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.

Prevalence of 18F-fluorodeoxyglucose positron emission tomography abnormalities in patients with arrhythmogenic right ventricular cardiomyopathy.

BACKGROUND: Arrhythmogenic right ventricular cardiomyopathy (ARVC) is a heritable heart muscle disease that causes sudden cardiac death in the young. Inflammatory myocardial infiltrates have been described at autopsy and on biopsy, but there are few data on the presence of myocarditis in living patients with ARVC using non-invasive imaging techniques. FDG-PET is a validated technique for detecting myocardial inflammation in clinically suspected myocarditis. We aimed to determine the prevalence of myocardial inflammation in patients with ARVC using 18F-fluorodeoxyglucose positron emission tomography (FDG-PET). METHODS AND RESULTS: We performed a retrospective analysis of a single centre cohort of patients with ARVC referred for FDG-PET scans between 2012 and 2017 for investigation of symptoms or suspected device infection. Sixteen patients (12 male; age 42 ±â€¯13 years) with a definite diagnosis of ARVC were identified. Seven had positive FDG-PET scans, two of whom had cardiac sarcoidosis on endomyocardial biopsy. Of the remaining five, two carried pathogenic desmoplakin mutations. FDG uptake was found in the left ventricular myocardium in all cases. One patient also had right ventricular uptake. CONCLUSION: In this exploratory study, we show that some patients with ARVC have evidence for myocardial inflammation on FDG-PET, suggesting that myocarditis plays a role in disease pathogenesis.

Adiponectin attenuates profibrotic extracellular matrix remodeling following cardiac injury by up-regulating matrix metalloproteinase 9 expression in mice.

Adiponectin (APN) is a multifunctional adipocytokine that inhibits myocardial fibrosis, dilatation, and left ventricular (LV) dysfunction after myocardial infarction (MI). Coxsackievirus B3 (CVB3) myocarditis is associated with intense extracellular matrix (ECM) remodeling which might progress to dilated cardiomyopathy. Here, we investigated in experimental CVB3 myocarditis whether APN inhibits adverse ECM remodeling following cardiac injury by affecting matrix metalloproteinase (MMP) expression. Cardiac injury was induced by CVB3 infection in APN knockout (APN-KO) and wild-type (WT) mice. Expression and activity of MMPs was quantified by qRT-PCR and zymography, respectively. Activation of protein kinases was assessed by immunoblot. In cardiac myocytes and fibroblasts APN up-regulates MMP-9 expression via activation of 5' adenosine monophosphate-activated protein kinase (AMPK) and extracellular signal-regulated kinase (ERK)1/2 which function as master regulators of inflammation-induced MMP-9 expression. Correspondingly, APN further increased up-regulation of MMP-9 expression triggered by tumor necrosis factor (TNF)α, lipopolysaccharide (LPS) and R-848 in cardiac fibroblasts. In vivo, compared to WT mice cardiac MMP-9 activity and serum levels of carboxy-terminal telopeptide of type I collagen (ICTP) were attenuated in APN-KO mice in subacute (day 7 p.i.) CVB3 myocarditis. Moreover, on day 3 and day 7 post CVB3 infection splenic MMP-9 expression was diminished in APN-KO mice correlating with attenuated myocardial immune cell infiltration in subacute CVB3 myocarditis. These results indicate that APN attenuates adverse cardiac remodeling following cardiac injury by up-regulating MMP-9 expression in cardiac and immune cells. Thus, APN mediates intensified collagen cleavage that might explain inhibition of LV fibrosis and dysfunction.

Human cardiac-derived adherent proliferating cells reduce murine acute Coxsackievirus B3-induced myocarditis.

BACKGROUND: Under conventional heart failure therapy, inflammatory cardiomyopathy typically has a progressive course, indicating a need for alternative therapeutic strategies to improve long-term outcomes. We recently isolated and identified novel cardiac-derived cells from human cardiac biopsies: cardiac-derived adherent proliferating cells (CAPs). They have similarities with mesenchymal stromal cells, which are known for their anti-apoptotic and immunomodulatory properties. We explored whether CAPs application could be a novel strategy to improve acute Coxsackievirus B3 (CVB3)-induced myocarditis. METHODOLOGY/PRINCIPAL FINDINGS: To evaluate the safety of our approach, we first analyzed the expression of the coxsackie- and adenovirus receptor (CAR) and the co-receptor CD55 on CAPs, which are both required for effective CVB3 infectivity. We could demonstrate that CAPs only minimally express both receptors, which translates to minimal CVB3 copy numbers, and without viral particle release after CVB3 infection. Co-culture of CAPs with CVB3-infected HL-1 cardiomyocytes resulted in a reduction of CVB3-induced HL-1 apoptosis and viral progeny release. In addition, CAPs reduced CD4 and CD8 T cell proliferation. All CAPs-mediated protective effects were nitric oxide- and interleukin-10-dependent and required interferon-γ. In an acute murine model of CVB3-induced myocarditis, application of CAPs led to a decrease of cardiac apoptosis, cardiac CVB3 viral load and improved left ventricular contractility parameters. This was associated with a decline in cardiac mononuclear cell activity, an increase in T regulatory cells and T cell apoptosis, and an increase in left ventricular interleukin-10 and interferon-γ mRNA expression. CONCLUSIONS: We conclude that CAPs are a unique type of cardiac-derived cells and promising tools to improve acute CVB3-induced myocarditis.

