CV impact of COVID persists even years after infection

A recent study points to interesting clinical and genetic associations with COVID-19, demonstrating that the disease continues to pose a significant public health burden with lingering adverse cardiovascular (CV) risk and genetic interaction with ABO blood types.

“[W]e leveraged the UK Biobank resource to demonstrate that patients at all levels of COVID-19 severity – from simply being PCR*-positive for SARS-CoV-2 to those requiring hospitalization – are at significantly increased long-term risk of major adverse cardiac events (MACE),” said the researchers.

COVID-19 at all levels of severity was associated with a significantly higher risk of MI, stroke, or all-cause mortality over 1,003 days of follow-up (hazard ratio [HR], 2.09; p<0.0005), with a more pronounced effect among those requiring hospitalization (HR, 3.85; p<0.0005). [Arterioscler Thromb Vasc Biol 2024;44:2321-2333]

COVID-19 hospitalization: A CAD risk equivalent

Among those not hospitalized for COVID-19, MACE risk was increased in patients with diabetes (HR, 1.88; p<0.0005), peripheral artery disease (HR, 5.08; p<0.0005), or CV disease (CVD; HR, 5.63; p<0.0005).

The risk of MACE was higher among those hospitalized for COVID-19 but without CVD history (HR, 7.04; p<0.0005).

Thrombotic risk was higher among primary prevention participants without known CVD who were hospitalized for COVID-19 and not on antiplatelets at the time of enrolment (HR, 1.98; p<0.0005).

“[T]hese results demonstrate that … hospitalization for COVID-19 increased the risk of MACE among primary prevention subjects to the same degree as in COVID-19-negative subjects with pre-existing CAD equivalent risk factors. Furthermore, our data suggest that thrombotic risk can potentially be mitigated by using antiplatelet agents,” the researchers explained.

Clinical guidelines across the globe** use CAD risk equivalence as a metric to escalate CVD risk reduction as part of primary prevention efforts, including LDL-C*** lowering and antiplatelet initiation. [Circulation 2019;139:e1046-e1081; Circulation 2019;140:e563-e595; Can J Cardiol 2021;37:1129-1150; Eur Heart J 2021;42:3227-3337; Med J Aust 2016;204:320; Heart Lung Circ 2016;25:895-951; Eur Cardiol 2021;16:e26; Eur Cardiol 2021;16:e54]

“Thus, our findings raise the question of whether hospitalized COVID-19 infection should also be given consideration as a CAD risk equivalent, which would invoke a discussion of altering preventive CV practice in patients previously hospitalized with COVID-19,” the researchers noted.

Genetic associations

Participants who did not have blood type O were more likely to test positive for SARS-CoV-2 (odds ratio, 1.16; p=2.3×10⁻¹⁰) but not for COVID-19 hospitalization. This aligns with evidence showing that non-O blood types are specifically tied to increased susceptibility to SARS-CoV-2 infection but not necessarily to the risk of developing its severe postinfection respiratory complications. [Microb Pathog 2022;169:105658]

A significant genetic interaction was seen between COVID-19 and the ABO locus (p_interaction=0.011), where COVID-19 hospitalization markedly increased the risk of MI and stroke in individuals with non-O blood types (HR, 1.65; p=4.8×10⁻⁵) vs those who were type O (HR, 0.96; p=0.82).

“[T]hese observations suggest that increased thrombosis risk among hospitalized COVID-19 patients differs as a function of ABO blood type,” said the researchers.

“It should be noted that ABO is one of the most pleiotropic loci in the genome and exhibits associations with numerous cardiometabolic traits, including coagulation biomarkers,” they highlighted. “Thus, increased thrombotic risk as a result of genetic interaction between ABO and COVID-19 could be due to synergistic effects of non-O blood types and SARS-CoV-2 infection at the level of the vessel wall that potentially destabilizes vulnerable plaques and renders the endothelium more prone to thrombus formation.”

Moreover, with about 60 percent of the global populace having non-O blood types, the results imply that a substantial proportion of individuals across the world who had COVID-19 are at increased risk for thrombosis, they pointed out.

More aggressive CV risk reduction efforts warranted

The investigators used data from the UK Biobank to identify patients who were positive for SARS-CoV-2 based on PCR tests (n=8,062) or received hospital-based ICD-10^# codes for COVID-19 (n=1,943) between February 1, 2020 and December 31, 2020. Population (n=217,730) and propensity score-matched controls (n=38,860) were also drawn from the dataset.

“Taken together, our data indicate that the elevated risk of MACE in COVID-19 patients shows no apparent signs of attenuation up to nearly 3 years after SARS-CoV-2 infection,” the researchers said. “Our findings demonstrate that the development of COVID-19 requiring hospitalization confers a CAD risk equivalent to the subject, with a heightened risk of thrombosis, particularly evident among cases with non-O blood types.”

“These results may have important clinical implications and represent, to our knowledge, one of the first examples of a gene-pathogen exposure interaction for thrombotic events,” they said.

The findings also imply that more aggressive CV risk reduction efforts may need to be integrated into primary prevention protocols for hospitalized COVID-19 patients, they added. The results also provide new avenues to understand the biological mechanisms that might explain the CVD-related adverse outcomes of severe SARS-CoV-2 infection.