COVID: cardiac problems very common; interpreting troponins

 I will do a few blogs on potential long-term consequences of Covid-19 infection, the 1^st one on cardiac involvement documented in a German study  (see covid cardiac probs common jamacardiol2020 in dropbox, or doi:10.1001/jamacardio.2020.3557)

 

Details: 

-- a prospective observational cohort study of 100 unselected patients who recovered from Covid-19 (all with positive PCR), identified at the University Hospital in Frankfurt Germany between April and June

-- 53% male, median age 49, BMI 25, systolic blood pressure 129/80, heart rate 67

-- pre-existing symptoms in those developing Covid-19 included hypertension in 22, diabetes 18, hyperlipidemia 22, known CAD 13, smoking 22, COPD or asthma 21

    --No difference in pre-existing symptoms between those who recovered at home or were hospitalized

-- severity of illness: 18 asymptomatic, 49 minor-to-moderate symptoms, 33 severe symptoms (2 underwent mechanical ventilation and 17 noninvasive ventilation with positive airway pressure)

-- 67 Covid-19 patients recovered at home, 33 required hospitalization

-- one patient received antivirals, 15 antibiotics, and 8 steroids

-- all had a negative PCR at the end of their isolation time.

-- cardiac markers and cardiovascular magnetic resonance (CMR) imaging were measured in all recovered patients, along with 50 age- and sex-matched controls, and 57 risk factor-matched patients

-- median time from Covid-19 infection to CMR: 71 days (64-92)

-- at the time of CMR, high-sensitivity troponin T (hs-TNT) levels were also assessed and detectable in 71% (>3 pg/mL), and very high in 5% (>13.9 pg/mL)

-- also, at the time of CMR examination, 17 patients had atypical chest pain and 20 had palpitations

    -- compared with pre-Covid-19 infection, 36% reported ongoing shortness of breath of whom 25 had symptoms during less than ordinary daily activities (only 4 of these 25 patients were previously hospitalized)

 

Results: 

-- 78 patients (78%) had abnormal CMR findings (see interpretation below)

    -- 73 had raised myocardial native T1 and 60 raised myocardial native T2 mappings

    -- 32 had myocardial late gadolinium enhancement, 12 suggestive of having an ischemic-type pattern

    -- 22 had pericardial enhancement

-- 60 patients (60%) had evidence of ongoing myocardial inflammation, independent of pre-existing conditions, severity and overall course of the Covid-19 illness, or time from its original diagnosis

-- compared to healthy controls and risk factor-matched controls, those who had Covid-19 infection had (all with p<0.001):

    -- lower left ventricular ejection fraction: 56% vs 60%

    -- higher left ventricular volumes: 86 vs 80 mL/m²

    -- higher left ventricular mass: 51 vs 47 g/m²

    -- lower right ventricular ejection fraction: 56% vs 60% (this was significant only to the p=0.004 level)

    -- higher native T1 and T2 mappings on CMR

-- there was a small but significant difference between patients who were hospitalized vs those who recovered at home, but only for native T1 mapping

-- none of these measures, including hs-TNT levels, correlated with time from Covid-19 diagnosis; and there was no correlation between the duration of a positive test for SARS-CoV-2 and any of the measures. And these findings were true even in patients 4 months after the infection 

-- there was as significant correlation between hs-TNT and native T2 mapping

-- there was significant increase in NT-proBNP: 69 vs 48 pg/mL

-- 3 patients with severe findings had a myocardial biopsy that revealed active lymphocytic inflammation with no evidence of any viral genome, and native T1 and T2 mappings were the best discriminators to detect Covid 19 related myocardial pathology

 

Commentary:  

-- so, 78% of those who had recovered from Covid-19 infection had continued cardiovascular involvement by CMR months later, and this was irrespective of pre-existing conditions, severity and overall course of the Covid-19 presentation, the time from the original diagnosis, or the presence of cardiac symptoms. And, there was no significant trend toward reduction of abnormalities by imaging or serologic findings during the recovery.

    -- their findings suggest that there is ongoing perimyocarditis months after the acute SARS-CoV-2 infection had resolved

    -- and, there was minimal correlation with the severity of illness: the persistence of longer-term cardiac symptoms was largely in the group who were not hospitalized

-- prior studies have found cardiac involvement from SARS-CoV-2 infection to be relatively common (see http://gmodestmedblogs.blogspot.com/2020/03/covid-cardiac-injury-common.html). This current study significantly extends this finding to suggest longer-term cardiac effects

-- other studies on Covid 19 have suggested that those with pre-existing cardiac conditions may have exacerbations of heart failure, as well as troponin elevations

