Abstract:
The new emerging SARS-CoV-2 is responsible for more than 640,395,651 cases and over 6,618,579 deaths worldwide. The SARS-CoV-2 infection is responsible for several concomitants, including severe thrombotic events, systemic inflammation, changes in hemostasis, and coagulation. Primary, the lung is affected regarding thrombi formation, but the heart, brain, liver, and kidney are also highly perceptible. Clinical cardiovascular complications frequently occur in hospitalized COVID-19 patients like acute heart failure and stroke, arrhythmias, venous thromboembolism, cardiogenic shock, arterial thrombosis, and myocarditis. Patients with cardiovascular diseases like coronary artery disease (CAD) are prone to develop severe clinical courses with worsening prognoses and life-threatening heart and lung injuries. Our study characterized important peripheral monocytes and thrombocytes in patients with a cardiovascular disease associated with an acute SARS-CoV-2 infection. Patients with a predisposition like CAD and an acute SARS-CoV-2 infection demonstrated a reduced number of peripheral non-classical monocytes with a changed phenotype indicating a defective migration and T cell activation behavior compared to CAD patients without infection. Further, a reduced number of non-classical monocytes below the calculated median represents a prognostic marker for rapidly progressive respiratory failure indicated by a HI < 200mmHg with subsequent mechanical ventilation. Characterizing peripheral thrombocytes in CAD patients following SARS-CoV-2 infection showed increased systemic platelet activation and hyper-inflammation. In addition, plasma levels of the convertase furin were significantly reduced in ICU-treated patients compared to patients with a mild disease progression. Further, furin functions as a prognostic plasma marker for a poor clinical outcome in SARS-CoV-2 positive CAD patients. SARS-CoV-2 infected patients with cardiovascular diseases demonstrated a significantly increased concentration of intracellular MIF in monocyte subsets after a recovery phase of three months. Further, phenotype of monocytes differed comparing acutely infected patients with a follow-up of three months. These results imply a prolonged immune response upon severe acute SARS-CoV-2 infection related to increased intracellular MIF expression and changes in monocyte phenotypes.
In summary, we demonstrated that the number of circulating non-classical monocytes can be used as a prognostic marker for rapidly progressive respiratory failure, and an association of the convertase furin with a poor clinical outcome upon SARS-CoV-2 infection.
The other part of the thesis gives insight into the role of thrombocytes and monocytes in patients with calcific aortic valve stenosis. Calcific aortic valve stenosis represents the most prevalent valve disease in western countries, particularly in the aging population. The aortic valve is affected by accelerating inflammation, fibrotic and calcific remodeling of the valve leaflets, thickening, and osteogenic formation leading to valve obstruction. Until now, no
pharmaceutical strategies are available to prevent inflammation, calcification, and osteogenic formation at an early stage of aortic stenosis. Thus, it is urgent to find new diagnostic and therapeutic targets to prevent severe disease progression. A huge cohort of patients with severe aortic stenosis demonstrated different phenotypes of slow and fast disease progression. Patients with a slow disease progression showed a calcific, pro-osteogenic and TGF-ß1 dependent phenotype. However, fast progressive aortic stenosis was characterized by an inflammatory and MIF-dependent phenotype. Further, the chemokine-like MIF may predict a fast disease progression in patients and is related to a local aortic valve tissue inflammation.
SARS-CoV-2, MIF, aortic valve disease