Approximately 9 months of the severe acute respiratory syndrome coronavius-2 (SARS-CoV-2 [COVID-19]) spreading across the globe has led to widespread COVID-19 acute hospitalizations and death. The rapidity and highly communicable nature of the SARS-CoV-2 outbreak has hampered the design and execution of definitive randomized, controlled trials of therapy outside of the clinic or hospital. In the absence of clinical trial results, physicians must use what has been learned about the pathophysiology of SARS-CoV-2 infection in determining early outpatient treatment of the illness with the aim of preventing hospitalization or death. This article outlines key pathophysiological principles that relate to the patient with early infection treated at home. Therapeutic approaches based on these principles include 1) reduction of reinoculation, 2) combination antiviral therapy, 3) immunomodulation, 4) antiplatelet/antithrombotic therapy, and 5) administration of oxygen, monitoring, and telemedicine. Future randomized trials testing the principles and agents discussed will undoubtedly refine and clarify their individual roles; however, we emphasize the immediate need for management guidance in the setting of widespread hospital resource consumption, morbidity, and mortality.

Cardiac fibroblasts are responsible for synthesis and deposition of fibrillar collagen types I and III. Transforming growth factor-,31 (TGF-j31) has been proved to increase collagen biosynthesis in various systems, both in vivo and in vitro. We have investigated the effect of TGF-P1 on collagen gene expression in cultured cardiac fibroblasts and have compared this effect with that of a mitogenic agent, phorbol myristate acetate (PMA). The regulation of collagen types I and III gene expression was examined by using cDNA probes to rat a£2 (I) and mouse a1 (III) procollagens. Quiescent cultured cardiac fibroblasts from rabbit heart were treated with TGF-(1 (10-15 ng/ml) and PMA (200 ng/ml). After 24 hours of treatment with TGF-f.1, the abundance of mRNA for pro-a2 (I) and pro-a1, (III) collagens was increased by 112% (p<0.001) and 97% (p=0.05), respectively, in treated fibroblasts compared with untreated cells. However, PMA-treated cells showed an opposite response: a 42% (p=0.01) decrease in mRNA levels for pro-a!2 (I) collagen was observed. Immunofluorescent staining of cardiac fibroblasts in culture with anti-type I collagen antibody showed that alterations in mRNA levels led to altered collagen synthesis: cellular collagen was relatively increased in TGF-f31-treated cells and significantly diminished in PMA-treated cells. The abundance of mRNA for pro-al (III) collagen was not affected by PMA treatment. Inereased collagen gene expression by TGF-f31 was abolished in the presence of cycloheximide, whereas the inhibitory effect of PMA on collagen type I mRNA did not change after addition of cycloheximide to the culture medium.

Cardiac fibroblasts are mainly responsible for the synthesis of major extracellular matrix proteins in the heart, including fibrillar collagen types I and m and fibronectin. In this report we show that these cells, when stimulated by transforming growth factor /31 , acquire certain myocyte-specific properties. Cultured cardiac fibroblasts from adult rabbit heart were treated with TGF-813 (10-15 ng/ml) for The myocardial cell population consists largely of cardiac myocytes that occupy "90% of the myocardial mass. Ninety to 95% of the nonmyocyte fraction of cardiac cells consists of cardiac fibroblasts (1, 2).Little is known about cardiac myogenesis. No stem cell has been identified and no cell line has been found that will convert into cardiac myocytes upon specific external stimuli.A highly significant finding in the last few years has been the discovery of the myoD family of genes that is able to promote conversion of fibroblasts into skeletal muscle cells (3). It would be highly desirable to develop a similar system for cardiac myocytes.(TGF-,31) Transforming growth-factor P3, has been shown to act as a mitogen and growth factor for various cultured cells. This growth factor is present in various tissues (4, 5). We (6) and others (7) have previously reported the presence and distribution of TGF-f31 in the rat myocardium. The purpose of the present study was to examine the effects of TGF-/31 on cardiac fibroblasts with respect to growth and differentiation. In this report, we present evidence indicating that cardiac fibroblasts obtained from hearts of adult rat, when exposed to TGF-,31, can differentiate into cells that display some of the phenotypic features of cardiac myocytes. METHODSCell Culture and Treatments. Adult male (New Zealand White) rabbits were anesthetized; hearts were excised, minced, and washed in phosphate-buffered saline (PBS). The tissue was treated at 350C with a mixture of 0.1% trypsin and 100 units of collagenase per ml (type IV, Sigma) for 10 min. Isolated cells were pelleted at the end of several 10-min digestion periods, plated on 100-mm culture dishes in Dulbecco's modified Eagle medium (DMEM) containing 10-15% fetal bovine serum (FBS), and incubated for 2 hr at 370C in an incubator with 90% 02/10% CO2 with a humidifier. At the end of that period, the unattached cells were discarded and attached cells were grown in DMEM with 10% FBS. The fibroblastic nature of confluent cells as well as the purity of the cultured cell population was determined by immunofluorescence staining of the cell layer with anti-human factor VIII antibody (Behring Diagnostics) for endothelial cells, anti-desmin (Calbiochem) for muscle cells, and anti-vimentin (2) for fibroblasts. In a confluent cell preparation only 1-2% of cells stained positively with anti-factor VIII and antidesmin. All cells were stained positively with anti-vimentin antibody. For all our studies cells from passages 4-6 were used. For each treatment, cells were grown to confluency in medium containing 10o FBS. They were then deprived...

Hypotension is commonly encountered during carotid artery stenting (CAS), mediated by vagal stimulation and suppression of sympathetic outflow. Some patients require treatment with intravenous vasopressors (dopamine, nor-epinephrine, or phenylephrine). The authors describe the successful use of the oral agent midodrine as an alternative to intravenous vasopressors in the treatment of hypotension related to CAS. Of 55 patients who underwent elective CAS, 19 (35%) experienced significant hypotension, and 15 (27%) required vasopressor therapy. Eleven patients received intravenous dopamine infusion in an intensive care setting, whereas 4 received oral midodrine in a regular telemetry unit. All patients eventually recovered and were discharged without any residual cardiovascular or neurological complications. No major side effects were noted with the use of both dopamine and midodrine. Cost of hospitalization was significantly higher in the dopamine group because of the need for ICU admission.

Myocardial stunning, a reversible decrease in the contractile function of the myocardium after an ischemic insult, often leads to hypotension that requires therapy with intravenous inotropes. We used the oral agent midodrine to treat hypotension that complicated myocardial stunning after successful revascularization with percutaneous coronary intervention in the setting of myocardial infarction and ischemia. Oral midodrine may offer a useful substitute to intravenous inotropic therapy and can shorten the duration of intensive care unit and hospital stay in this setting.