Cardiovascular aspects of COVID-19.

Coronavirus disease 2019 (COVID-19) is primarily a pulmonary disease, but also affects the cardiovascular system in multiple ways. In this review, we will summarise and put into perspective findings and debates relating to the diverse aspects of cardiovascular involvement of COVID-19. We will review evidence for the role of the renin-angiotensin-aldosterone system (RAAS), the risk of pre-existing cardiovascular disease in COVID-19 susceptibility and course, and the mechanism of acute and long-term myocardial injury. The severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) uses membrane-bound angiotensin converting-enzyme-2 (ACE2) as a receptor for cell entry. ACE2 is part of an important counter-regulatory circuit antagonising the harmful effects of angiotensin II on lung and heart. Modulation of ACE2 may therefore affect disease susceptibility and disease course. However, observational clinical studies and one randomised trial have so far not yielded evidence for harmful or beneficial effects of blockers of the RAAS during COVID-19. Age, gender, and multi-morbidity all increase susceptibility to SARS-CoV-2. In contrast, pre-existing cardiovascular diseases do so only minimally, but they may aggravate the disease course. Direct SARS-CoV-2 infection of the heart tissue and myocytes is rare. Nevertheless, COVID-19 may lead to myocarditis-like acute cardiac injury, characterised by myocardial oedema, but lacking extensive myocyte loss and lymphocytic infiltration. Independent of this, increases in cardiac biomarkers (troponin, N-terminal pro-brain natriuretic peptide, D-dimer) are frequent, especially in the phase of severe systemic inflammation and acute respiratory distress syndrome, and quantitatively associated with poor outcome. The pulmonary infection may result initially in right ventricular dysfunction, but in cases with severe systemic infection hypoxia, hyperinflammation and cytokine storm heart failure may eventually ensue. Unlike other infections and inflammatory states, COVID-19 does not appear to trigger acute coronary syndromes. In children, even mild COVID-19 can induce a multisystem inflammatory syndrome with Kawasaki-like symptoms frequently accompanied by cardiogenic shock.

Comparison of Outcomes in Patients With COVID-19 and Thrombosis Versus Those Without Thrombosis.

The occurrence of venous thromboembolisms in patients with COVID-19 has been established. We sought to evaluate the clinical impact of thrombosis in patients with COVID-19 over the span of the pandemic to date. We analyzed patients with COVID-19 with a diagnosis of thrombosis who presented to the MedStar Health system (11 hospitals in Washington, District of Columbia, and Maryland) during the pandemic (March 1, 2020, to March 31, 2021). We compared the clinical course and outcomes based on the presence or absence of thrombosis and then, specifically, the presence of cardiac thrombosis. The cohort included 11,537 patients who were admitted for COVID-19. Of these patients, 1,248 had noncardiac thrombotic events and 1,009 had cardiac thrombosis (myocardial infarction) during their hospital admission. Of the noncardiac thrombotic events, 562 (45.0%) were pulmonary embolisms, 480 (38.5%) were deep venous thromboembolisms, and 347 (27.8%) were strokes. In the thrombosis arm, the mean age of the cohort was 64.5 ± 15.3 years, 53.3% were men, and the majority were African-American (64.9%). Patients with thrombosis tended to be older with more co-morbidities. The in-hospital mortality rate was significantly higher (16.0%) in patients with COVID-19 with concomitant non-cardiac thrombosis than in those without thrombosis (7.9%, p <0.001) but lower than in patients with COVID-19 with cardiac thrombosis (24.7%, p <0.001). In conclusion, patients with COVID-19 with thrombosis, especially cardiac thrombosis, are at higher risk for in-hospital mortality. However, this prognosis is not as grim as for patients with COVID-19 and cardiac thrombosis. Efforts should be focused on early recognition, evaluation, and intensifying antithrombotic management for these patients.

SARS-COV-2 colonizes coronary thrombus and impairs heart microcirculation bed in asymptomatic SARS-CoV-2 positive subjects with acute myocardial infarction.

