Although COVID-19 is most well known for causing substantial respiratory pathology, it can also result in several extrapulmonary manifestations. These conditions include thrombotic complications, myocardial dysfunction and arrhythmia, acute coronary syndromes, acute kidney injury, gastrointestinal symptoms, hepatocellular injury, hyperglycemia and ketosis, neurologic illnesses, ocular symptoms, and dermatologic complications. Given that ACE2, the entry receptor for the causative coronavirus SARS-CoV-2, is expressed in multiple extrapulmonary tissues, direct viral tissue damage is a plausible mechanism of injury. In addition, endothelial damage and thromboinflammation, dysregulation of immune responses, and maladaptation of ACE2-related pathways might all contribute to these extrapulmonary manifestations of COVID-19. Here we review the extrapulmonary organ-specific pathophysiology, presentations and management considerations for patients with COVID-19 to aid clinicians and scientists in recognizing and monitoring the spectrum of manifestations, and in developing research priorities and therapeutic strategies for all organ systems involved.

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Extrapulmonary manifestations of COVID-19.

Background Understanding the epidemiology and clinical course of multisystem inflammatory syndrome in children (MIS-C) and its temporal association with coronavirus disease 2019 (Covid-19)...

https://www.nejm.org/doi/pdf/10.1056/NEJMoa2021680?articleTools=true

Multisystem Inflammatory Syndrome in U.S. Children and Adolescents.

RAAS Inhibitors in Patients with Covid-19 The effects of renin–angiotensin–aldosterone system blockers on angiotensin-converting enzyme 2 levels and activity in humans are uncertain. The authors hy...

https://www.nejm.org/doi/pdf/10.1056/NEJMsr2005760?articleTools=true

Renin-Angiotensin-Aldosterone System Inhibitors in Patients with Covid-19.

/pdf/covid-19-and-african-americans-55okpupl4g.pdf

COVID-19 and African Americans.

Importance Coronavirus disease 2019 (COVID-19) continues to cause considerable morbidity and mortality worldwide. Case reports of hospitalized patients suggest that COVID-19 prominently affects the cardiovascular system, but the overall impact remains unknown. Objective To evaluate the presence of myocardial injury in unselected patients recently recovered from COVID-19 illness. Design, Setting, and Participants In this prospective observational cohort study, 100 patients recently recovered from COVID-19 illness were identified from the University Hospital Frankfurt COVID-19 Registry between April and June 2020. Exposure Recent recovery from severe acute respiratory syndrome coronavirus 2 infection, as determined by reverse transcription–polymerase chain reaction on swab test of the upper respiratory tract. Main Outcomes and Measures Demographic characteristics, cardiac blood markers, and cardiovascular magnetic resonance (CMR) imaging were obtained. Comparisons were made with age-matched and sex-matched control groups of healthy volunteers (n = 50) and risk factor–matched patients (n = 57). Results Of the 100 included patients, 53 (53%) were male, and the mean (SD) age was 49 (14) years. The median (IQR) time interval between COVID-19 diagnosis and CMR was 71 (64-92) days. Of the 100 patients recently recovered from COVID-19, 67 (67%) recovered at home, while 33 (33%) required hospitalization. At the time of CMR, high-sensitivity troponin T (hsTnT) was detectable (greater than 3 pg/mL) in 71 patients recently recovered from COVID-19 (71%) and significantly elevated (greater than 13.9 pg/mL) in 5 patients (5%). Compared with healthy controls and risk factor–matched controls, patients recently recovered from COVID-19 had lower left ventricular ejection fraction, higher left ventricle volumes, and raised native T1 and T2. A total of 78 patients recently recovered from COVID-19 (78%) had abnormal CMR findings, including raised myocardial native T1 (n = 73), raised myocardial native T2 (n = 60), myocardial late gadolinium enhancement (n = 32), or pericardial enhancement (n = 22). There was a small but significant difference between patients who recovered at home vs in the hospital for native T1 mapping (median [IQR], 1119 [1092-1150] ms vs 1141 [1121-1175] ms;P = .008) and hsTnT (4.2 [3.0-5.9] pg/dL vs 6.3 [3.4-7.9] pg/dL;P = .002) but not for native T2 mapping. None of these measures were correlated with time from COVID-19 diagnosis (native T1:r = 0.07;P = .47; native T2:r = 0.14;P = .15; hsTnT:r = −0.07;P = .50). High-sensitivity troponin T was significantly correlated with native T1 mapping (r = 0.33;P  Conclusions and Relevance In this study of a cohort of German patients recently recovered from COVID-19 infection, CMR revealed cardiac involvement in 78 patients (78%) and ongoing myocardial inflammation in 60 patients (60%), independent of preexisting conditions, severity and overall course of the acute illness, and time from the original diagnosis. These findings indicate the need for ongoing investigation of the long-term cardiovascular consequences of COVID-19.

