COVID-19 and the cardiovascular system: implications for risk assessment, diagnosis, and treatment options.

The novel coronavirus disease (COVID-19) outbreak, caused by SARS-CoV-2, represents the greatest medical challenge in decades. We provide a comprehensive review of the clinical course of COVID-19, its comorbidities, and mechanistic considerations for future therapies. While COVID-19 primarily affects the lungs, causing interstitial pneumonitis and severe acute respiratory distress syndrome (ARDS), it also affects multiple organs, particularly the cardiovascular system. Risk of severe infection and mortality increase with advancing age and male sex. Mortality is increased by comorbidities: cardiovascular disease, hypertension, diabetes, chronic pulmonary disease, and cancer. The most common complications include arrhythmia (atrial fibrillation, ventricular tachyarrhythmia, and ventricular fibrillation), cardiac injury [elevated highly sensitive troponin I (hs-cTnI) and creatine kinase (CK) levels], fulminant myocarditis, heart failure, pulmonary embolism, and disseminated intravascular coagulation (DIC). Mechanistically, SARS-CoV-2, following proteolytic cleavage of its S protein by a serine protease, binds to the transmembrane angiotensin-converting enzyme 2 (ACE2) -a homologue of ACE-to enter type 2 pneumocytes, macrophages, perivascular pericytes, and cardiomyocytes. This may lead to myocardial dysfunction and damage, endothelial dysfunction, microvascular dysfunction, plaque instability, and myocardial infarction (MI). While ACE2 is essential for viral invasion, there is no evidence that ACE inhibitors or angiotensin receptor blockers (ARBs) worsen prognosis. Hence, patients should not discontinue their use. Moreover, renin-angiotensin-aldosterone system (RAAS) inhibitors might be beneficial in COVID-19. Initial immune and inflammatory responses induce a severe cytokine storm [interleukin (IL)-6, IL-7, IL-22, IL-17, etc.] during the rapid progression phase of COVID-19. Early evaluation and continued monitoring of cardiac damage (cTnI and NT-proBNP) and coagulation (D-dimer) after hospitalization may identify patients with cardiac injury and predict COVID-19 complications. Preventive measures (social distancing and social isolation) also increase cardiovascular risk. Cardiovascular considerations of therapies currently used, including remdesivir, chloroquine, hydroxychloroquine, tocilizumab, ribavirin, interferons, and lopinavir/ritonavir, as well as experimental therapies, such as human recombinant ACE2 (rhACE2), are discussed.

The assessment of treatment outcomes in patients with acute viral myocarditis by speckle tracking and tissue Doppler methods.

OBJECTIVES: The aim was to evaluate the role of tissue Doppler imaging (TDI) and speckle tracking echocardiography (STE), to identify myocardial dysfunction, and to evaluate myocardial segmental deformation in acute viral myocarditis. METHODS: Twenty-one patients and twelve healthy children were studied prospectively. The TDI and STE were performed before and after treatment. The myocardial velocities (Sm , Em , and Am ) and time intervals (isovolumic contraction, isovolumic relaxation, and ejection times [ET]) at interventricular septum (IVS), left, and right ventricular basal segments were examined by TDI. The left ventricular global longitudinal strain (LVGLS) and strain rate (LVGLSR), left ventricular global circumferential strain (LVGCS) and strain rate (LVGCSR), and right ventricular global longitudinal strain (RVGLS) and strain rate (RVGLSR) were examined by STE. RESULTS: Sm and Em at IVS and at LV, ET at IVS, ET at RV, ET at LV were significantly lower in patients before treatment than controls. LVGLS, LVGLSR, LVGCS, LVGCSR, RVGLS, RVGLSR were significantly decreased in patients before treatment than controls. There was significant improvement for LVGLS, LVGLSR, LVGCS, LVGCSR, and RVGLS in patients after treatment. Sm , Em , and Am at LV were significantly lower in patients before treatment than in patients after treatment. In spite of improvements, Sm , Em , and ET at IVS, LVGLS, LVGLSR, LVGCS, LVGCSR were significantly lower in patients after treatment than controls. CONCLUSIONS: The TDI and STE were useful methods for detection of early myocardial dysfunction and evaluation of treatment outcomes in acute viral myocarditis.

Young patient with hantavirus-induced myocarditis detected by comprehensive cardiac magnetic resonance assessment.

BACKGROUND: We report a case of hantavirus-induced myocarditis in a young adult. Hantavirus showed a rapid increase of infections in the year 2017. Only scarce data is available about potential myocardial involvement in hantavirus infections. With ECG and echocardiography providing often inconclusive results, a multiparametric cardiac magnetic resonance protocol with distinct myocardial tissue characterization seems to be the adequate tool for detecting even slight myocardial alterations. CASE PRESENTATION: This case started with the presentation of young adult suffering from headache and abdominal pain. Thrombocytes were decreased, creatinine was elevated, and there was massive proteinuria. Puumala virus IgG ELISA turned out to be positive, and specific antibodies (IgG and IgM) could be detected in the serum, and confirmed by immunoassay. The patient was admitted to the nephrology department for supportive therapy. Few days later, the patient reported chest pain and dyspnea. High sensitivity troponin I rose up to 0.32 µg/l (normal range below 0.04 µg/l) with an increase of the creatinkinase to 319 U/l (normal max. 190 U/l), no dynamic ECG changes could be observed. Echocardiography revealed a normal left ventricular function without regional wall motion abnormalities, no pericardial effusion or valve abnormalities, coronary artery disease could be excluded by computed tomography. A multiparametric cardiac magnetic resonance protocol including recent mapping techniques confirmed myocardial involvement induced by acute hantavirus infection. In the next few weeks, the patient's state of health rapidly improved and symptoms of chest pain and dyspnea disappeared. Follow up multiparametric CMR exam showed substantial decrease of the previously observed myocardial alterations during acute hantavirus infection suggesting myocardial healing. CONCLUSIONS: This case demonstrates that a CMR protocol including recent mapping techniques and established late gadolinium enhancement technique is an adequate non-invasive tool for both 1) initial detection, and 2) follow up of patients with hantavirus-induced myocarditis, which might be more common than previously known.

