Cardiac symptoms are increasingly recognized as late complications of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection in previously well individuals with mild initial illness, but the underlying pathophysiology leading to long-term cardiac symptoms remains unclear. In this study, we conducted serial cardiac assessments in a selected population of individuals with Coronavirus Disease 2019 (COVID-19) with no previous cardiac disease or notable comorbidities by measuring blood biomarkers of heart injury or dysfunction and by performing magnetic resonance imaging. Baseline measurements from 346 individuals with COVID-19 (52% females) were obtained at a median of 109 days (interquartile range (IQR), 77–177 days) after infection, when 73% of participants reported cardiac symptoms, such as exertional dyspnea (62%), palpitations (28%), atypical chest pain (27%) and syncope (3%). Symptomatic individuals had higher heart rates and higher imaging values or contrast agent accumulation, denoting inflammatory cardiac involvement, compared to asymptomatic individuals. Structural heart disease or high levels of biomarkers of cardiac injury or dysfunction were rare in symptomatic individuals. At follow-up (329 days (IQR, 274–383 days) after infection), 57% of participants had persistent cardiac symptoms. Diffuse myocardial edema was more pronounced in participants who remained symptomatic at follow-up as compared to those who improved. Female gender and diffuse myocardial involvement on baseline imaging independently predicted the presence of cardiac symptoms at follow-up. Ongoing inflammatory cardiac involvement may, at least in part, explain the lingering cardiac symptoms in previously well individuals with mild initial COVID-19 illness.

Pulmonary embolism (PE) results from deep vein thrombosis (DVT) and can lead to chronic thromboembolic pulmonary hypertension (CTEPH) involving vascular dysfunction. Mechanisms are incompletely understood, in part due to lack of mouse models. We induced PE in C57BL/6 mice by intravenous injection of thrombin (166 U/kg BW), confirmed by a sudden bradycardia, bradypnea, and an increase in pulmonary artery (PA) pressure observed by high-frequency ultrasound. While symptoms resolved rapidly after single thrombin application, repeated PEs resulted in sustained PA-pressure increase, increased PA superoxide formation assessed by oxidative fluorescent microtopography, increased PA gp91phox expression, and endothelial dysfunction assessed by isometric tension studies of isolated PA segments after 24 hours. DVT was modeled in C57BL/6 mice by ligation of the inferior vena cava (IVC). Importantly, small pulmonary emboli could be detected along with a mild phenotype of PA endothelial dysfunction and oxidative stress in the absence of PA-pressure elevation. mRNA expression of plasminogen activator inhibitor-1 was increased in PAs of mice with recurrent PE after repetitive thrombin injections and to a lesser extent in DVT mice. In summary, our data suggest that PA endothelial dysfunction, induced by gp91phox-derived ROS, is an early event upon repetitive PE. This phenomenon might help to elucidate the mechanisms of PA dysfunction in the pathogenesis of CTEPH.

Background Long COVID (LC) is an increasingly recognized late complication of COVID-19 infection. Cardiovascular involvement has also been implicated, however, the type and extent of the underlying cardiovascular injury remains unknown. Purpose To evaluate the association between ongoing symptoms and findings with cardiovascular magnetic resonance (CMR) in consecutive patients recently recovered from COVID-19 illness. Methods Prospective observational cohort study of patients recently recovered from COVID-19 illness and no previously known cardiovascular disease were included between April 2020 and April 2021. Demographic characteristics, cardiac blood markers, and CMR imaging a minimum of 4 weeks from the diagnosis were obtained. Results Of the 389 included patients, 192 (49%) were male, the mean (±standard deviation) age was 44 (±13) years and 61 (16%) required hospitalization during the acute illness. The median (IQR) time interval between COVID-19 diagnosis and CMR was 94 (71–165) days. 298 (77%) of patients continued to experience ongoing cardiovascular symptoms (long COVID, LC), including dyspnea, palpitations, atypical chest pain and fatigue at the time of CMR at least 4 weeks after the infection. In most patients, the symptoms were only effort related 137 (46%), whereas in 98 (33%) the symptoms affected the activities of daily life; 10 (3%) had severe and debilitating symptoms at rest. Compared to those with no LC (NLC, n=91), LC patients were more commonly hospitalized, had significantly higher native T1, native T2, and showed pericardial enhancement and effusion (Figure 1). There were no differences in cardiac biomarkers, left ventricular (LV) and right ventricular ejection fraction and mass. Proportionally, men and women were similarly affected (n=144 (73%) vs. n=157 (80%), p=0.18). Previous hospitalization was associated with hypertension and ongoing detectable troponin. LC status was associated with previous hospitalization and CMR findings of raised native T1 and native T2, and in females also pericardial enhancement. Severity of symptoms were associated with increased native T1 and T2 and decreased end-diastolic volume, whereas cardiac function showed no significant difference. Conclusions In this cohort of patients recently recovered from COVID-19 infection, ongoing cardiovascular symptoms were common. The LC status was related to previous hospitalization and CMR imaging findings of myopericardial inflammation. The extent and type of cardiovascular findings was associated with the severity of symptoms. These findings indicate the need for ongoing investigation of the long-term cardiovascular consequences of COVID-19. FUNDunding Acknowledgement Type of funding sources: Foundation. Main funding source(s): The German Heart Foundation (Deutsche Herzstiftung) and Bayer AG, Leverkusen, Germany Figure 1

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