The likelihood of COVID-19 patients dying was up to 81 times higher in the first three weeks, compared to uninfected individuals

InHealth — institute for health transformation

Joaquim Cardoso MSc — Founder, CEO and CSO
January 21, 2023



  • COVID-19 infection, including long-COVID, is associated with increased short- and long-term risks of CVD and mortality.

  • Ongoing monitoring of signs and symptoms of developing these cardiovascular complications post diagnosis and up till at least a year post recovery may benefit infected patients, especially those with severe disease.

  • COVID-19 is associated with higher risks of cardiovascular disease and death in the short- and long-term, according to a study in nearly 160,000 participants published today in Cardiovascular Research, a journal of the European Society of Cardiology (ESC).1

  • Compared with the two uninfected cohorts, patients with COVID-19 were approximately four times more likely to develop major cardiovascular disease in the acute phase and 40% more likely in the post-acute phase.

  • Compared to uninfected individuals, the risk of death in COVID-19 patients was up to 81-fold higher in the acute phase and five-fold higher in the post-acute phase.

  • Patients with severe COVID-19 were more likely to develop major cardiovascular disease or die than non-severe cases.



COVID-19 patients retain elevated risk of death for at least 18 months after infection

Sophia Antipolis, 19 January 2023

COVID-19 is associated with higher risks of cardiovascular disease and death in the short- and long-term, …

… according to a study in nearly 160,000 participants published today in Cardiovascular Research, a journal of the European Society of Cardiology (ESC).1

Compared to uninfected individuals, the likelihood of COVID-19 patients dying was up to 81 times higher in the first three weeks of infection and remained five times higher up to 18 months later.

“COVID-19 patients were more likely to develop numerous cardiovascular conditions compared to uninfected participants, which may have contributed to their higher risks of death,” said study author Professor Ian C.K. Wong of the University of Hong Kong, China. 

“The findings indicate that patients with COVID-19 should be monitored for at least a year after recovering from the acute illness to diagnose cardiovascular complications of the infection, which form part of long COVID.”

This study compared the occurrence of cardiovascular conditions and death in infected versus uninfected individuals recruited before December 2020, when no vaccines were available in the UK. 

More than 7,500 patients with COVID-19 infection diagnosed from 16 March 2020 to 30 November 2020 were identified from UK Biobank.2 

Each patient was matched with up to 10 individuals without COVID-19 during the study period (16 March 2020 to the end of follow-up on 31 August 2021) and a historical cohort before the pandemic (16 March 2018 to 30 November 2018). 

Each uninfected group had more than 70,000 participants who were similar to the COVID-19 group for age, sex, smoking, diabetes, high blood pressure, cardiovascular and other health conditions, body mass index, ethnicity, and deprivation. 

In all three groups, the average age was 66 years and there were nearly equal numbers of women and men.

Professor Wong explained: “The historical control cohort was included to rule out the effect of routine healthcare services being reduced or cancelled during the pandemic, which led to worsening health and increased mortality even in uninfected people.”

Data were obtained from medical and death records for outcomes including major cardiovascular disease (a composite of heart failure, stroke and coronary heart disease); numerous cardiovascular conditions such as stroke, atrial fibrillation and myocardial infarction; death from cardiovascular disease; and all-cause death. 

Associations were evaluated for the acute phase (within 21 days of COVID-19 diagnosis) and the post-acute phase (starting at 22 days after diagnosis and continuing up to 18 months). 

Participants with a history of a particular outcome were excluded from that analysis.

Compared with the two uninfected cohorts, patients with COVID-19 were approximately four times more likely to develop major cardiovascular disease in the acute phase and 40% more likely in the post-acute phase. 

Compared to uninfected individuals, the risk of death in COVID-19 patients was up to 81-fold higher in the acute phase and five-fold higher in the post-acute phase. Patients with severe COVID-19 were more likely to develop major cardiovascular disease or die than non-severe cases.

