Functional Effects of Cardiomyocyte Injury in COVID-19.

COVID-19 affects multiple organs. Clinical data from the Mount Sinai Health System show that substantial numbers of COVID-19 patients without prior heart disease develop cardiac dysfunction. How COVID-19 patients develop cardiac disease is not known. We integrated cell biological and physiological analyses of human cardiomyocytes differentiated from human induced pluripotent stem cells (hiPSCs) infected with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in the presence of interleukins (ILs) with clinical findings related to laboratory values in COVID-19 patients to identify plausible mechanisms of cardiac disease in COVID-19 patients. We infected hiPSC-derived cardiomyocytes from healthy human subjects with SARS-CoV-2 in the absence and presence of IL-6 and IL-1ß. Infection resulted in increased numbers of multinucleated cells. Interleukin treatment and infection resulted in disorganization of myofibrils, extracellular release of troponin I, and reduced and erratic beating. Infection resulted in decreased expression of mRNA encoding key proteins of the cardiomyocyte contractile apparatus. Although interleukins did not increase the extent of infection, they increased the contractile dysfunction associated with viral infection of cardiomyocytes, resulting in cessation of beating. Clinical data from hospitalized patients from the Mount Sinai Health System show that a significant portion of COVID-19 patients without history of heart disease have elevated troponin and interleukin levels. A substantial subset of these patients showed reduced left ventricular function by echocardiography. Our laboratory observations, combined with the clinical data, indicate that direct effects on cardiomyocytes by interleukins and SARS-CoV-2 infection might underlie heart disease in COVID-19 patients. IMPORTANCE SARS-CoV-2 infects multiple organs, including the heart. Analyses of hospitalized patients show that a substantial number without prior indication of heart disease or comorbidities show significant injury to heart tissue, assessed by increased levels of troponin in blood. We studied the cell biological and physiological effects of virus infection of healthy human iPSC-derived cardiomyocytes in culture. Virus infection with interleukins disorganizes myofibrils, increases cell size and the numbers of multinucleated cells, and suppresses the expression of proteins of the contractile apparatus. Viral infection of cardiomyocytes in culture triggers release of troponin similar to elevation in levels of COVID-19 patients with heart disease. Viral infection in the presence of interleukins slows down and desynchronizes the beating of cardiomyocytes in culture. The cell-level physiological changes are similar to decreases in left ventricular ejection seen in imaging of patients' hearts. These observations suggest that direct injury to heart tissue by virus can be one underlying cause of heart disease in COVID-19.

Memory discrimination is promoted by the expression of the transcription repressor WT1 in the dentate gyrus.

The hippocampus is critical for the precise formation of contextual memories. Overlapping inputs coming from the entorhinal cortex are processed by the trisynaptic pathway to form distinct memories. Disruption in any step of the circuit flow can lead to a lack of memory precision, and to memory interference. We have identified the transcriptional repressor Wilm's Tumor 1 (WT1) as an important regulator of synaptic plasticity involved in memory discrimination in the hippocampus. In male mice, using viral and transgenic approaches, we showed that WT1 deletion in granule cells of the dentate gyrus (DG) disrupts memory discrimination. With electrophysiological methods, we then identified changes in granule cells' excitability and DG synaptic transmission indicating that WT1 knockdown in DG granule cells disrupts the inhibitory feedforward input from mossy fibers to CA3 by decreasing mIPSCs and shifting the normal excitatory/inhibitory (E/I) balance in the DG → CA3 circuit in favor of excitation. Finally, using a chemogenetic approach, we established a causal link between granule cell hyperexcitability and memory discrimination impairments. Our results suggest that WT1 enables a circuit-level computation that drives pattern discrimination behavior.