The hidden burden of influenza: A review of the extra-pulmonary complications of influenza infection.

Severe influenza infection represents a leading cause of global morbidity and mortality. Although influenza is primarily considered a viral infection that results in pathology limited to the respiratory system, clinical reports suggest that influenza infection is frequently associated with a number of clinical syndromes that involve organ systems outside the respiratory tract. A comprehensive MEDLINE literature review of articles pertaining to extra-pulmonary complications of influenza infection, using organ-specific search terms, yielded 218 articles including case reports, epidemiologic investigations, and autopsy studies that were reviewed to determine the clinical involvement of other organs. The most frequently described clinical entities were viral myocarditis and viral encephalitis. Recognition of these extra-pulmonary complications is critical to determining the true burden of influenza infection and initiating organ-specific supportive care.

Cardiovascular magnetic resonance assessment of human myocarditis: a comparison to histology and molecular pathology.

BACKGROUND: Myocarditis can occasionally lead to sudden death and may progress to dilated cardiomyopathy in up to 10% of patients. Because the initial onset is difficult to recognize clinically and the diagnostic tools available are unsatisfactory, new strategies to diagnose myocarditis are needed. METHODS AND RESULTS: Cardiovascular MR imaging (CMR) was performed in 32 patients who were diagnosed with myocarditis by clinical criteria. To determine whether CMR visualizes areas of active myocarditis, endomyocardial biopsy was taken from the region of contrast enhancement and submitted to histopathologic analysis. Follow-up was performed 3 month later. Contrast enhancement was present in 28 patients (88%) and was usually seen with one or several foci in the myocardium. Foci were most frequently located in the lateral free wall. In the 21 patients in whom biopsy was obtained from the region of contrast enhancement, histopathologic analysis revealed active myocarditis in 19 patients (parvovirus B19, n=12; human herpes virus type 6 [HHV 6], n=5). Conversely, in the remaining 11 patients, in whom biopsy could not be taken from the region of contrast enhancement, active myocarditis was found in one case only (HHV6). At follow-up, the area of contrast enhancement decreased from 9+/-11% to 3+/-4% of left ventricular mass as the left ventricular ejection fraction improved from 47+/-19% to 60+/-10%. CONCLUSIONS: Contrast enhancement is a frequent finding in the clinical setting of suspected myocarditis and is associated with active inflammation defined by histopathology. Myocarditis occurs predominantly in the lateral free wall. Contrast CMR is a valuable tool for the evaluation and monitoring of inflammatory heart disease.

Host gene regulation during coxsackievirus B3 infection in mice: assessment by microarrays.

Host genetic responses that characterize enteroviral myocarditis have not yet been determined. The injurious and inflammatory process in heart muscle may reflect host responses of benefit to the virus and ultimately result in congestive heart failure and dilated cardiomyopathy. On the other hand, host responses within the myocardium may secure the host against acute or protracted damage. To investigate the nature of modified gene expression in comparison with normal tissue, mRNA species were assessed in myocardium using cDNA microarray technology at days 3, 9, and 30 after infection. Of 7000 clones initially screened, 169 known genes had a level of expression significantly different at 1 or more postinfection time points as compared with baseline. The known regulated genes were sorted according to their functional groups and normalized expression patterns and, subsequently, interpreted in the context of viremic, inflammatory, and healing phases of the myocarditic process.

Nucleotide sequence of an attenuated mutant of coxsackievirus B3 compared with the cardiovirulent wildtype: assessment of candidate mutations by analysis of a revertant to cardiovirulence.

BACKGROUND: Coxsackievirus B3 (CVB3) causes myocarditis in the SWR (H2q) mouse model and persistence of CVB3 in myocardium disposes to the development of dilated cardiomyopathy. An attenuated strain of CVB3 has been isolated, sequenced and several candidate mutations for attenuation identified. Derivation of a revertant to cardiovirulence allows the significance of these mutations to be assessed. OBJECTIVES: To ascertain which candidate mutation(s) determine(s) the attenuated phenotype. STUDY DESIGN: A revertant to cardiovirulence was isolated following passage through severe combined immunodeficient disease (SCID) mouse heart. The 5'-non-translated region (NTR) and region coding for capsid proteins were sequenced and compared to the wildtype and attenuant. RESULTS: There are five candidates for attenuation: (1) A-G at base 580 in the 5'-NTR; (2) A-T at base 690 in the 5'-NTR; (3) CG-GC at bases 1401/2 (Thr to Ser at amino acid 151 in VP2); (4) AA-GT at bases 2691/2 (Lys to Ser at amino acid 80 in VP1); (5) A-G at base 2916 (Asp to Gly at amino acid 155 in VP1). It was shown previously that mutations at 580, 690 and 2691/2 are not important in attenuation. Additionally, there are three novel mutations in the coding region of the revertant and one in the 5'-NTR which are unlikely to be relevant for attenuation as they are not present in the attenuant. Of nucleotide changes seen at 1401/2 and 2916 in the attenuant, only 2916 reverts to the wildtype sequence and so is a strong candidate for a determinant of attenuation.