The impact of genetic and lifestyle factors on the risk of major cardiovascular and thromboembolic events post-COVID-19 diagnosis

Cardiovascular disease is known to be the leading cause of death throughout the world. Recently, cardiovascular morbidity and mortality have increased further due to the direct and indirect impact of the coronavirus disease 2019 (COVID-19) pandemic. The repercussions and long-term consequences of COVID-19 could lead to a further increase in the cardiovascular burden to abnormal levels.

Background

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Prevention of life-threatening cardiovascular and thromboembolic events (CVE) is important for treating COVID-19 patients at the individual level. However, accurately identifying individuals at sufficient risk that might require high surveillance or targeted pharmacological interventions is challenging.

General risk factors such as age, obesity, and sex have been reported to be important predictors of COVID-19 severity, hospitalization, and the requirement for mechanical ventilation. However, they are not very effective in determining CVE risk. Polygenic risk scores (PRSs), a sum of genetic risk for a specific trait, have been identified as an important tool for precision medicine and early cardiovascular risk categorization. Although, whether genetic susceptibility to CVE will impact the occurrence of COVID-19-associated CVE during post-acute or acute illness periods is unknown.

Additionally, effective public health interventions are required immediately to reduce the cardiovascular burden of the population, especially due to the increase in COVID-19 infections following the removal of the early restrictions. In 2022 the US Preventive Service Task Force updated its recommendations for promoting healthy behavior counseling for all adults to prevent cardiovascular complications. However, all public and clinical health guidelines cannot determine the impact of healthy lifestyle modifications in reducing COVID-19 cardiovascular complications, mostly due to the lack of sufficient evidence.

A new study posted to the medRxiv* preprint server aimed to analyze the association between lifestyle risk factors, PRSs, and their interactions along with the risk of CVE within 90 days post-COVID-19 diagnosis.

About the study

The study involved participants from UK Biobank who had a positive PCR test for COVID-19 between 1st March 2020 and 30th September 2021. Two sets of PRS, standard and enhanced, were developed and validated by the UK Biobank. The PRS for ischaemic stroke (ISS), coronary artery disease (CAD), venous thromboembolic disease (VTE), and atrial fibrillation (AF) were used in the primary analysis, while enhanced PRS was used in one of the analyses. Moreover, the categorization of the continuous PRS was carried out as high-risk, low-risk, and intermediate-risk.

A composite healthy lifestyle index was defined through a combination of nine lifestyle component data that involved alcohol drinking, smoking status, television viewing time, physical activity, intake of oily fish, intake of processed meat, intake of red meat, intake of fruit and vegetable, and sleep duration. Every lifestyle factor was assigned 0 points if it was healthy and 1 point if it was unhealthy. After that, a summation of all the lifestyle factors was carried out, scores ranging from 0 to 4 were categorized as a healthy lifestyle, and those ranging from 5 to 9 were categorized as an unhealthy lifestyle.

Finally, the COVID-19 first infection date was defined as the index date, and participants were followed up for 90 days. Analysis of four major CVEs (VTE, CAD, AF, and ISS) reported as COVID-19-related cardiovascular complications were carried out. International Classification of Diseases 10th Revision (ICD-10) codes similar to those used in PRS development was used to determine clinical outcomes.

Study findings

The results indicated that the average age of the COVID-19 participants was 65.99 years, out of which most belonged to White ethnicity and were women. The prevalence of the nine unhealthy lifestyle factors was observed to range from 10.8% for smoking status to 48.5% for low intake of oily fish. Overall, a total of 8.6% of infected individuals were reported to live an unhealthy lifestyle.

Following infection, 135 VTE, 29 ISS, 244 CAD, and 422 AF events were reported to occur during the follow-up period, which accounted for 0.53%, 0.12%, 0.96%, and 1.67% of the COVID-19 cohort, respectively. The rate of incidence was reported to be 6.12 per 1,000 person-years for ISS, 86.9 for AF, 48.5 for CAD, and 28.0 for VTE.

Furthermore, a higher PRS for VTE, AF, or CVD was reported to be associated with a higher risk of post-COVID-19 CVE. However, no association was observed between ISS-PRS and post-COVID-19 ISS. The overall association between VTE, CAD, and AF with each PRS was observed to be similar despite differences in baseline risks. Additionally, participants with higher genetic risk were reported to show a higher incidence of CVE post-COVID-19.

People with healthier habits were found to have a lower risk of CAD, AF, and ISS, while no association was observed for VTE. The prevented fraction of CVE outcomes on changing to a healthy lifestyle was reported to be  5.86% for ISS, 2.95% for CAD, and  2.46% for AF. No interaction was observed between lifestyle and genetic factors for any CVE outcomes.

Moreover, the results of the sensitivity analysis were observed to be similar to the primary analysis. The extent of PRS association was reduced for the sensitivity analysis of hospital admission-related events and incident events compared to the estimates of events diagnosed after infection.

Therefore, the current study demonstrated that the genetic risk of cardiovascular disease could be associated with short-term risk of VTE, AF, and VAD complications following COVID-19 infection. However, the risk was lower for people who adhered to a healthy lifestyle, independent of their genetic risk. This suggests that healthy lifestyle interventions can reduce the cardiovascular burden of the population during the ongoing pandemic, irrespective of their genetic background.

Limitations

The study has certain limitations. First, the PRS score might not be able to indicate the maxim genetic contribution to COVID-19 cardiovascular complications. Second, the study might record overdiagnoses for COVID-19 patients. Third, PRS might not be able to provide additional predictive information. Fourth, the lifestyle behavior data collected ten years ago might be subjected to misclassification and bias. Finally, the UK Biobank participants represent a healthier population than the general population and are of European ancestry, which might limit the generalisability of the results.

*Important notice

medRxiv publishes preliminary scientific reports that are not peer-reviewed and, therefore, should not be regarded as conclusive, guide clinical practice/health-related behavior, or treated as established information.

Written by

Suchandrima Bhowmik

Suchandrima has a Bachelor of Science (B.Sc.) degree in Microbiology and a Master of Science (M.Sc.) degree in Microbiology from the University of Calcutta, India. The study of health and diseases was always very important to her. In addition to Microbiology, she also gained extensive knowledge in Biochemistry, Immunology, Medical Microbiology, Metabolism, and Biotechnology as part of her master's degree.