COVID-19 Predisposition Inherently Increases Cardiovascular Risk Before SARS-CoV-2 Infection

As COVID-19 transitions to an endemic stage, its long-term impacts on health, particularly cardiovascular disease (CVD), remain significant. While prior studies have focused on cardiovascular complications following SARS-CoV-2 infection, the question of inherent cardiovascular risk associated with genetic predisposition to COVID-19 has been less explored. This study investigates whether individuals genetically predisposed to COVID-19 may also be at higher risk for CVD, independent of actual infection. Using Mendelian randomization (MR) analysis with data from pre-pandemic, SARS-CoV-2-naive populations, this study assessed the impact of genetic susceptibility to COVID-19 on various CVD outcomes across 18 distinct cohorts. This approach allowed us to simulate COVID-19 predisposition without infection, providing insights into cardiovascular risks associated solely with genetic susceptibility. These findings reveal a significant association between genetic predisposition to COVID-19 and elevated risks for several CVD outcomes, particularly hypertensive heart disease. Notably, individuals with a genetic profile linked to severe COVID-19 (hospitalization-prone) showed a marked increase in risk for hypertensive heart disease. These findings suggest a shared genetic architecture that predisposes individuals to both COVID-19 and cardiovascular risks, irrespective of viral exposure. COVID-19 susceptibility, thus, may act as a "natural stress test," revealing latent cardiovascular vulnerabilities. This connection implies that individuals predisposed to severe COVID-19 may have inherently higher cardiovascular risks, even without SARS-CoV-2 infection. This study highlights the value of COVID-19 susceptibility as a novel marker for assessing CVD risk, enabling timely preventive strategies and mitigating future CVD burden in the post-COVID-19 era. Moreover, this study highlights disease predisposition as a "black box" until clinical onset. While COVID-19 demands an external viral trigger for acute onset, cardiovascular disease unfolds much more slowly, requiring prolonged exposure to detrimental lifestyle and genetic factors. Together, their intersection illustrates how acute environmental triggers and chronic disease processes can converge to influence overall health outcomes.