COVID-19 patients had a greater likelihood of several cardiovascular conditions compared with uninfected participants in both the short- and long-term including myocardial infarction, coronary heart disease, heart failure, and deep vein thrombosis. 

Risks of some cardiovascular conditions — for example stroke and atrial fibrillation — were elevated in COVID-19 patients in the short-term but then returned to normal levels.

Professor Wong said: “This study was conducted during the first wave of the pandemic, and future research should evaluate subsequent outbreaks. Previous research has indicated that COVID-19 vaccination may prevent complications, and further studies are needed to investigate its effectiveness in reducing the risks of cardiovascular disease and death after COVID-19 infection in patients with COVID-19 vaccination compared to those without vaccination.”

ESC spokesperson Professor Héctor Bueno of the National Centre for Cardiovascular Research (CNIC), Madrid, Spain said: “COVID-19 has had a huge impact on patients with cardiovascular disease, who were less likely to receive optimal care during the pandemic and more likely to die from the infection. 

This study shows that COVID-19 also increases the risk of having cardiovascular complications and dying in the first weeks after the infection and remains high for months, suggesting that specific cardiovascular monitoring may be appropriate in these patients.”

Originally published at


This work was funded by Collaborative Research Fund, University Grants Committee, The Government of the Hong Kong Special Administrative Region (Ref. No. C7154–20GF) and the start-up fund from the University of Hong Kong. ICKW and FTTL are partially supported by the Laboratory of Data Discovery for Health (D24H) funded by the by AIR@InnoHK administered by Innovation and Technology Commission.


Association of COVID-19 with short- and long-term risk of cardiovascular disease and mortality: a prospective cohort in UK Biobank

European Society of Cardiology — Cardiovascular Research

Eric Yuk Fai Wan, Sukriti Mathur, Ran Zhang, Vincent Ka Chun Yan, Francisco Tsz Tsun Lai, Celine Sze Ling Chui, Xue Li, Carlos King Ho Wong, Esther Wai Yin Chan, Kai Hang Yiu, Ian Chi Kei Wong

19 January 2023



  • This study aims to evaluate the short- and long-term associations between COVID-19 and development of cardiovascular disease (CVD) outcomes and mortality in the general population.

Methods and Results

  • A prospective cohort of patients with COVID-19 infection between 16 March 2020 and 30 November 2020 was identified from UK Biobank, and followed for up to 18 months, until 31 August 2021. 
  • Based on age (within 5 years) and sex, each case was randomly matched with up to 10 participants without COVID-19 infection from two cohorts — a contemporary cohort between 16 March 2020 and 30 November 2020 and a historical cohort between 16 March 2018 and 30 November 2018. 
  • The characteristics between groups were further adjusted with propensity score-based marginal mean weighting through stratification. To determine the association of COVID-19 with CVD and mortality within 21 days of diagnosis (acute phase) and after this period (post-acute phase), Cox regression was employed. 
  • In the acute phase, patients with COVID-19 (n = 7584) were associated with a significantly higher short-term risk of CVD {hazard ratio (HR): 4.3 [95% confidence interval (CI): 2.6– 6.9]; HR: 5.0 (95% CI: 3.0–8.1)} and all-cause mortality [HR: 81.1 (95% CI: 58.5–112.4); HR: 67.5 (95% CI: 49.9–91.1)] than the contemporary (n = 75 790) and historical controls (n = 75 774), respectively. 
  • Regarding the post-acute phase, patients with COVID-19 (n = 7139) persisted with a significantly higher risk of CVD in the long-term [HR: 1.4 (95% CI: 1.2–1.8); HR: 1.3 (95% CI: 1.1– 1.6)] and all-cause mortality [HR: 5.0 (95% CI: 4.3–5.8); HR: 4.5 (95% CI: 3.9–5.2) compared to the contemporary (n = 71 296) and historical controls (n = 71 314), respectively.