Assessment of diffuse myocardial fibrosis in rats using small-animal Look-Locker inversion recovery T1 mapping.

BACKGROUND: The concentration of gadopentetate dimeglumine in myocardium and blood can be assessed from T1 measurements and can be used to calculate the extracellular volume (ECV) of the myocardium. We hypothesized that diffuse myocardial fibrosis in a small-animal model could be quantitatively assessed by measuring myocardial ECV using small-animal Look-Locker inversion recovery T1 mapping. METHODS AND RESULTS: Sprague-Dawley rats (n=10) were subjected to continuous angiotensin-2 (AT2) infusion for 2 weeks via a subcutaneously implanted minipump system. Magnetic resonance imaging (MRI) was performed both before and after AT2 infusion. The MRI protocol included multislice cine imaging and before-and-after contrast small-animal Look-Locker inversion recovery T1 mapping and late gadolinium enhancement imaging. Myocardial ECV was calculated from hematocrit and T1 values of blood and myocardium. During the course of AT2 infusion, the mean±SD systolic blood pressure increased from 122±10.9 to 152±27.5 mm Hg (P=0.003). Normalized heart weight was significantly higher in AT2-treated animals than in control littermates (P=0.033). Cine MRI documented concentric left ventricular hypertrophy. Postcontrast myocardial T1 times were shortened after treatment (median [interquartile range], 712 [63] versus 820 [131] ms; P=0.002). Myocardial ECV increased from 17.2% (4.3%) before to 23.0% (6.2%) after AT2 treatment (P=0.031), which was accompanied by perivascular fibrosis and microscarring on myocardial histological analysis. There was a moderate level of correlation between ECV and collagen volume fraction, as assessed by histological analysis (r=0.69, P=0.013). CONCLUSIONS: In a small-animal model of left ventricular hypertrophy, contrast-enhanced T1 mapping can be used to detect diffuse myocardial fibrosis by quantification of myocardial ECV.

Matricellular signaling molecule CCN1 attenuates experimental autoimmune myocarditis by acting as a novel immune cell migration modulator.

BACKGROUND: CCN1 is an evolutionary ancient matricellular protein that modulates biological processes associated with tissue repair. Induction at sites of injury was observed in conditions ranging from skin wounds to cardiac diseases, including ischemic and inflammatory cardiomyopathy. Here, we provide evidence of a novel function of CCN1 as a modulator of immune cell migration. METHODS AND RESULTS: to understand the role of CCN1 in cardiomyopathies and to evaluate its therapeutic potential, we overexpressed CCN1 using an adenoviral hepatotropic vector in murine experimental autoimmune myocarditis, a model of human inflammatory cardiomyopathy. CCN1 gene transfer significantly reduced cardiac disease score and immune cell infiltration. In vivo tracking of hemagglutinin epitope-tagged CCN1 revealed binding to spleen macrophages but not to cardiomyocytes. Unexpectedly, CCN1 therapy left cardiac chemokine and cytokine expression unchanged but instead strongly inhibited the migration of spleen macrophages and lymphocytes, as evidenced by ex vivo transwell assays. In accordance with the ex vivo data, in vitro preincubation with CCN1 diminished transwell migration of human monocytes and abrogated their chemotactic response to monocyte chemoattractant protein-1, macrophage inflammatory protein-1α, and stromal cell-derived factor-1α. Further mechanistic studies showed that CCN1-driven modulation of immune cell migration is mimicked in part by cyclic RGD peptides currently in clinical evaluation for cancer therapy. CONCLUSIONS: our proof-of-concept study suggests investigation of CCN1 as a novel, endogenous "parent compound" for chemotaxis modulation and of cyclic RGD peptides as a class of partially CCN1-mimetic drugs with immediate potential for clinical evaluation in cardiac diseases associated with chronic pathogenic inflammation.

A common MLP (muscle LIM protein) variant is associated with cardiomyopathy.

RATIONALE: We previously discovered the human 10T-->C (Trp4Arg) missense mutation in exon 2 of the muscle LIM protein (MLP, CSRP3) gene. OBJECTIVE: We sought to study the effects of this single-nucleotide polymorphism in the in vivo situation. METHODS AND RESULTS: We now report the generation and detailed analysis of the corresponding Mlp(W4R/+) and Mlp(W4R/W4R) knock-in animals, which develop an age- and gene dosage-dependent hypertrophic cardiomyopathy and heart failure phenotype, characterized by almost complete loss of contractile reserve under catecholamine induced stress. In addition, evidence for skeletal muscle pathology, which might have implications for human mutation carriers, was observed. Importantly, we found significantly reduced MLP mRNA and MLP protein expression levels in hearts of heterozygous and homozygous W4R-MLP knock-in animals. We also detected a weaker in vitro interaction of telethonin with W4R-MLP than with wild-type MLP. These alterations may contribute to an increased nuclear localization of W4R-MLP, which was observed by immunohistochemistry. CONCLUSIONS: Given the well-known high frequency of this mutation in Caucasians of up to 1%, our data suggest that (W4R-MLP) might contribute significantly to human cardiovascular disease.