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

Importance Coronavirus disease 2019 (COVID-19) has resulted in considerable morbidity and mortality worldwide since December 2019. However, information on cardiac injury in patients affected by COVID-19 is limited. Objective To explore the association between cardiac injury and mortality in patients with COVID-19. Design, Setting, and Participants This cohort study was conducted from January 20, 2020, to February 10, 2020, in a single center at Renmin Hospital of Wuhan University, Wuhan, China; the final date of follow-up was February 15, 2020. All consecutive inpatients with laboratory-confirmed COVID-19 were included in this study. Main Outcomes and Measures Clinical laboratory, radiological, and treatment data were collected and analyzed. Outcomes of patients with and without cardiac injury were compared. The association between cardiac injury and mortality was analyzed. Results A total of 416 hospitalized patients with COVID-19 were included in the final analysis; the median age was 64 years (range, 21-95 years), and 211 (50.7%) were female. Common symptoms included fever (334 patients [80.3%]), cough (144 [34.6%]), and shortness of breath (117 [28.1%]). A total of 82 patients (19.7%) had cardiac injury, and compared with patients without cardiac injury, these patients were older (median [range] age, 74 [34-95] vs 60 [21-90] years;P  Conclusions and Relevance Cardiac injury is a common condition among hospitalized patients with COVID-19 in Wuhan, China, and it is associated with higher risk of in-hospital mortality.

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

AIMS: To investigate the characteristics and clinical significance of myocardial injury in patients with severe coronavirus disease 2019 (COVID-19). METHODS AND RESULTS: We enrolled 671 eligible hospitalized patients with severe COVID-19 from 1 January to 23 February 2020, with a median age of 63 years. Clinical, laboratory, and treatment data were collected and compared between patients who died and survivors. Risk factors of death and myocardial injury were analysed using multivariable regression models. A total of 62 patients (9.2%) died, who more often had myocardial injury (75.8% vs. 9.7%; P < 0.001) than survivors. The area under the receiver operating characteristic curve of initial cardiac troponin I (cTnI) for predicting in-hospital mortality was 0.92 [95% confidence interval (CI), 0.87-0.96; sensitivity, 0.86; specificity, 0.86; P < 0.001]. The single cut-off point and high level of cTnI predicted risk of in-hospital death, hazard ratio (HR) was 4.56 (95% CI, 1.28-16.28; P = 0.019) and 1.25 (95% CI, 1.07-1.46; P = 0.004), respectively. In multivariable logistic regression, senior age, comorbidities (e.g. hypertension, coronary heart disease, chronic renal failure, and chronic obstructive pulmonary disease), and high level of C-reactive protein were predictors of myocardial injury. CONCLUSION: The risk of in-hospital death among patients with severe COVID-19 can be predicted by markers of myocardial injury, and was significantly associated with senior age, inflammatory response, and cardiovascular comorbidities.

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Characteristics and clinical significance of myocardial injury in patients with severe coronavirus disease 2019.