  • COVID-19 infection, including long-COVID, is associated with increased short- and long-term risks of CVD and mortality.

  • Ongoing monitoring of signs and symptoms of developing these cardiovascular complications post diagnosis and up till at least a year post recovery may benefit infected patients, especially those with severe disease.


1. Introduction

SARS-CoV-2 infection leading to COVID-19 is increasingly associated with cardiovascular dysfunction and complications,1,2 in addition to respiratory and other systemic diseases.3 Prior studies reported the incidence of cardiovascular pathologies such as myocarditis, pericarditis, ischaemic stroke, arrhythmias, and cardiomyopathy in COVID-19 patients, manifesting at different time points during the acute and post-acute phase of infection.1,4 These cardiovascular disease (CVD) symptoms were notably persistent in more than half of the patients (∼57%) recruited for observational studies, complaining of cardiac symptoms many weeks post recovery5 with evidence of cardiac structural and functional abnormalities such as myocardial injury.6,7 This persistence of ongoing COVID-19 signs and symptoms, including CVD-associated symptoms, beyond 4 to 12 weeks after recovery from COVID-19 has been internationally recognized as ‘long-COVID’8,9 or post-acute sequelae SARS-CoV-2 infection. The exact pathophysiology of long-COVID is not yet understood, however, the possibility of COVID-19 in accelerating the risk for cardiovascular complications over time has been proposed from preliminary clinical data, warranting more conclusive evidence.10 Interestingly, clinical reports found that severe cardiac complications were evident even in healthy individuals such as high-performance athletes,6,11,12 and in those exhibiting asymptomatic/mild COVID-19 symptoms13–15 after infection, highlighting the need to evaluate the overall long-COVID-associated cardiovascular risks in the general population through comparison of infected vs. uninfected individuals.

Prior studies have analysed the relationship between CVD and COVID-19 in infected/recovered patients by examining the cardiovascular effects of COVID-19 largely based on the prevalence of CVD-associated clinical characteristics and symptoms, particularly cardiac injury (identified from elevated cardiac-troponin levels).16,17 Limited evidence on the development of short- and long-term cardiovascular outcomes and their incident risks in patients during infection and post recovery through follow-up studies is available.1,17 The scope of such evidence is further limited by short follow-up durations averaging at 3 months,18,19 small sample sizes, and/or being exclusively restricted to hospitalized patients with severe COVID-19 infection20 or to those with pre-existing myocardial complications due to underlying CVD.21–23 Only one large-scale study has extended the analysis to report the 1 year risks and burdens of cardiovascular outcomes in infected vs. uninfected COVID-19 patients.1 However, the generalizability of the findings was compromised owing to the recruitment of participants from the male-dominant US Department of Veterans Affairs database. Further, their analysis was focused on evaluating only the long-term cardiovascular outcomes of COVID-19.

Hence, this study aims to add to the currently limited body of long-term evidence on cardiac presentation in COVID-19, especially long-COVID, and confirm the findings of previous studies through a longitudinal, retrospective study design with a long follow-up period of 18 months. Moreover, the progressive manifestation of cardiovascular outcomes is captured by identifying CVD and mortality short- and long-term risks in both, male and female patients, at the acute and beyond the acute (post-acute) phase of infection, respectively.

2.Methods 3.Results & Other Sections

See the original publication (this is an excertp version only)


