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Recovered COVID-19 infection is associated with higher risk of myocardial infarction
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The risk of acute myocardial infarction was 93% higher in COVID-19 recovered patients compared to the general population.
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The risk was higher in the early phase after the infection
Abstract
Background
Few studies have analyzed the incidence and the risk of acute myocardial infarction (AMI) during the post-acute phase of COVID-19 infection.
Objective
To assess the incidence and risk of AMI in COVID-19 survivors after SARS-CoV-2 infection by a systematic review and meta-analysis of the available data.
Methods
Data were obtained searching MEDLINE and Scopus for all studies published at any time up to September 1, 2022 and reporting the risk of incident AMI in patients recovered from COVID-19 infection. AMI risk was evaluated using the Mantel–Haenszel random effects models with Hazard ratio (HR) as the effect measure with 95% confidence interval (CI) while heterogeneity was assessed using Higgins and Thomson I2 statistic.
Results
Among 2765 articles obtained by our search strategy, four studies fulfilled the inclusion criteria for a total of 20,875,843 patients (mean age 56.1 years, 59.1% males). Of them, 1,244,604 had COVID-19 infection. Over a mean follow-up of 8.5 months, among COVID-19 recovered patients AMI occurred in 3.5 cases per 1.000 individuals compared to 2.02 cases per 1.000 individuals in the control cohort, defined as those who did not experience COVID-19 infection in the same period). COVID-19 patients showed an increased risk of incident AMI (HR: 1.93, 95% CI: 1.65–2.26, p < 0.0001, I2 = 83.5%). Meta-regression analysis demonstrated that the risk of AMI was directly associated with age (p = 0.01) and male gender (p = 0.001), while an indirect relationship was observed when the length of follow-up was utilized as moderator (p < 0.001).
Conclusion
COVID-19 recovered patients had an increased risk of AMI.
Previous investigations have already reported that viral infections may represent a potential cause of AMI, especially when the respiratory tract is involved [
]. However, recent studies examining the relationship between AMI and SARS-CoV-2 infection have mainly focused on the potential pathophysiological mechanisms underlying this relationship [
]. Conversely, data regarding the risk of AMI as a post-acute COVID-19 sequelae remain scant. Aim of the present manuscript is to assess the risk of incident AMI in COVID-19 recovered patients by performing a systematic review and meta-analysis of the available data.
2. Material and methods
2.1 Study design
This study followed the Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) reporting guideline (Supplementary file 1) [
]. Data were obtained searching MEDLINE and Scopus for all studies published at any time up to September 1, 2022 and reporting the risk of incident AMI in COVID-19 recovered patients diagnosed between 4 months (minimum follow-up length of revised investigations) and a maximum of 12 months post discharge (maximum follow-up length of revised studies) after the infection. In the revised manuscripts, this group of patients were compared to contemporary cohorts, defined as subjects who did not experience the SARS-CoV-2 infection and developed an AMI in the same follow-up period.
2.2 Data extraction and quality assessment
The selection of studies included in our analysis was independently conducted by two authors (M.Z., C.B.) in a blinded fashion. Any discrepancies in study selection were resolved by consulting a third author (G.R.). The following MeSH terms were used for the search: “Acute myocardial infarction” AND “COVID-19 sequelae” OR “Acute myocardial infarction” AND “COVID-19”. Moreover, we searched the bibliographies of the target studies for additional references. Specifically, inclusion criteria were: (i) studies enrolling subjects with previous confirmed COVID-19 infection (ii) providing the hazard ratio (HR) and relative 95% confidence interval (CI) for the risk of incident AMI after the infection compared to contemporary control cohorts. Conversely, case reports, review articles, abstracts, editorials/letters, and case series with <10 participants were excluded. Data extraction was independently conducted by two authors (M.Z., G.R). For all the reviewed investigations we extracted, when provided, the number of enrolled patients, the mean age, the gender, the prevalence of cardiovascular comorbidities such as arterial hypertension (HT), diabetes mellitus (DM), chronic obstructive pulmonary disease (COPD), chronic kidney disease (CKD), obesity, pre-existing heart failure (HF), cerebrovascular disease and the length of follow-up. The quality of included studies was graded using the Newcastle-Ottawa quality assessment scale (NOS) [
Continuous variables were expressed as mean while categorical variables were presented as numbers and relative percentages. The cumulative incidence of incident AMI (n/N), defined as the ratio between patients experiencing the event during the follow-up period (n) and the number of patients enrolled in each study (N), were pooled using a random effects model and presented with the corresponding 95% confidence interval (CI). Conversely for the estimation of AMI risk within one year from the infection, the hazard ratio (HR) with the related 95% confidence interval (CI) was pooled using a random- effect. Predefined sensitivity analyses (leave-one-out analysis) were performed removing one study at the time, to evaluate the stability of our results. Statistical heterogeneity between groups was measured using the Higgins I2 statistic. The presence of potential publication bias was verified by visual inspection of the funnel plot. Due to the low number of the included studies (<10), small-study bias was not examined as our analysis was underpowered to detect such bias. To further appraise the impact of potential baseline confounders, a meta-regression analysis was also performed. All meta-analyses were conducted using Comprehensive Meta-Analysis software, version 3 (Biostat, USA).