It has been reported that patients with major depressive disorder (MDD) are prone to developing ventricular arrhythmias. Moreover, the Sigma-1 receptor not only plays a crucial role in MDD but has also been shown to have antiarrhythmic properties. The Sigma-1 receptor is a common receptor related to depression and ventricular arrhythmias. We analyzed the effects of the Sigma-1 receptor on depression and ventricular repolarization-related ion remodeling in MDD rats. MDD was induced in rats by chronic unpredictable mild stress (CUMS), and 28 days later, the rats were subjected to behavior tests. Protein expression was measured by western blotting, and cardiac morphological changes were observed by Masson staining. Electrophysiological measurement of the myocardium was performed with the whole-cell patch-clamp technique. Compared with the control rats, the MDD rats exhibited lower transient outward potassium current (Ito) and L-type calcium current (ICa-L) amplitudes. On the other hand, a trend of depolarization of Ito and hyperpolarization of ICa-L was observed in the MDD rats. Thus, we investigated the effect of fluvoxamine, a Sigma-1 receptor agonist, on Ito and ICa-L. Fluvoxamine enhanced Ito and altered its current kinetics, as shown by acceleration of activation and recovery from inactivation. In contrast, fluvoxamine inhibited the Ca2+ by hyperpolarizing the steady-state activation of ICa-L. All these effects were blocked by BD1047. Taken together, our results indicate that Sigma-1 receptor modulates the functions of Ito and ICa-L to possibly exert antiarrhythmic effects.

Sigma-1 receptor ligands improves ventricular repolarization-related ion remodeling in rats with major depression disorder.

Background: Anxiety disorder (AD) is the most common mental disorder, which is closely related to atrial fibrillation (AF) and is considered to be a trigger of AF. Pinocembrin has been demonstrated to perform a variety of neurological and cardiac protective effects through its anti-inflammatory and antioxidant activities. The current research aims to explore the antiarrhythmic effect of pinocembrin in anxiety disorder rats and its underlying mechanisms. Methods: 60 male Sprague-Dawley rats were distributed into four groups: CTL group: control rats + saline; CTP group: control rats + pinocembrin; Anxiety disorder group: anxiety disorder rats + saline; ADP group: anxiety disorder rats + pinocembrin. Empty bottle stimulation was conducted to induce anxiety disorder in rats for 3 weeks, and pinocembrin was injected through the tail vein for the last 2 weeks. Behavioral measurements, in vitro electrophysiological studies, biochemical assays, ELISA, Western blot and histological studies were performed to assess the efficacy of pinocembrin. In addition, HL-1 atrial cells were cultured in vitro to further verify the potential mechanism of pinocembrin. Results: After 3 weeks of empty bottle stimulation, pinocembrin significantly improved the exploration behaviors in anxiety disorder rats. Pinocembrin alleviated electrophysiological remodeling in anxiety disorder rats, including shortening the action potential duration (APD), prolonging the effective refractory period (ERP), increasing the expression of Kv1.5, Kv4.2 and Kv4.3, decreasing the expression of Cav1.2, and ultimately reducing the AF susceptibility. These effects may be attributed to the amelioration of autonomic remodeling and structural remodeling by pinocembrin, as well as the inhibition of oxidative stress with upregulation of the nuclear factor erythroid 2-related factor 2 (Nrf2) and heme oxygenase-1 (HO-1) pathway. Conclusion: Pinocembrin can reduce AF susceptibility in anxiety disorder rats induced by empty bottle stimulation, with the inhibition of autonomic remodeling, structural remodeling, and oxidative stress. Therefore, pinocembrin is a promising treatment for AF in patients with anxiety disorder.

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Bo Shen

Papers

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

Characteristics and clinical significance of myocardial injury in patients with severe coronavirus disease 2019.

Sigma-1 receptor ligands improves ventricular repolarization-related ion remodeling in rats with major depression disorder.

Pinocembrin ameliorates atrial fibrillation susceptibility in rats with anxiety disorder induced by empty bottle stimulation