4. Discussion

From previous studies and clinical reports, commonly occurring cardiovascular complications in COVID-19 patients include myocardial injury (21% of patients), arrhythmia (10.4% of patients), and heart failure (2.8% of patients) in acute settings; also observed and confirmed by this study.41–44 Over time, these symptoms may persist and develop into a variety of CVD sequelae in the long-term, and a comprehensive list of such probable cardiovascular events or outcomes was identified and analysed. The findings from this study identify a significant increase in incident risks associated with several cardiovascular complications in patients with COVID-19 (cases) than those without COVID-19 (undiagnosed controls), potentially contributing to the substantially higher risks of CVD mortality and all-cause mortality — found to be associated with infected patients in both phases of infection. Particularly, patients in the acute phase of infection were associated with ∼4 times higher risk of developing major CVD (composite of stroke, CHD, and heart failure) and at ∼81 times higher risk of all-cause mortality than controls; while in the post-acute phase, infected patients were associated with a ∼50% increase in the risk of major CVD in addition to 5 times the risk of all-cause mortality than uninfected controls, highlighting the long-term cardiovascular sequelae of COVID-19. Further, consistent with previous studies, patients identified with severe COVID-19 were associated with higher risks of CVD and mortality than those with non-severe disease, although those with non-severe disease also exhibited increased risk associated with these outcomes over uninfected controls. In addition, risks of cardiovascular outcomes were evident in both male and female patients. In the short-term (acute phase), male patients were generally associated with a relatively higher risk of developing most cardiovascular complications and facing mortality than female patients (consistent with the previous study45); while in the long-term during the post-acute phase, both genders demonstrated a roughly similar likelihood of developing outcomes, including major CVD and mortality. Altogether, these findings suggest that continuous monitoring for signs and symptoms of CVD and related cardiovascular complications in COVID-19 patients post infection and up till at least a year post recovery, especially in those with severe disease, may be beneficial in potentially reducing COVID-19-associated cardiovascular morbidity and mortality in the short- and long-term.

Strengthened by being consistent with previous studies, this study adds evidence in support of increased short-term risks along with long-term risks of cardiovascular complications spanning several disorders in infected patients, up till at least 12 months post survival and recovery from the acute phase of COVID-19.46 It concurs with findings of the only previous large-scale longitudinal study conducted in the US1 based on patient records from the US Veteran Health Administration (VHA) database, reporting a 50% increase in overall risk of developing any cardiovascular complication than uninfected controls [HR: 1.63 (95% CI: 1.59–1.68)] during the post-acute phase, specifically demonstrating increased relative risk (in HR) for cerebrovascular outcomes [HR: 1.53 (95% CI: 1.45–1.61)], dysrhythmias [HR: 1.69 (95% CI: 1.64–1.75)], inflammatory diseases of the heart and pericardium [HR: 2.02 (95% CI: 1.77–2.30)], ischaemic heart diseases [HR: 1.66 (95% CI: 1.52–1.8)], thromboembolic disorders [HR: 2.39 (95% CI: 2.27–2.51)] and other cardiovascular disorders including heart failure, cardiac arrest, and cardiogenic shock [HR: 1.72 (95% CI: 1.65–1.79)]. These calculated risks may differ numerically for the same outcomes as in this study, since their analysis majorly represents the demographic of male-dominant US veterans, while this study captures these risks in the (UK Biobank) UKB, comprising both male and female participants, aiming to present findings with higher generalizability. However, both studies agree on evidence in support of the increased likelihood of COVID-19 patients in developing a variety of CVD outcomes over time. Results from a UK-based short follow-up study up to 4 months also concur with these findings. Building a cohort of 47 780 hospitalized COVID-19 patients (mean age 65 years, 55% men), they report a three-fold increase in risk over uninfected controls for major adverse cardiovascular events up to 4 months from diagnosis with COVID-19.19

On the contrary, another short follow-up (60 days) retrospective study comparing CVD events (ischaemic/haemorrhagic stroke, heart failure, and early MI) and new-onset heart disease in 77 364 COVID-19-positive testing vs. COVID-19-negative testing women veterans using clinical data from the US VHA database reported infected patients to be at a lower risk of experiencing cardiovascular events and developing new-onset CVD within 60 days, although at a 4 times higher risk of mortality, than the uninfected controls.18 The authors of the study acknowledged that the risks in the women veteran population, similar to the male veteran population, do not accurately capture the risks for the general population due to demographical differences including median age, prevailing comorbidities, access to healthcare, etc. Further, the discrepancy between these findings from the current study and the previous longitudinal studies implies that CVD outcomes are indeed more likely to develop and manifest over a long period of time after the acute phase of infection, highlighting the advantage of long-term follow-up studies in assessing the true risk of CVD and associated mortality. Thus, infected patients should undergo continuous follow-up monitoring up till at least a year post recovery for detection of any long-term cardiovascular complications and CVD outcomes, to ensure that these complications do not go undiagnosed and untreated due to premature assessment when their manifestation is not apparent.