3. Results
3.1 Search results and included studies
A total of 2765 articles were obtained using our search strategy. After excluding duplicates and preliminary screening, 621 full-text articles were assessed for eligibility, 617 studies were excluded for not meeting the inclusion criteria, leaving 4 investigations fulfilling the inclusion criteria (Fig. 1) [
Risk of persistent and new clinical sequelae among adults aged 65 years and older during the post-acute phase of SARS-CoV-2 infection: retrospective cohort study.
Long-term cardiovascular outcomes in COVID-19 survivors among non-vaccinated population: a retrospective cohort study from the TriNetX US collaborative networks.
Fig. 1PRISMA flowchart. * Articles excluded because not provided data on acute myocardial infarction events; ** Articles excluded because not provided Hazard ratio for acute myocardial infarction.
Risk of persistent and new clinical sequelae among adults aged 65 years and older during the post-acute phase of SARS-CoV-2 infection: retrospective cohort study.
Long-term cardiovascular outcomes in COVID-19 survivors among non-vaccinated population: a retrospective cohort study from the TriNetX US collaborative networks.
].). Among them 1,245,157 had confirmed COVID-19 infection. The general characteristics of the included studies are showed in Table 1. Although the demographic characteristics and the concomitant comorbidities were not systematically recorded in all the investigations, the cohorts mainly consisted of middle-aged patients. The mean length of follow-up was 8.5 months ranging between 4 and 12 months. The reviewed investigations identified the occurrence of AMI by screening the medical records of enrolled patients using the International Classification of Diseases 10th Revision (ICD-10) codes I21 and I22 [
Risk of persistent and new clinical sequelae among adults aged 65 years and older during the post-acute phase of SARS-CoV-2 infection: retrospective cohort study.
Long-term cardiovascular outcomes in COVID-19 survivors among non-vaccinated population: a retrospective cohort study from the TriNetX US collaborative networks.
Risk of persistent and new clinical sequelae among adults aged 65 years and older during the post-acute phase of SARS-CoV-2 infection: retrospective cohort study.
Long-term cardiovascular outcomes in COVID-19 survivors among non-vaccinated population: a retrospective cohort study from the TriNetX US collaborative networks.
Risk of persistent and new clinical sequelae among adults aged 65 years and older during the post-acute phase of SARS-CoV-2 infection: retrospective cohort study.
Long-term cardiovascular outcomes in COVID-19 survivors among non-vaccinated population: a retrospective cohort study from the TriNetX US collaborative networks.
]. A random effect model revealed a pooled incidence of post COVID-19 AMI in 0.5% of cases (95% CI:0.3–0.0.8, I2: 99.8%) (Fig. 2, Panel A). Sensitivity analysis showed a combined incidence rate, which remained statistically significant, across a range from 0.3% of cases (95% CI:0.1–0.5, I2:99.8%) to 0.7% of cases (95% CI: 0.2 to 1.2; I2:99.3%), suggesting that no single investigation had an undue impact on the study outcome. The visual inspection of the funnel plot is presented in Supplementary file 2, Panel A); however, the visual assessment of the funnel plot cannot reassure about the presence of an asymmetry due to the limited number of studies included into the analysis. Conversely, always a random-effect model showed a pooled incidence of AMI among contemporary controls in 0.2 of cases (95% CI: 0.18–0.23, I2: 99.7%) (Supplementary file 3, Panels A and B for the forest and the funnel plots, respectively). Also in this case, sensitivity analysis confirmed yielded results.
