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.

Physiology of cardiomyocyte injury in COVID-19.

COVID-19 affects multiple organs. Clinical data from the Mount Sinai Health System shows 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 integrate cell biological and physiological analyses of human cardiomyocytes differentiated from human induced pluripotent stem cells (hiPSCs) infected with SARS-CoV-2 in the presence of interleukins, with clinical findings, to investigate 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 interleukins. We find that interleukin treatment and infection results in disorganization of myofibrils, extracellular release of troponin-I, and reduced and erratic beating. Although interleukins do not increase the extent, they increase the severity of 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 prior 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 can underlie the heart disease in COVID-19 patients.

The association of an alpha2C adrenoreceptor gene polymorphism with vasomotor symptoms in African American women.

OBJECTIVE: The alpha2C adrenoreceptor deletion 322-325 (ADRA2C del 322-325) polymorphism has been associated with autonomic activity and thermoregulation, which are implicated in the vasomotor symptom (VMS) mechanism. The ADRA2C del (322-325) has higher prevalence in African American women, a group known to experience more frequent and bothersome VMS. We assessed whether the ADRA2C del (322-325) genotype is associated with increased frequency of VMS in African American women. METHODS: DNA samples from African American (N = 400) women participating in the Study of Women's Health Across the Nation (SWAN) were genotyped for the ADRA2C del (322-325) polymorphism. Longitudinal data on VMS were obtained from the SWAN repository. The relation of ADRA2C del (322-325) genotypes (deletion/deletion [D/D]; insertion/deletion [I/D]; insertion/insertion [I/I]) with VMS over the menopausal transition for up to 12 years of follow-up was examined using generalized estimating equations. Primary models considered the outcome of frequent VMS (6 or more days in the prior 2 wk vs VMS <6 d in the prior 2 wk) by stage of menopause. RESULTS: Four hundred DNA samples from African American women were included. Seventy-five women (18.8%) were found to carry the homozygous variant allele (D/D). There was no significant difference in the trajectory of frequent VMS over the menopausal transition between women with D/D and I/I + I/D genotypes (P = 0.39). CONCLUSIONS: In this preliminary study among African American women in SWAN, ADRA2C del (322-325) was not significantly related to self-reported VMS. Further studies are warranted to help us understand the role of the adrenergic system in the physiology of VMS to tailor medical therapy to patient needs.

Hospital readmissions after hospital discharge for hip fracture: surgical and nonsurgical causes and effect on outcomes.

OBJECTIVES: To examine the causes of hospital readmission after hip fracture and the relationships between hospital readmission and 6-month physical function and mortality. DESIGN: Prospective, multisite, observational cohort study. SETTING: Four hospitals in the New York City metropolitan area. PARTICIPANTS: Five hundred sixty-two patients hospitalized for hip fracture aged 50 and older and discharged alive in 1997-1998. MEASUREMENTS: Patient demographic characteristics, type of fracture and repair, comorbid conditions, postoperative complications, do not resuscitate status, and active clinical problems at the time of hospital discharge. Prefracture and 6-month mobility were measured using the Functional Independence Measure. Hospital readmissions and International Classification of Diseases, Ninth Revision principal diagnoses were ascertained from hospital admission/discharge databases, the New York Statewide Planning and Research Cooperative System, medical record review, and patient self-report. RESULTS: Eighty-two percent of participants were women, and 93% were white. Within 6 months after hospital discharge, 178 (32%) patients were readmitted to the hospital, with 45 (8%) readmitted more than once. Forty-seven of 233 readmissions (20%) occurred within the first 2 weeks after discharge, and 80 (34%) occurred within 4 weeks. Over 6 months, 89% of readmissions were for nonsurgical problems, of which infectious (21%) and cardiac (12%) diseases were the most common. In multivariate analyses, patients who were readmitted were more likely to require total assistance with ambulation at 6 months (odds ratio (OR) = 2.7, 95% confidence interval (CI) = 1.6-4.6) and to die (OR = 4.0, 95% CI = 2.2-7.3) than those not readmitted. CONCLUSION: Hospital readmissions after hip fracture are largely due to nonsurgical illness and are associated with increased morbidity and mortality.

Association of timing of surgery for hip fracture and patient outcomes.

CONTEXT: Previous studies of surgical timing in patients with hip fracture have yielded conflicting findings on mortality and have not focused on functional outcomes. OBJECTIVE: To examine the association of timing of surgical repair of hip fracture with function and other outcomes. DESIGN: Prospective cohort study including analyses matching cases of early (< or =24 hours) and late (>24 hours) surgery with propensity scores and excluding patients who might not be candidates for early surgery. SETTING: Four hospitals in the New York City metropolitan area. PARTICIPANTS: A total of 1206 patients aged 50 years or older admitted with hip fracture over 29 months, ending December 1999. MAIN OUTCOME MEASURES: Function (using the Functional Independence Measure), survival, pain, and length of stay (LOS). RESULTS: Of the patients treated with surgery (n = 1178), 33.8% had surgery within 24 hours. Earlier surgery was not associated with improved mortality (hazard ratio, 0.75; 95% confidence interval [CI], 0.52-1.08) or improved locomotion (difference of -0.04 points; 95% CI, -0.49 to 0.39). Earlier surgery was associated with fewer days of severe and very severe pain (difference of -0.22 days; 95% CI, -0.41 to -0.03) and shorter LOS by 1.94 days (P<.001), but postoperative pain and LOS after surgery did not differ. Analyses with propensity scores yielded similar results. When the cohort included only patients who were medically stable at admission and therefore eligible for early surgery, the results were unchanged except that early surgery was associated with fewer major complications (odds ratio, 0.26; 95% CI, 0.07-0.95). CONCLUSIONS: Early surgery was not associated with improved function or mortality, but it was associated with reduced pain and LOS and probably major complications among patients medically stable at admission. Additional research is needed on whether functional outcomes may be improved. In the meantime, patients with hip fracture who are medically stable should receive early surgery when possible.