No conclusive mechanism can currently explain the pathophysiology of long-COVID resulting in cardiovascular sequelae. Probable mechanisms include direct effects mediated via direct interaction of SARS-CoV-2 with the angiotensin-converting enzyme 2 (ACE2) receptor, given that this receptor is highly expressed in the heart (more so than the lungs) and its blood vessels such as the coronary arteries.47 The virus may be directly infecting the myocardium and other cardiovascular cell types, supported by the histological finding of a marked increase in macrophage infiltration in infected patients with myocardial damage.48 Further, consumption of ACE2 for SARS-CoV-2 cellular entry causing increased angiotensin II level is believed to induce vasoconstriction, reducing blood flow and promoting coagulation, leading to AF and consequent thromboembolic events.49 However, incident myocarditis is uncommon in the acute phase of COVID-19,50 as is evident in this study, increasing the likelihood that the cardiovascular outcomes result from the indirect effects of uncontrollable SARS-CoV-2 replication, triggering a cytokine storm including interleukin-6 and tumour necrosis factor-α, causing systemic inflammation.51,52 This results in organ damage, including myocardial injury, known to be independently associated with an increased risk of mortality.53 Inflammation also exacerbates any pre-existing CVDs and/or activates them in those with a dormant risk for CVD outcomes, demonstrated in a mouse model.54 Moreover, a bidirectional relationship associating long-COVID with increased risk for cardiovascular complications has also been proposed,10 based on clinical reports demonstrating a higher prevalence of underlying cardiovascular comorbidities in patients suffering an outcome of COVID-19-associated mortality (attributable to an increased expression of ACE2-receptor in failing hearts promoting severe SARS-CoV-2 infection55), along with an increase in the incidence of cardiovascular disorders in infected patients.39 Therefore, increased CVD risks in patients with COVID-19, even post recovery, are an amalgamation of both direct and indirect effects of SARS-CoV-2 infection at different time points, which are further enhanced by the bidirectional relationship between COVID-19 and cardiovascular complications.

Indeed, this study finds a higher incidence and relative risk of cardiovascular outcomes other than major CVD in infected patients over controls, with propositions of direct and indirect mechanisms of SARS-CoV-2 infection underlying their manifestation.56–58 While a ∼7.5-fold increased risk is associated with AF (possibly explaining the ∼10-fold associated risk of stroke and a five-fold risk of heart failure, since AF is independently associated with both59) and a ∼22-fold risk is associated with DVT during the acute phase60; in the post-acute phase the emergence of a ∼five-fold increased risk associated with pericarditis and superficial vein thrombosis, in addition to the persistent (but reduced from acute phase) ∼1.5-fold risk of DVT, is observed. Consistent with this study, previous studies also report higher risks of these outcomes in association with COVID-19. Hospitalized infected patients (age ≥ 18) were at higher odds for the onset of AF over COVID-19-negative patients [odds ratio (OR): 1.19 (95% CI: 1.00–1.1)],61 with AF being proposed as a strong predictor of in-hospital all-cause mortality [HR: 1.405 (95% CI: 1.027–1.992)].62 Patients with COVID-19 were associated with a five-fold increased risk of DVT 30 days post diagnosis (acute phase) and up to 3 months post recovery,63 persisting even after 1 year of recovery [HR: 2.09 (95% CI: 1.94–2.24)], demonstrated in another study.1 Systemic inflammation and consequent endothelial damage are believed to underlie development of pericardial complications, including pericarditis, also demonstrated to be persistent up till at least a year post recovery [HR: 1.85 (95% CI: 1.61–2.13)].

