key: cord-0988841-mhi85px5
authors: Siddiqi, Hasan K.; Weber, Brittany; Zhou, Guohai; Regan, James; Fajnzylber, Jesse; Coxen, Kendyll; Corry, Heather; Yu, Xu G.; DiCarli, Marcelo; Li, Jonathan Z.; Bhatt, Deepak L.
title: Increased prevalence of myocardial injury in patients with SARS-CoV-2 viremia.
date: 2020-11-10
journal: Am J Med
DOI: 10.1016/j.amjmed.2020.09.046
sha: 1f2d416412a801b44f92c64ad2bcb381104e78be
doc_id: 988841
cord_uid: mhi85px5

BACKGROUND: Patients with COVID-19 have a high prevalence of detectable troponin and myocardial injury. In addition, a subset of COVID-19 patients have detectable SARS-CoV-2 viral loads. The objective of this study is to understand the relationship between SARS-CoV-2 viremia, detectable troponin, and myocardial injury in hospitalized COVID-19 patients. METHODS: SARS-CoV-2 plasma viral load was measured in plasma samples drawn from patients hospitalized for COVID-19 at two academic medical centers. Baseline characteristics and clinically obtained high-sensitivity cardiac troponin T (hs-cTnT) values were abstracted from the medical record. The main outcome was detectable hs-cTnT (≥6ng/mL) and myocardial injury (hs-cTnT ≥14ng/mL; >99th percentile for assay). RESULTS: 70 hospitalized COVID-19 patients were included in this study, with 39% females and median age 58 +/- 17 years. 21 patients (30%) were found to have detectable SARS-CoV-2 viral load and were classified in the viremia group. Patients with viremia were significantly older than those without viremia. 100% of viremic patients had detectable troponin during hospitalization, compared to 59% of non-viremic patients (p=0.0003). Myocardial injury was seen in 76% of viremic patients and 38% of non-viremic patients (p=0.004). CONCLUSIONS: Hospitalized COVID-19 patients with SARS-CoV-2 viremia have a significantly higher prevalence of detectable troponin and myocardial injury during their hospitalization, compared to non-viremic patients. This first report of the relationship between SARS-CoV-2 viremia, detectable troponin and myocardial injury in COVID-19 patients points to additional mechanistic pathways that require deeper study to understand the complex interplay between these unique findings, cardiovascular outcomes and mortality in COVID-19.

Background: Patients with COVID-19 have a high prevalence of detectable troponin and myocardial injury. In addition, a subset of COVID-19 patients have detectable SARS-CoV-2 viral loads. The objective of this study is to understand the relationship between SARS-CoV-2 viremia, detectable troponin, and myocardial injury in hospitalized COVID-19 patients.

Methods: SARS-CoV-2 plasma viral load was measured in plasma samples drawn from patients hospitalized for COVID-19 at two academic medical centers. Baseline characteristics and clinically obtained high-sensitivity cardiac troponin T (hs-cTnT) values were abstracted from the medical record. The main outcome was detectable hs-cTnT (≥6ng/mL) and myocardial injury (hs-cTnT ≥14ng/mL; >99th percentile for assay).

Results: 70 hospitalized COVID-19 patients were included in this study, with 39% females and median age 58 +/-17 years. 21 patients (30%) were found to have detectable SARS-CoV-2 viral load and were classified in the viremia group. Patients with viremia were significantly older than those without viremia. 100% of viremic patients had detectable troponin during hospitalization, compared to 59% of non-viremic patients (p=0.0003). Myocardial injury was seen in 76% of viremic patients and 38% of non-viremic patients (p=0.004).

Conclusions: Hospitalized COVID-19 patients with SARS-CoV-2 viremia have a significantly higher prevalence of detectable troponin and myocardial injury during their hospitalization, compared to non-viremic patients. This first report of the relationship between SARS-CoV-2 viremia, detectable troponin and myocardial injury in COVID-19 patients points to additional mechanistic pathways that require deeper study to understand the complex interplay between these unique findings, cardiovascular outcomes and mortality in COVID-19.

 Association of SARS-CoV-2 viremia and myocardial injury is currently unknown.

 Out of 70 COVID-19 positive hospitalized adults, 30% had SARS-CoV-2 viremia.

 SARS-CoV-2 viremia was associated with a greater rate of detectable troponin.

 SARS-CoV-2 viremia was associated with a greater rate of myocardial injury.

Background Myocardial injury is a common feature in patients with Coronavirus Disease 2019 (COVID-19) caused by Severe Acute Respiratory Syndrome-CoronaVirus-2 (SARS-CoV-2), a finding reported in at least 20% of hospitalized COVID-19 patients and associated with increased morbidity and mortality. [1] [2] [3] Beyond myocardial injury, detectable troponin is reported in COVID-19 patients and correlated with abnormal cardiac magnetic resonance imaging findings in convalescent patients. 4 Early data indicate that the presence of detectable troponin is associated with worse outcomes in COVID-19 patients, and the highest elevations correlate with the poorest outcomes. 5 Mechanisms of myocardial injury and detectable troponin in patients with COVID-19 are currently unknown, with proposed hypotheses invoking several possibilities including direct viral myocardial injury and immune-mediated cardiac injury. 1, 6, 7 In the SARS pandemic caused by the related SARS-CoV-1, worse clinical outcomes including respiratory failure and death were associated with serum viremia. 8 The detection of plasma viral SARS-CoV-2 RNA has been described in limited reports and may be associated with worse in-hospital mortality in COVID-19 patients. [9] [10] [11] However, the relationship between SARS-CoV-2 viremia and cardiovascular injury is currently unknown. We hypothesized that there would be a higher prevalence of detectable troponin and myocardial injury in hospitalized COVID-19 patients with SARS-CoV-2 viremia compared to those without viremia.