BACKGROUND: The viral load of asymptomatic SAR-COV-2 positive (ASAP) persons has been equal to that of symptomatic patients. On the other hand, there are no reports of ST-elevation myocardial infarction (STEMI) outcomes in ASAP patients. Therefore, we evaluated thrombus burden and thrombus viral load and their impact on microvascular bed perfusion in the infarct area (myocardial blush grade, MBG) in ASAP compared to SARS-COV-2 negative (SANE) STEMI patients. METHODS: This was an observational study of 46 ASAP, and 130 SANE patients admitted with confirmed STEMI treated with primary percutaneous coronary intervention and thrombus aspiration. The primary endpoints were thrombus dimension + thrombus viral load effects on MBG after PPCI. The secondary endpoints during hospitalization were major adverse cardiovascular events (MACEs). MACEs are defined as a composite of cardiovascular death, nonfatal acute AMI, and heart failure during hospitalization. RESULTS: In the study population, ASAP vs. SANE showed a significant greater use of GP IIb/IIIa inhibitors and of heparin (p < 0.05), and a higher thrombus grade 5 and thrombus dimensions (p < 0.05). Interestingly, ASAP vs. SANE patients had lower MBG and left ventricular function (p < 0.001), and 39 (84.9%) of ASAP patients had thrombus specimens positive for SARS-COV-2. After PPCI, a MBG 2-3 was present in only 26.1% of ASAP vs. 97.7% of SANE STEMI patients (p < 0.001). Notably, death and nonfatal AMI were higher in ASAP vs. SANE patients (p < 0.05). Finally, in ASAP STEMI patients the thrombus viral load was a significant determinant of thrombus dimension independently of risk factors (p < 0.005). Thus, multiple logistic regression analyses evidenced that thrombus SARS-CoV-2 infection and dimension were significant predictors of poorer MBG in STEMI patients. Intriguingly, in ASAP patients the female vs. male had higher thrombus viral load (15.53 ± 4.5 vs. 30.25 ± 5.51 CT; p < 0.001), and thrombus dimension (4.62 ± 0.44 vs 4.00 ± 1.28 mm2; p < 0.001). ASAP vs. SANE patients had a significantly lower in-hospital survival for MACE following PPCI (p < 0.001). CONCLUSIONS: In ASAP patients presenting with STEMI, there is strong evidence towards higher thrombus viral load, dimension, and poorer MBG. These data support the need to reconsider ASAP status as a risk factor that may worsen STEMI outcomes.

A cardiovascular magnetic resonance imaging-based pilot study to assess coronary microvascular disease in COVID-19 patients.

Coronavirus disease 2019 (COVID-19) is caused by severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) and is primarily characterised by a respiratory disease. However, SARS-CoV-2 can directly infect vascular endothelium and subsequently cause vascular inflammation, atherosclerotic plaque instability and thereby result in both endothelial dysfunction and myocardial inflammation/infarction. Interestingly, up to 50% of patients suffer from persistent exercise dyspnoea and a post-viral fatigue syndrome (PVFS) after having overcome an acute COVID-19 infection. In the present study, we assessed the presence of coronary microvascular disease (CMD) by cardiovascular magnetic resonance (CMR) in post-COVID-19 patients still suffering from exercise dyspnoea and PVFS. N = 22 patients who recently recovered from COVID-19, N = 16 patients with classic hypertrophic cardiomyopathy (HCM) and N = 17 healthy control patients without relevant cardiac disease underwent dedicated vasodilator-stress CMR studies on a 1.5-T MR scanner. The CMR protocol comprised cine and late-gadolinium-enhancement (LGE) imaging as well as velocity-encoded (VENC) phase-contrast imaging of the coronary sinus flow (CSF) at rest and during pharmacological stress (maximal vasodilation induced by 400 µg IV regadenoson). Using CSF measurements at rest and during stress, global myocardial perfusion reserve (MPR) was calculated. There was no difference in left ventricular ejection-fraction (LV-EF) between COVID-19 patients and controls (60% [57-63%] vs. 63% [60-66%], p = NS). There were only N = 4 COVID-19 patients (18%) showing a non-ischemic pattern of LGE. VENC-based flow measurements showed that CSF at rest was higher in COVID-19 patients compared to controls (1.78 ml/min [1.19-2.23 ml/min] vs. 1.14 ml/min [0.91-1.32 ml/min], p = 0.048). In contrast, CSF during stress was lower in COVID-19 patients compared to controls (3.33 ml/min [2.76-4.20 ml/min] vs. 5.32 ml/min [3.66-5.52 ml/min], p = 0.05). A significantly reduced MPR was calculated in COVID-19 patients compared to healthy controls (2.73 [2.10-4.15-11] vs. 4.82 [3.70-6.68], p = 0.005). No significant differences regarding MPR were detected between COVID-19 patients and HCM patients. In post-COVID-19 patients with persistent exertional dyspnoea and PVFS, a significantly reduced MPR suggestive of CMD-similar to HCM patients-was observed in the present study. A reduction in MPR can be caused by preceding SARS-CoV-2-associated direct as well as secondary triggered mechanisms leading to diffuse CMD, and may explain ongoing symptoms of exercise dyspnoea and PVFS in some patients after COVID-19 infection.

Progress in cardiac research: from rebooting cardiac regeneration to a complete cell atlas of the heart.