Fig. 2(A) Forest plots investigating the pooled incidence of acute myocardial infarction after 8.5 months from COVID-19 infection. (B) Forest plots investigating the risk of acute myocardial infarction after 8.5 months from COVID-19 infection.
After a mean follow-up of 8.5 months, recovered COVID-19 patients presented a higher risk of incident AMI (HR: 1.93, 95% CI: 1.65—2.26, p < 0.0001, I2 = 83.5%) (Fig. 2, Panel B). Also in this case, the visual assessment of the funnel plot cannot reassure about the presence of an asymmetry due to the limited number of studies included into the analysis accordingly to the inclusion criteria (Supplementary file 4) while the sensitivity analysis confirmed the yielded results reporting an HR ranging between 1.88 (95% CI: 1.60–2.21, p < 0.0001) and 2.00 (95% CI; 1.87–2.13, p < 0.0001), implying that the obtained results were not driven by any single study. A meta-regression analysis showed a significant direct relationship between the risk of incident AMI and age (p = 0.01) and male gender as moderators, while an indirect association was observed when the follow-up length (p < 0.001) was adopted as moderating variables (Table 2).
Table 2Meta regression analysis for the risk of acute myocardial infarction after COVID-19 infection. CI: Confidence interval.
Our findings, based on a large population of >20 million subjects, demonstrated that AMI occurred in about 0.5% of COVID-19 recovered patients over the follow-up period. Furthermore, after COVID-19 recovery, survivors had an approximately 93% excess in the risk of AMI, which was inversely related with the length of the follow-up. Notably, the incidence and the risk of AMI in COVID-19 recovered patients resulted higher compared to controls over a mean follow-up of 8.5 months. Conversely, the risk of AMI after hospital discharge was lower compared to that observed after other inflammatory conditions of the respiratory tract, such as pneumonia [
Risk of acute respiratory infection and acute cardiovascular events following acute respiratory infection among adults with increased cardiovascular risk in England between 2008 and 2018: a retrospective, population-based cohort study.
]. However, we cannot exclude that missed AMI events may have contributed to the high risk observed in our analysis, being the AMI cases identified by the revision of ICD codes in the population analyzed. Furthermore, this uncertainty is reflected by the observed high statistical heterogeneity. Meta-regression analysis contributed to define this high heterogeneity showing that the risk of AMI events directly increased with aging, as previously reported in subjects from the general population, as well as in men. However, it is also true that the comparison of rates between gender strictly depends by the age range of the population under study. Furthermore, when the death rate is high from causes other than the disease of interest, the incidence rates of the illness are generally overestimated in traditional Kaplan–Meier survival analysis due to existence of competing risks. Moreover, our results evidenced that the AMI risk was is not just limited to the acute phase of COVID-19 but also during the early phase after recovery. Unfortunately, the revised studies did not systematically report data regarding potential risk factors for AMI, as well as their clinical presentation and type (i.e., with ST-segment elevation or not). Moreover, no data were provided regarding the AMI-related mortality rate either in recovered COVID-19 subjects as well as for controls. The observed AMI incidence in COVID-19 recovered patients was about 3.5 AMI cases per 1000 people. However, making a real comparison with the current epidemiological records derived from the general population is difficult because those data are generally based on 1000 persons per year while our results cannot be referred to the same period. However, a previous investigation reporting the incidence of recognized and unrecognized AMI in subjects aged >55 years, demonstrated that during a mean follow-up of 6.4 years, the incidence rate of this event was 5.0 per 1000 person years. This result appears higher compared to that observed in our cohort of COVID-19 recovered patients which perhaps had similar demographical features [
]. Nevertheless, it should be noted that the study by Torbal et al. was based on a longer follow-up period and performed into the 1990s, when several cardioprotective agents were different and differently influenced the cardiovascular protection [
]. Probably, we have underestimated the incidence of AMI both in COVID-19 recovered patients as well as in the control groups. Indeed, previous investigations have widely reported a lower incidence of acute coronary syndromes during the COVID-19 pandemic; moreover, we cannot exclude that some AMIs have been underdiagnosed or misinterpreted as cardiovascular injuries related to the acute infection [
Società Italiana di Cardiologia and the CCU academy investigators group. Reduction of hospitalizations for myocardial infarction in Italy in the COVID-19 era.
