litigation in 2022–5 nor has he received any compensation in 2022–5. He reports that he is a member of the Medical Advisory Board for the North American Thrombosis Forum (VasuLearn Network), and serves on the Data Safety and Monitory Board of the NAIL-IT trial funded by the National Heart, Lung, and Blood Institute, and Translational Sciences. He is a collaborating consultant with the International Consulting Associates and the US Food and Drug Administration in a study to generate knowledge about utilization, predictors, retrieval, and safety of IVC filters. He receives compensation as an Associate Editor for the New England Journal of Medicine Journal Watch Cardiology, as an Associate Editor for Thrombosis Research, and as an Executive Associate Editor for the Journal of the American College of Cardiology, and is a Section Editor for Thrombosis and Haemostasis (no compensation). He is supported by NIH grant NIH/NHLBI T32HL007227. All other authors declare no disclosure of interest for this contribution.