In patients with coronavirus disease 2019 (COVID-19), cardiovascular involvement occurs frequently. Myocardial injury with elevated troponin levels is described in patients hospitalized with COVID-19¹ and seems to be associated with outcome.² The origin of myocardial injury can result from ischemia due to thrombotic coronary obstruction but can also include other causes such as heart failure, pulmonary embolism, tachycardia, and sepsis.³ Obviously, an infection of the myocardium with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is another alternative for elevated troponin. Next to elevated biomarkers for cardiac injury, myocardial dysfunction determined by echocardiography is also reported in up to 70% of hospitalized patients.⁴ This makes cardiac involvement during COVID-19, which manifests primarily as a pulmonary disease, likely.

Extrapulmonary manifestations of COVID-19 have gained attention due to their links to clinical outcomes and their potential long-term sequelae¹. Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) displays tropism towards several organs, including the heart and kidney. Whether it also directly affects the liver has been debated^2,3. Here we provide clinical, histopathological, molecular and bioinformatic evidence for the hepatic tropism of SARS-CoV-2. We find that liver injury, indicated by a high frequency of abnormal liver function tests, is a common clinical feature of COVID-19 in two independent cohorts of patients with COVID-19 requiring hospitalization. Using autopsy samples obtained from a third patient cohort, we provide multiple levels of evidence for SARS-CoV-2 liver tropism, including viral RNA detection in 69% of autopsy liver specimens, and successful isolation of infectious SARS-CoV-2 from liver tissue postmortem. Furthermore, we identify transcription-, proteomic- and transcription factor-based activity profiles in hepatic autopsy samples, revealing similarities to the signatures associated with multiple other viral infections of the human liver. Together, we provide a comprehensive multimodal analysis of SARS-CoV-2 liver tropism, which increases our understanding of the molecular consequences of severe COVID-19 and could be useful for the identification of organ-specific pharmacological targets.

We investigated whether the pro-fibrotic matricellular protein osteopontin (OPN) is associated with the enzymes involved in the extracellular synthesis of fibril-forming collagen type I (i.e. procollagen C-proteinase, PCP) and its cross-linking to form insoluble fibrils (i.e. lysyl oxidase, LOX) in heart failure (HF) of hypertensive origin. OPN, PCP, and LOX were assessed by histochemical and molecular methods in the myocardium of 21 patients with hypertensive heart disease (HHD) and HF. Whereas the myocardial expression of OPN was very scarce in control hearts (n = 10), it was highly expressed in HF patients (P < 0.0001). OPN was directly correlated with LOX (r = 0.460, P = 0.041), insoluble collagen (r = 0.534, P = 0.015), pulmonary capillary wedge pressure (r = 0.558; P = 0.009), and left-ventricular (LV) chamber stiffness (r = 0.458, P = 0.037), and inversely correlated with LV ejection fraction (r = −0.513, P = 0.017) in all patients. OPN did not correlate with PCP and other parameters assessing collagen synthesis by fibroblasts or degradation by matrix metalloproteinases. In vitro studies showed that OPN significantly (P < 0.05) increases the expression and activity of LOX in human cardiac and dermal fibroblasts. An excess of OPN is associated with increased LOX and insoluble collagen, as well as with LV stiffness and systolic dysfunction in patients with HHD and HF. In addition, OPN up-regulates LOX in human fibroblasts. It is suggested that the OPN–LOX axis might facilitate the formation of insoluble collagen (i.e. stiff and resistant to degradation) and the subsequent alteration in LV mechanical properties and function in patients with HHD and HF.

Cardiovascular diseases (CVDs) remain the leading cause of death worldwide. Most cardiovascular deaths are caused by ischaemic heart diseases such as myocardial infarction (MI). Hereby atherosclerosis in the coronary arteries often precedes disease manifestation. Since tissue remodelling plays an important role in the development and progression of atherosclerosis as well as in outcome after MI, regulation of matrix metalloproteinases (MMPs) as the major ECM-degrading enzymes with diverse other functions is crucial. Here, we provide an overview of the expression profiles of MMPs in coronary artery and left ventricular tissue using publicly available data from whole tissue to single-cell resolution. To approach an association between MMP expression and the development and outcome of CVDs, we further review studies investigating polymorphisms in MMP genes since polymorphisms are known to have an impact on gene expression. This review therefore aims to shed light on the role of MMPs in atherosclerosis and MI by summarizing current knowledge from publically available datasets, human studies, and analyses of polymorphisms up to preclinical and clinical trials of pharmacological MMP inhibition.