Association between the cardiac abnormalities in COVID-19 patients, and disease severity and mortality

The frequency of cardiac complications, the magnitude of the onset, risk, and mortality are not yet fully known. The objective of the study was to estimate the rate in which COVID-19 patients had heart abnormalities and determine the association between detected abnormalities, their severity, and mortality of the disease.

To characterize heart disease, any form of cardiac abnormality was included in the analysis as found through diagnostic tests, such as echocardiography, cardiac MRI, electrocardiogram, and serum biomarkers, such as troponin. Patients with confirmed COVID-19 disease without the above-mentioned abnormalities in the cardiac tests were used as the control group.

The results accounted in the evaluation were severity, intrahospital mortality, or both. Included in the meta-analysis (analysis that brings together several clinical papers of similar characteristics), were studies published in any language, from December 1st, 2019 to September 30th, 2020. The studies were independently reviewed by two peers who evaluated their quality according to the framework established for this purpose by Dans and collaborators (see Dans, A., Dans, L. & Silvestre, M. Painless Evidence-Based Medicine 2nd ed. Wiley, 2017).

For the final analysis, 24 items were selected. 20 of them were included in the prevalence estimate as a group, and 19 articles were included in the OR (Overall Risk) odds ratios. Among the 24 articles mentioned, there are four case control studies, two cross-sectional studies and 18 cohort follow-up studies.

A total of 20 studies (two cross-sectional studies and 18 cohort studies) were included in the calculation of group prevalence, with a total of 4,393 patients, of whom 1,040 had at least one abnormal result in a cardiac test, resulting in a group prevalence of 0.31 [95% CI (0.23; 0.41)].

By doing a prevalence analysis according to the modality of the study, cohort studies showed a combined prevalence of 0.33 [95% CI (0.23; 0.44)], and cross-sectional ones a combined prevalence of 0.22 [95% CI (0.12; 0.36)].Regarding the association of heart abnormalities with the severity or mortality of the disease, a total of 19 studies (two cross-sectional studies, three case evaluation and controls and 14 cohort follow-up) were included. Their joint analysis showed an OR estimation of 6.87 [95% CI (3.92; 12.05)].

Subgroup analyses based on test type showed:

• For troponin I (TnI), an OR of 12,43 [ 95% CI (2,44; 19,77)] with significant heterogeneity (I2 = 94%, τ2 = 3. 0468, p < 0,01).

• For NT-proBNP, an OR of 12,43 [95% CI (5,69; 27,15)] with minimal heterogeneity (I2 = 1%, τ2 = 0,0035, p = 0,37)
• For 2D echocardiography, an OR of 2. 79 [95% CI (1,12; 6,94)] with significant heterogeneity (I2 = 58%, τ2 = 0,4984, p = 0,07).
• For troponin T (TnT), an OR of 8,06 [95% CI (5,06; 12. 83)] with minimal heterogeneity (I2 = 0%, τ2 = 0, p = 0,70).
• * For creatinine kinase(CK), an OR of 3,64 [95% CI (2,04; 6,50)] with minimal heterogeneity (I2 = 0%, τ2 = 0, p = 0,33).

Heterogeneity between the evaluated studies forestalls a definitive conclusion about the magnitude of the risk, and the severity or mortality associated with the abnormal result in a given test. However, subgroup analyses of certain cardiac biomarkers, such as CK, troponin T, NT-proBNP, as well as troponin I (when we eliminate the case study and controls of Nie et al.),show more reliable odds ratios with disappearance of heterogeneity. All the Forest Plots of these variables show a clear trend towards a definitive increase in the risk of mortality, or severity, among COVID-19 patients exposed to an abnormal finding in any of these tests.

In another meta-analysis of 35 studies, the pooled frequency of acute heart injury among COVID-19 patients was 25.3%, which is within the confidence interval limits of 95% estimated for this study (between23 and 41%). Hypertension was the most common pre-existing comorbidity in these patients, with a grouped frequency of 29.2% (95% CI: 24.7-33.6%), followed by diabetes, with a pooled frequency of 13.5% (95% CI: 11.5-15.4%). Overall, less than one-fifth of patients had pre-existing cardiovascular disease, with 12.6% (C10.0-15.2%). The risk of mortality in the presence of acute cardiac injury increases almost 20 fold [OR x 19.64; (IC 10.28-37.53)].

In this study, a grouped risk ratio (OR) of 6.87 [95% CI (3.92-12.05)] means that COVID-19 patients with an abnormal heart tests, are 6.87 times more likely to die or have severe disease than COVID-19 patients with no abnormal heart tests. At a 5% significance level, the chances of dying range from 4 to 12 times compared to those patients with no abnormalities.

Nie et al., McCullough et al. and Shi et al. are considered atypical studies because they used a case and control study design, a finding in the EKG to define a heart abnormality, and serum myoglobin to define a heart abnormality, respectively.

In terms of severity, persistence of symptoms has been reported even after COVID-19 recovery, which has been linked to heart, lung and neurological complications. In a study of 143 patients who recovered from COVID-19, 87.4% reported persistence of, at least, fatigue or dyspnea. In another study of 100 patients recovered from COVID-19, high-sensitivity troponin T (hsTnt) was detectable (at levels of 3 pg/mL or more) in 71 patients (71%), and was significantly elevated (levels of 13.9 pg/mL or more) in 5 patients (5%). In the same study, 78 patients (78%) had abnormal findings in CMR, and endomyocardial biopsy in patients with severe findings showed active lymphocytic inflammation.

All of this helps to describe an emerging epidemic of "COVID-19-associated cardiomyopathy" that can affect survivors regardless if they suffered mild, moderate, severe, or critical COVID-19 infection.

The findings of this meta-analysis may provide an explanation for those anecdotal reports of sudden deaths outside the hospital. As well as for rising rates of "recovered patients" who end up dying or developing more serious illnesses, and also for deaths morbid conditions among COVID-19 survivors.

Despite significant heterogeneity in most comparisons, there is a significant tendency to increased risk of mortality or severity among COVID-19 patients with any positive heart abnormality test. Due to the high uncertainty in the prevalence, and/or clustered incidence of heart abnormalities. Even though increased risk is certain, the magnitude of risk of severity or mortality among patients with COVID-19 is unquantifiable. Many more long-term studies are needed to clarify the prognosis of the disease, as well as to formalize the definitive criteria for "COVID-19-associated cardiomyopathy".

This study is important evidence that we are possibly underestimating the risk for that subgroup of patients with abnormalities in cardiac function tests. Mainly, in those with abnormalities in the biochemical markers of heart injury that, evidently, constitute about 25 to 30% of cases of COVID-19, especially if they have a history arterial hypertension or diabetes. 

Source: https://www.nature.com/articles/s41598-021-87961-x