We consented and enrolled 70 hospitalized patients with COVID-19 in a prospective cohort study with appropriate institutional review board approval. Baseline characteristics and clinically obtained high-sensitivity cardiac troponin-T (hs-cTnT) values during hospitalization were extracted from the medical record. SARS-CoV-2 viral load was measured from patient samples collected during the hospitalization using methods described below. SARS-CoV-2 viral loads below 40 RNA copies/mL were categorized as undetectable. Patients with detectable plasma SARS-CoV-2 RNA were classified in the viremic group and all others classified as nonviremic. Detectable troponin was defined as hs-cTnT concentration at or above the lowest level of detection (≥6 ng/ml) at any time point during admission. Myocardial injury was defined as a peak hs-cTnT concentration >99 th percentile of assay (≥14 ng/ml) during hospitalization.

SARS-CoV-2 viral load was quantified using the US CDC 2019-nCoV_N1 primers and probe set. 12 Each reaction contained extracted RNA, 1X TaqPath™ 1-Step RT-qPCR Master Mix, CG (ThermoFisher), CDC N1 forward and reverse primers, and probe 12 . Viral copy numbers were quantified using N1 qPCR standards in 16-fold dilutions to generate a standard curve. The assay was run in triplicate for each sample and two non-template control wells (negative controls). Importin-8 (IPO8) housekeeping gene RNA level was quantified to determine quality of respiratory sample collection. An internal virion control (RCAS) was spiked into each sample and quantified to determine RNA extraction and qPCR amplification efficiency. 13 Statistical analysis:

Fisher's exact and X 2 tests were used as appropriate for statistical comparisons. A two-sided p<0.05 was considered statistically significant.

Amongst 70 hospitalized COVID-19 patients, 21 patients (30%) had detectable SARS-CoV-2 viremia. In those with viremia, median viral load was 2.4 log 10 RNA copies/mL (range 1.8 -3.8 log 10 RNA copies/mL). Baseline characteristics of the cohort are presented in Table 1 .

Viremic patients were significantly older (67 +/-13 years vs. 54 +/-17 years, p=0.001), with a trend towards fewer females with viremia compared to those without viremia (24% vs. 45%, p=0.1). There were no significant differences in race or BMI between groups. Compared to nonviremic patients, those with viremia had a trend towards more baseline cardiovascular co- Next, we investigated the relationship between SARS-CoV-2 viremia, detectable troponin, and myocardial injury (Figure 1 ). During hospitalization, detectable troponin was measured in all patients with viremia (21/21, 100%) and in 59% (29/49) of those without viremia (p=0.0003, Figure 1A ). Myocardial injury was present in 16/21 (76%) patients with viremia and 18/49 (38%) patients without viremia (p=0.004, Figure 1B ).

Our study is the first to examine the relationship between SARS-CoV-2 viremia and cardiovascular injury. We report a uniquely high rate of troponin positivity and myocardial injury amongst hospitalized individuals with detectable SARS-CoV-2 viremia, in contrast to patients without detectable viremia. Patients with viremia were older, more likely to be male, and tended to have more baseline cardiovascular comorbidities than those without viremia. These findings suggest that the most vulnerable hospitalized COVID-19 patients are more likely to have SARS-CoV-2 viremia and have a greater degree of ensuing myocardial injury.

This study must be assessed in the context of its limitations. The major limitation is the small cohort size and therefore a limited ability to control for co-variates and possible confounders. As a result, the exact relationship between patient age, sex, pre-existing cardiovascular disease, SARS-CoV-2 viremia, and myocardial injury could not be completely assessed in the current study. Therefore, while these findings point towards a strong association between SARS-CoV-2 viremia and myocardial injury in hospitalized COVID-19 patients, they do not provide insight into the possible mediators and mechanism of this relationship.

Despite these limitations, to our knowledge, this study is the first to demonstrate a high prevalence of cardiovascular injury in the setting of SARS-CoV-2 viremia. Cardiovascular injury in COVID-19 patients is associated with significantly worse outcomes including death, making it a key priority to understand the mechanism of this relationship. 3, 5 Plasma viremia, with its associated systemic and immunologic disturbances, could be a mediator of this relationship. 

COVID-19 for the Cardiologist

Acute myocardial injury in patients hospitalized with COVID-19 infection: A review. Progress in Cardiovascular Diseases

Association of Cardiac Injury With Mortality in Hospitalized Patients With COVID-19 in Wuhan, China

Outcomes of Cardiovascular Magnetic Resonance Imaging in Patients Recently Recovered From Coronavirus Disease 2019 (COVID-19)

Prevalence and Impact of Myocardial Injury in Patients Hospitalized With COVID-19 Infection

A current review of COVID-19 for the cardiovascular specialist

Potential Effects of Coronaviruses on the Cardiovascular System: A Review

Viral Loads in Clinical Specimens and SARS Manifestations

Relationship Between serum SARS-CoV-2 nucleic acid(RNAemia) and Organ Damage in COVID-19 Patients: A Cohort Study

Detectable Serum Severe Acute Respiratory Syndrome Coronavirus 2 Viral Load (RNAemia) Is Closely Correlated With Drastically Elevated Interleukin 6 Level in Critically Ill Patients With Coronavirus Disease

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Information for Laboratories about Coronavirus (COVID-19)

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This study was partly funded by the Massachusetts Consortium for Pathogen Readiness through grants from the Evergrande Fund, Mark and Lisa Schwartz.