-- this finding may be extremely important: these cardiac abnormalities, especially well after resolution of the infection, increases the likelihood that there may be permanent myocardial damage, perhaps manifesting itself as dilated cardiomyopathy with its significant potential morbidity and mortality in the future. And, several of their findings have been found in other inflammatory cardiomyopathies and are associated with worse future outcomes

    --the issue here is that with SARS-CoV-2 infection, as with many other viral illnesses, one can be associated with an acute fulminant myocarditis, though this seems to be pretty uncommon with SARS-CoV-2: a Chinese study found that fulminant myocarditis was suspected in 7% of patients with fatal outcomes, 5 of 68 fatal cases: see https://link.springer.com/article/10.1007/s00134-020-05991-x#article-info ; as another example, see http://gmodestmedblogs.blogspot.com/2020/03/covid-myocarditis.html

    --but, it seems that chronic perimyocardial inflammation is much more common, as in above study where there were clinically small changes (though statistically significant) along with apparently ongoing inflammation. will this lead to clinically important dilated cardiomyopathies in the future? if so, when? in 6 months? in 20+ years?? (about 1/2 of cases of people presenting with symptomatic dilated cardiomyopathy do not have a clear etiology. is it from viral or other infections decades before???: not an unreasonable assumption)

-- proposed mechanisms for cardiac injury: inflammatory plaque rupture, stent thrombosis, cardiac stress from high cardiac output, systemic endothelitis, and the increased ACE2 levels in the heart (receptors for SARS-CoV-2)

-- in terms of interpretation of the CMR findings: the late gadolinium enhancement suggests regional damage due to myocardial inflammation, increased native T1 represents diffuse myocardial fibrosis and/or edema, increased native T2 is specific for edema. Hence patients with increased T1 and T2 likely have an active inflammatory processes, those with increased T1 but normal T2 more likely have residual diffuse myocardial damage

 

limitations of the study:

-- only those over 18 were involved, so not generalizable to younger patients

-- they comment that these results do not apply to those who had asymptomatic SARS-CoV-2 infection (though data not supplied, and there were only 18 such patients in the study)

-- these results are very concerning about long-term outcomes, but we will not know these outcomes (and the real concern about these findings) potentially for many years.

 

So,

--it seems that cardiac symptoms are common months after Covid-19 infection resolution, found in 36%. and this seems to be independent of how sick the patients were at the time of infection (most were in those not hospitalized)

--MRI changes suggestive of ongoing inflammation or significant myocardial injury was found in 78% !!!, with many already displaying some cardiac dysfunction. many of these patients may well go on to significant dilated cardiomyopathies sometime later, with their attendant morbidity and mortality

--and all of this reflects the fact that SARS-CoV-2 is a really bad virus. unfortunately, many of us and the general population remember from the early studies that 80% of people had mild cases, and that our fear-some "leader" grossly minimized the significance of the infection and dramatically delayed a response to it (leading to tens of thousands of preventable deaths). this study suggests that even those with mild infections might have prolonged symptoms and perhaps really bad longterm outcomes.... time will tell

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One sideline to this issue is on whom to measure cardiac troponins and what to do with them (this was elaborated in a recent article that came out in pre-print/pre-peer review form: see covid cardiac troponin interp jacc2020 in dropbox, or doi.org/10.1016/j.jacc.2020.06.068)

--the issue here is that troponins are often elevated with covid-19 infections because of myocardial injury, and:

    --increased troponin levels are associated with poorer outcomes and specifically with higher risk for death and arrhythmias, and the risk increases with increasing troponin levels

    --there is increased risk of nonischemic myocardial injury (eg, from myocarditis, as above)

    --there is increased risk of stress cardiomyopathy

    --but there is also increased risk of ischemic cardiac injury: those with covid-related injury tend to have more covid comorbidities, many of which predispose to atherosclerotic MI (hypertension, diabetes, hyperlipidemia); people also tend to be older (a major CAD risk factor); and they are at higher risk of thromboses related to covid-19

--and, given the aggressiveness of this virus, it may be harder to get the necessary imaging studies to differentiate the cause (more patient evaluations increase the risk to health care workers, others), and recommendations to date are to image only if there is "strong clinical information that the results will impact patient management", which will unfortunately miss many people with less impressive presentations who might still have benefitted from interventions

--these authors cannot come to clear conclusions given the lack of real data, but suggest that following serial troponins may be useful:

    -- those with an alternative diagnosis (not an acute MI), such as those with stress cardiomyopathy, myocarditis, or acute heart failure, could just be followed according to the usual guidelines. in these cases the troponin levels are unlikely to increase markedly over time

    -- and, those with overt myocardial ischemia and an acute MI, should get routine care as per TIMI

--but, again, these suggestions are not evidence-based

geoff

 

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