Hematopoietic progenitor cell liabilities and alarmins S100A8/A9-related inflammaging associate with frailty and predict poor cardiovascular outcomes in older adults.

Frailty affects the physical, cognitive, and social domains exposing older adults to an increased risk of cardiovascular disease and death. The mechanisms linking frailty and cardiovascular outcomes are mostly unknown. Here, we studied the association of abundance (flow cytometry) and gene expression profile (RNAseq) of stem/progenitor cells (HSPCs) and molecular markers of inflammaging (ELISA) with the cardiorespiratory phenotype and prospective adverse events of individuals classified according to levels of frailty. Two cohorts of older adults were enrolled in the study. In a cohort of pre-frail 35 individuals (average age: 75 years), a physical frailty score above the median identified subjects with initial alterations in cardiorespiratory function. RNA sequencing revealed S100A8/A9 upregulation in HSPCs from the bone marrow (>10-fold) and peripheral blood (>200-fold) of individuals with greater physical frailty. Moreover higher frailty was associated with increased alarmins S100A8/A9 and inflammatory cytokines in peripheral blood. We then studied a cohort of 104 more frail individuals (average age: 81 years) with multidomain health deficits. Reduced levels of circulating HSPCs and increased S100A8/A9 concentrations were independently associated with the frailty index. Remarkably, low HSPCs and high S100A8/A9 simultaneously predicted major adverse cardiovascular events at 1-year follow-up after adjustment for age and frailty index. In conclusion, inflammaging characterized by alarmin and pro-inflammatory cytokines in pre-frail individuals is mirrored by the pauperization of HSPCs in frail older people with comorbidities. S100A8/A9 is upregulated within HSPCs, identifying a phenotype that associates with poor cardiovascular outcomes.

The SARS-CoV-2 Spike protein disrupts human cardiac pericytes function through CD147 receptor-mediated signalling: a potential non-infective mechanism of COVID-19 microvascular disease.

The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) causes a broad range of clinical responses including prominent microvascular damage. The capacity of SARS-CoV-2 to infect vascular cells is still debated. Additionally, the SARS-CoV-2 Spike (S) protein may act as a ligand to induce non-infective cellular stress. We tested this hypothesis in pericytes (PCs), which are reportedly reduced in the heart of patients with severe coronavirus disease-2019 (COVID-19). Here we newly show that the in vitro exposure of primary human cardiac PCs to the SARS-CoV-2 wildtype strain or the α and δ variants caused rare infection events. Exposure to the recombinant S protein alone elicited signalling and functional alterations, including: (1) increased migration, (2) reduced ability to support endothelial cell (EC) network formation on Matrigel, (3) secretion of pro-inflammatory molecules typically involved in the cytokine storm, and (4) production of pro-apoptotic factors causing EC death. Next, adopting a blocking strategy against the S protein receptors angiotensin-converting enzyme 2 (ACE2) and CD147, we discovered that the S protein stimulates the phosphorylation/activation of the extracellular signal-regulated kinase 1/2 (ERK1/2) through the CD147 receptor, but not ACE2, in PCs. The neutralisation of CD147, either using a blocking antibody or mRNA silencing, reduced ERK1/2 activation, and rescued PC function in the presence of the S protein. Immunoreactive S protein was detected in the peripheral blood of infected patients. In conclusion, our findings suggest that the S protein may prompt PC dysfunction, potentially contributing to microvascular injury. This mechanism may have clinical and therapeutic implications.

Treatment of COVID-19 by stage: any space left for mesenchymal stem cell therapy?

In many countries, COVID-19 now accounts for more deaths per year than car accidents and even the deadliest wars. Combating the viral pandemics requires a coordinated effort to develop therapeutic protocols adaptable to the disease severity. In this review article, we summarize a graded approach aiming to shield cells from SARS-CoV-2 entry and infection, inhibit excess inflammation and evasion of the immune response, and ultimately prevent systemic organ failure. Moreover, we focus on mesenchymal stem cell therapy, which has shown safety and efficacy as a treatment of inflammatory and immune diseases. The cell therapy approach is now repurposed in patients with severe COVID-19. Numerous trials of mesenchymal stem cell therapy are ongoing, especially in China and the USA. Leader companies in cell therapy have also started controlled trials utilizing their quality assessed cell products. Results are too premature to reach definitive conclusions.

COVID-19, State of the Adult and Pediatric Heart: From Myocardial Injury to Cardiac Effect of Potential Therapeutic Intervention.

While the COVID-19 pandemic continues to spread rapidly, resulting in considerable morbidity and mortality worldwide, multiple efforts are being made by the international scientific community to understand the pathogenesis of the viral infection and its clinical outcome. Older age and comorbidities have consistently been reported as risk factors for unfavorable prognosis, with cardiovascular disease accounting for up to 10 % of comorbid conditions among the infected patients. An understanding of the mechanism underlying the effect of this infection on patients with cardiovascular disease is essential to manage and improve clinical strategies against the disease in that population. In this review, we summarize the impact of COVID-19 on patients with underlying cardiovascular conditions and the cardiac implications of known and emerging therapeutic strategies. Our future effort will aim to further elucidate how the type and severity of the cardiac disease, with particular regard to Congenital Heart Disease, influences the prognosis and the outcome of the viral infection.