Collagen-Specific HSP47+ Myofibroblasts and CD163+ Macrophages Identify Profibrotic Phenotypes in Deceased Hearts With SARS-CoV-2 Infections.

Background Cardiac fibrosis complicates SARS-CoV-2 infections and has been linked to arrhythmic complications in survivors. Accordingly, we sought evidence of increased HSP47 (heat shock protein 47), a stress-inducible chaperone protein that regulates biosynthesis and secretion of procollagen in heart tissue, with the goal of elucidating molecular mechanisms underlying cardiac fibrosis in subjects with this viral infection. Methods and Results Using human autopsy tissue, immunofluorescence, and immunohistochemistry, we quantified Hsp47+ cells and collagen α 1(l) in hearts from people with SARS-CoV-2 infections. Because macrophages are also linked to inflammation, we measured CD163+ cells in the same tissues. We observed irregular groups of spindle-shaped HSP47+ and CD163+ cells as well as increased collagen α 1(I) deposition, each proximate to one another in "hot spots" of ≈40% of hearts after SARS-CoV-2 infection (HSP47+ P<0.05 versus nonfibrotics and P<0.001 versus controls). Because HSP47+ cells are consistent with myofibroblasts, subjects with hot spots are termed "profibrotic." The remaining 60% of subjects dying with COVID-19 without hot spots are referred to as "nonfibrotic." No control subject exhibited hot spots. Conclusions Colocalization of myofibroblasts, M2(CD163+) macrophages, and collagen α 1(l) may be the first evidence of a COVID-19-related "profibrotic phenotype" in human hearts in situ. The potential public health and diagnostic implications of these observations require follow-up to further define mechanisms of viral-mediated cardiac fibrosis.

Impact of the COVID-19 Pandemic on Cardiovascular Science: Anticipating Problems and Potential Solutions: A Presidential Advisory From the American Heart Association.

The coronavirus disease 2019 (COVID-19) pandemic has had worldwide repercussions for health care and research. In spring 2020, most non-COVID-19 research was halted, hindering research across the spectrum from laboratory-based experimental science to clinical research. Through the second half of 2020 and the first half of 2021, biomedical research, including cardiovascular science, only gradually restarted, with many restrictions on onsite activities, limited clinical research participation, and the challenges associated with working from home and caregiver responsibilities. Compounding these impediments, much of the global biomedical research infrastructure was redirected toward vaccine testing and deployment. This redirection of supply chains, personnel, and equipment has additionally hampered restoration of normal research activity. Transition to virtual interactions offset some of these limitations but did not adequately replace the need for scientific exchange and collaboration. Here, we outline key steps to reinvigorate biomedical research, including a call for increased support from the National Institutes of Health. We also call on academic institutions, publishers, reviewers, and supervisors to consider the impact of COVID-19 when assessing productivity, recognizing that the pandemic did not affect all equally. We identify trainees and junior investigators, especially those with caregiving roles, as most at risk of being lost from the biomedical workforce and identify steps to reduce the loss of these key investigators. Although the global pandemic highlighted the power of biomedical science to define, treat, and protect against threats to human health, significant investment in the biomedical workforce is required to maintain and promote well-being.

Pneumocytes are distinguished by highly elevated expression of the ER stress biomarker GRP78, a co-receptor for SARS-CoV-2, in COVID-19 autopsies.

Vaccinations are widely credited with reducing death rates from COVID-19, but the underlying host-viral mechanisms/interactions for morbidity and mortality of SARS-CoV-2 infection remain poorly understood. Acute respiratory distress syndrome (ARDS) describes the severe lung injury, which is pathologically associated with alveolar damage, inflammation, non-cardiogenic edema, and hyaline membrane formation. Because proteostatic pathways play central roles in cellular protection, immune modulation, protein degradation, and tissue repair, we examined the pathological features for the unfolded protein response (UPR) using the surrogate biomarker glucose-regulated protein 78 (GRP78) and co-receptor for SARS-CoV-2. At autopsy, immunostaining of COVID-19 lungs showed highly elevated expression of GRP78 in both pneumocytes and macrophages compared with that of non-COVID control lungs. GRP78 expression was detected in both SARS-CoV-2-infected and un-infected pneumocytes as determined by multiplexed immunostaining for nucleocapsid protein. In macrophages, immunohistochemical staining for GRP78 from deceased COVID-19 patients was increased but overlapped with GRP78 expression taken from surgical resections of non-COVID-19 controls. In contrast, the robust in situ GRP78 immunostaining of pneumocytes from COVID-19 autopsies exhibited no overlap and was independent of age, race/ethnicity, and gender compared with that from non-COVID-19 controls. Our findings bring new insights for stress-response pathways involving the proteostatic network implicated for host resilience and suggest that targeting of GRP78 expression with existing therapeutics might afford an alternative therapeutic strategy to modulate host-viral interactions during SARS-CoV-2 infections.

Hypertriglyceridemia during hospitalization independently associates with mortality in patients with COVID-19.

BACKGROUND: Alteration in blood triglyceride levels have been found in patients with coronavirus disease 2019 (COVID-19). However, the association between hypertriglyceridemia and mortality in COVID-19 patients is unknown. OBJECTIVE: To investigate the association between alteration in triglyceride level and mortality in hospitalized COVID-19 patients. METHODS: We conducted a retrospective study of 600 hospitalized patients with COVID-19 diagnosis (ICD10CM:U07.1) and/or SARS-CoV-2 positive testing results between March 1, 2020 and December 21, 2020 at a tertiary academic medical center in Milwaukee, Wisconsin. De-identified data, including demographics, medical history, and blood triglyceride levels were collected and analyzed. Of the 600 patients, 109 patients died. The triglyceride value on admission was considered the baseline and the peak was defined as the highest level reported during the entire period of hospitalization. Hypertriglyceridemia was defined as greater than 150 mg/dl. Logistic regression analyses were performed to evaluate the association between hypertriglyceridemia and mortality. RESULTS: There was no significant difference in baseline triglyceride levels between non-survivors (n = 109) and survivors (n = 491) [Median 127 vs. 113 mg/dl, p = 0.213]. However, the non-survivors had significantly higher peak triglyceride levels during hospitalization [Median 179 vs. 134 mg/dl, p < 0.001]. Importantly, hypertriglyceridemia independently associated with mortality [odds ratio=2.3 (95% CI: 1.4-3.7, p = 0.001)], after adjusting for age, gender, obesity, history of hypertension and diabetes, high CRP, high leukocyte count and glucocorticoid treatment in a multivariable logistic regression model. CONCLUSIONS: Hypertriglyceridemia during hospitalization is independently associated with 2.3 times higher mortality in COVID-19 patients. Prospective studies are needed to independently validate this retrospective analysis.