]. To this regard, it has been described that the risk of AMI returns to baseline within few months after resolution of the infection and the risk of acute events seems to be more pronounced among patients with a more severe disease [
Società Italiana di Cardiologia and the CCU academy investigators group. Reduction of hospitalizations for myocardial infarction in Italy in the COVID-19 era.
]. Unfortunately, data on the severity of the SARS-CoV-2 infection were not systematically collected by the reviewed studies, making impossible a specific sub-analysis. From a pathophysiological point of view, it has been reported that COVID-19 patients may exhibit prolonged SARS-CoV-2 Ribonucleic Acid (RNA) shedding for up to 83 days in the upper respiratory tract, associated with high viral RNA loads [
]. Furthermore, in infected as well as in recovered patients, a persistent hypercoagulable state may further increase the risk of coronary thrombosis at the sites of plaque disruption [
]. Doubtless, other concomitant factors may contribute to coronary thrombosis, such as the production of neutrophil extracellular traps (NETs) from intraplaque and circulating neutrophils, increased platelet activity, impaired fibrinolysis and overall decreased anticoagulant function of the endothelium [
]. Although further dedicated studies are needed to exactly determine the incidence of AMI after COVID-19 infection, our data may be useful for minimizing the risk of AMI after in COVID-19 survivors, although our results must be considered preliminary and cannot be directly translated into clinical practice as recommendations regarding the type and regimen of antiplatelet therapies or thrombophylactic strategies.
4.1 Limitations
Our study has several limitations related to the observational nature of the reviewed studies with all their inherited biases. Potential underestimation of the AMI incidence could derive from the absence of a specific and dedicated follow-up; indeed, the larger part of the articles reviewed identified the occurrence of incident AMIs from larger medical records dataset using the relative ICD-10 codes and it is known that this methodological approach has modest sensitivity to diagnose AMI in the general population [
]. Furthermore, few studies have analyzed the risk of AMI in patients recovered from COVID-19 infection, limiting the number of the observations included in the meta-analysis; however, the number of patients enrolled mitigates, at least partially, this limit. We cannot exclude that sampling bias by the competing risk of death may also have led to the underestimation of the real cumulative incidence of AMIs. Similarly, no data regarding the type and number of vaccinations against SARS-CoV-2 as well as the patients experiencing AMI during the acute phase of the infection were systematically reported, making impossible any type of sub-analysis. At the same manner, the absence of information regarding the different COVID-19 variants has further limited our conclusions. Finally, the reviewed data may have underestimated the real impact of AMI after COVID-19 especially during the early phase of the pandemic, both due to the presence of undiagnosed cases and patients lost during the follow-up period. Despite these limitations, to the best of our knowledge, this study is the first systematic review and meta-analysis providing a clear estimation on the incidence and the risk of AMI in patients who recovered from COVID-19.
5. Conclusions
AMI represents a relatively rare but potential post-acute COVID-19 sequelae in the long-term period that might benefit from aggressive prevention strategies and appropriate follow-up of COVID-19 patients.
Data availability statement
The data that support the findings of this study are available from the reviewed studies.
Author statement
Marco Zuin: Conceptualization, Data Curation, Methodology, Writing- Original draft, Formal analysis; Statistical analysis. Gianluca Rigatelli: Investigation, Data curation, Writing- Original draft preparation. Valentina Battisti: Investigation, data collection. Giulia Costola: Investigation, data collection. Loris Roncon: Reviewing and Editing. Claudio Bilato: Validation, Supervision, Reviewing and Editing.
Declaration of Competing Interest
None of the authors have conflicts of interest to declare.
Supplementary file 3: Forest (A) and funnel (B) plots for the incidence of acute myocardial infarction over 8.5 months in control patients, defined as those experience the cardiovascular events without a previous COVID-19 infection, in the same period.
Risk of persistent and new clinical sequelae among adults aged 65 years and older during the post-acute phase of SARS-CoV-2 infection: retrospective cohort study.
Long-term cardiovascular outcomes in COVID-19 survivors among non-vaccinated population: a retrospective cohort study from the TriNetX US collaborative networks.
Risk of acute respiratory infection and acute cardiovascular events following acute respiratory infection among adults with increased cardiovascular risk in England between 2008 and 2018: a retrospective, population-based cohort study.
Società Italiana di Cardiologia and the CCU academy investigators group. Reduction of hospitalizations for myocardial infarction in Italy in the COVID-19 era.
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