This study has several strengths. By using the vast and rich database of the UK Biobank, a large cohort of patients was built, inclusive of both male and female patients. Rather than analysing the different phases of COVID-19 infection in isolation, the study design involved a long-term follow-up in the same patient cohort, allowed monitoring of the development of an extensive list of pre-specified cardiovascular outcomes over 18 months. The dynamic changes in the incidence and risk of cardiovascular complications and mortality as the disease progressed from the acute to the post-acute phase in patients may give an insight into the underlying mechanisms leading to these outcomes. To ensure the robustness of our results, two control groups were employed to conduct the comparative analysis — a historical and a contemporary cohort — as previous evidence had demonstrated the indirect effect of COVID-19 in deteriorating the health conditions of individuals with non-COVID-19-associated disease due to disruptions in regular healthcare services.28 Thus, a comparison with the historical control cohort ruled out the indirect effect of COVID-19 infection. In addition, a recent study suggested that COVID-19 vaccination may protect against the complications of COVID-19 infection.64 Since vaccination records for the participants were unavailable for this study, this limitation was overcome by restricting the inclusion period to before December 2020, when vaccines were not available in the UK (although these findings should be confirmed in a vaccinated cohort in the future to reinforce the effectiveness of vaccination in reducing these CVD and mortality risks identified in the unvaccinated population). Nevertheless, this study faces some specific limitations. Firstly, being an observational study, only the association between COVID-19 infection and risks for the specific disease outcomes can be established, rather than causality. Secondly, since the mean age of UKB participants tends to be older and is primarily of European ancestry, whether these findings apply across different ethnicities and age groups cannot be determined. Thirdly, some potential confounders, including lifestyle factors, clinical parameters indicative of disease severity (including heart rate, blood pressure, PCR values, leucocyte, oxygen saturation, etc.), and history of medication (such as prior use of anticoagulant or antiplatelet drugs), were unavailable and thereby unaccounted for in this study, although matching by age and sex and weighting by age, sex, ethnicity, baseline BMI, index of multiple deprivation and a comprehensive list of comorbidities (including Charlson Comorbidity Index score, history of cardiovascular complications, hypertension, and diabetes) were used to minimize selection and confounding biases. Further, subgroup analyses were employed to account for confounding by severity of infection or gender differences on the risks of cardiovascular complications. Owing to the limited sample size of severe COVID-19 cases and inconsistency in the definition of severe COVID-19 in the current literature, further analysis in future studies is warranted. Fourthly, since the cases were distinguished from controls based on the latter not having a positive COVID-19 PCR test result and/or not being hospitalized with a COVID-19-related diagnosis admission code, the possibility of asymptomatic, undiagnosed COVID-19 infected individuals being included in the contemporary control group and/or excluded from recruitment into the COVID-19 patient cohort still remains. However, this should only bias the results towards the null; moreover, since the results for the contemporary cohort were comparable with the historical cohort, we perceive that such contamination had minimal effects on the results, ensuring that they remain robust. Lastly, risks of certain complications could not reach statistical significance stemming from the inherent rarity of the outcome and low prevalence in COVID-19 patients, leading to low event rates and high CIs.

Future studies on larger cohorts and across age groups, and ethnicities are warranted to validate these findings. In addition, evaluating whether these risks differ in vaccinated cohorts and/or change(d) with the advent of the second and third wave of the outbreak and beyond, warrants further study.


5. Conclusion

This study demonstrates patients with COVID-19 to be associated with increased risks of CVD and mortality post infection (acute phase). These risks remain increased even up till a year post recovery and are associated with long-COVID. Ongoing monitoring of signs and symptoms of CVD in the short- and long-term may be beneficial in patients post infection and recovery. Further study is warranted to compare the findings in a vaccinated cohort.


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