We review some of the important discoveries and advances made in basic and translational cardiac research in 2020. For example, in the field of myocardial infarction (MI), new aspects of autophagy and the importance of eosinophils were described. Novel approaches, such as a glycocalyx mimetic, were used to improve cardiac recovery following MI. The strategy of 3D bio-printing was shown to allow the fabrication of a chambered cardiac organoid. The benefit of combining tissue engineering with paracrine therapy to heal injured myocardium is discussed. We highlight the importance of cell-to-cell communication, in particular, the relevance of extracellular vesicles, such as exosomes, which transport proteins, lipids, non-coding RNAs, and mRNAs and actively contribute to angiogenesis and myocardial regeneration. In this rapidly growing field, new strategies were developed to stimulate the release of reparative exosomes in ischaemic myocardium. Single-cell sequencing technology is causing a revolution in the study of transcriptional expression at cellular resolution, revealing unanticipated heterogeneity within cardiomyocytes, pericytes and fibroblasts, and revealing a unique subpopulation of cardiac fibroblasts. Several studies demonstrated that exosome- and non-coding RNA-mediated approaches can enhance human induced pluripotent stem cell (iPSC) viability and differentiation into mature cardiomyocytes. Important details of the mitochondrial Ca2+ uniporter and its relevance were elucidated. Novel aspects of cancer therapeutic-induced cardiotoxicity were described, such as the novel circular RNA circITCH, which may lead to novel treatments. Finally, we provide some insights into the effects of SARS-CoV-2 on the heart.

Endothelial Dysfunction in the Brain: Setting the Stage for Stroke and Other Cerebrovascular Complications of COVID-19.

The Coronavirus disease 2019 (COVID)-19 pandemic has already affected millions worldwide, with a current mortality rate of 2.2%. While it is well-established that severe acute respiratory syndrome-coronavirus-2 causes upper and lower respiratory tract infections, a number of neurological sequelae have now been reported in a large proportion of cases. Additionally, the disease causes arterial and venous thromboses including pulmonary embolism, myocardial infarction, and a significant number of cerebrovascular complications. The increasing incidence of large vessel ischemic strokes as well as intracranial hemorrhages, frequently in younger individuals, and associated with increased morbidity and mortality, has raised questions as to why the brain is a major target of the disease. COVID-19 is characterized by hypercoagulability with alterations in hemostatic markers including high D-dimer levels, which are a prognosticator of poor outcome. Together with findings of fibrin-rich microthrombi, widespread extracellular fibrin deposition in affected various organs and hypercytokinemia, this suggests that COVID-19 is more than a pulmonary viral infection. Evidently, COVID-19 is a thrombo-inflammatory disease. Endothelial cells that constitute the lining of blood vessels are the primary targets of a thrombo-inflammatory response, and severe acute respiratory syndrome coronavirus 2 also directly infects endothelial cells through the ACE2 (angiotensin-converting enzyme 2) receptor. Being highly heterogeneous in their structure and function, differences in the endothelial cells may govern the susceptibility of organs to COVID-19. Here, we have explored how the unique characteristics of the cerebral endothelium may be the underlying reason for the increased rates of cerebrovascular pathology associated with COVID-19.

Cardiovascular and Cerebrovascular Complications With COVID-19.

The coronavirus disease 2019 (COVID-19) caused by the severe acute respiratory syndrome coronavirus-2 has affected the health of people across the globe. Cardiovascular diseases (CVDs) have a significant relationship with COVID-19, both as a risk factor and prognostic indicator, and as a complication of the disease itself. In addition to predisposing to CVD complications, the ongoing pandemic has severely affected the delivery of timely and appropriate care for cardiovascular conditions resulting in increased mortality. The etiology behind the cardiac injury associated with severe acute respiratory syndrome coronavirus-2 is likely varied, including coronary artery disease, microvascular thrombosis, myocarditis, and stress cardiomyopathy. Further large-scale investigations are needed to better determine the underlying mechanism of myocardial infarction and other cardiac injury in COVID-19 patients and to determine the incidence of each type of cardiac injury in this patient population. Telemedicine and remote monitoring technologies can play an important role in optimizing outcomes in patients with established CVD. In this article, we summarize the various impacts that COVID-19 has on the cardiovascular system, including myocardial infarction, myocarditis, stress cardiomyopathy, thrombosis, and stroke.

The role of SARS-CoV-2 target ACE2 in cardiovascular diseases.

SARS-CoV-2, the virus responsible for the global coronavirus disease (COVID-19) pandemic, attacks multiple organs of the human body by binding to angiotensin-converting enzyme 2 (ACE2) to enter cells. More than 20 million people have already been infected by the virus. ACE2 is not only a functional receptor of COVID-19 but also an important endogenous antagonist of the renin-angiotensin system (RAS). A large number of studies have shown that ACE2 can reverse myocardial injury in various cardiovascular diseases (CVDs) as well as is exert anti-inflammatory, antioxidant, anti-apoptotic and anticardiomyocyte fibrosis effects by regulating transforming growth factor beta, mitogen-activated protein kinases, calcium ions in cells and other major pathways. The ACE2/angiotensin-(1-7)/Mas receptor axis plays a decisive role in the cardiovascular system to combat the negative effects of the ACE/angiotensin II/angiotensin II type 1 receptor axis. However, the underlying mechanism of ACE2 in cardiac protection remains unclear. Some approaches for enhancing ACE2 expression in CVDs have been suggested, which may provide targets for the development of novel clinical therapies. In this review, we aimed to identify and summarize the role of ACE2 in CVDs.

Home-based exercise is associated with improved cardiac functional performance in patients after acute myocardial infarction.

OBJECTIVE: To evaluate the effects of home-based exercise and physical activity on cardiac functional performance in patients after acute myocardial infarction (MI) during the coronavirus disease 2019 (COVID-19) pandemic. METHODS: This retrospective study enrolled patients that received treatment of acute ST-segment elevation MI between and were followed-up 6 months later. The patients were divided into physically active and inactive groups based on their levels of home exercise after hospital discharge. RESULTS: A total of 78 patients were enrolled in the study: 32 were physically active and 46 were physically inactive. The baseline characteristics were comparable between the two groups. At the 6-month visit, left ventricular ejection fraction and six-minute walking test (6MWT) were significantly improved while the proportion of patients with a New York Heart Association (NYHA) functional III classification was decreased in the active patients, whereas these parameters were not significantly changed in the inactive patients. In addition, the 6MWT was greater while the proportion of patients with an NYHA III classification was lower in the active group than the inactive group at the 6-month visit. CONCLUSION: Maintaining physical activity at home was associated with improved cardiac functional performance in patients after acute MI during the COVID-19 pandemic.

The effect of the severity COVID-19 infection on electrocardiography.

OBJECTIVE: Acute myocardial damage is detected in a significant portion of patients with coronavirus 2019 disease (COVID-19) infection, with a reported prevalence of 7-28%. The aim of this study was to investigate the relationship between electrocardiographic findings and the indicators of the severity of COVID-19 detected on electrocardiography (ECG). METHODS: A total of 219 patients that were hospitalized due to COVID-19 between April 15 and May 5, 2020 were enrolled in this study. Patients were divided into two groups according to the severity of COVID-19 infection: severe (n = 95) and non-severe (n = 124). ECG findings at the time of admission were recorded for each patient. Clinical characteristics and laboratory findings were retrieved from electronic medical records. RESULTS: Mean age was 65.2 ± 13.8 years in the severe group and was 57.9 ± 16.0 years in the non-severe group. ST depression (28% vs. 14%), T-wave inversion (29% vs. 16%), ST-T changes (36% vs. 21%), and the presence of fragmented QRS (fQRS) (17% vs. 7%) were more frequent in the severe group compared to the non-severe group. Multivariate analysis revealed that hypertension (odds ratio [OR]: 2.42, 95% confidence interval [CI]:1.03-5.67; p = 0.041), the severity of COVID-19 infection (OR: 1.87, 95% CI: 1.09-2.65; p = 0.026), presence of cardiac injury (OR: 3.32, 95% CI: 1.45-7.60; p = 0.004), and d-dimer (OR: 3.60, 95% CI: 1.29-10.06; p = 0.014) were independent predictors of ST-T changes on ECG. CONCLUSION: ST depression, T-wave inversion, ST-T changes, and the presence of fQRS on admission ECG are closely associated with the severity of COVID-19 infection.

Cardiovascular Manifestations and Mechanisms in Patients with COVID-19.

Coronavirus disease 2019 (COVID-19) patients with pre-existing cardiovascular disease (CVD) or with cardiovascular complications have a higher risk of mortality. The main cardiovascular complications of COVID-19 include acute cardiac injury, acute myocardial infarction (AMI), myocarditis, arrhythmia, heart failure, shock, and venous thromboembolism (VTE)/pulmonary embolism (PE). COVID-19 can cause cardiovascular complications or deterioration of coexisting CVD through direct or indirect mechanisms, including viral toxicity, dysregulation of the renin-angiotensin-aldosterone system (RAAS), endothelial cell damage and thromboinflammation, cytokine storm, and oxygen supply-demand mismatch. We systematically review cardiovascular manifestations, histopathology, and mechanisms of COVID-19, to help to formulate future research goals and facilitate the development of therapeutic management strategies.