Introduction: Data on the incidence of type 2 NSTEMI (T2MI) in hospitalized patients with COVID-19 infection has been limited to single-center studies. We propose to define the incidence of T2MI in a national cohort and identify pre-hospital patient characteristics associated with a diagnosis of T2MI in hospitalized patients with COVID-19. We will also examine the impact of T2MI on morbidity and mortality. Methods: We performed a retrospective analysis on data from the American Heart Association COVID-19 Cardiovascular Disease Quality Improvement Registry. This national registry contains data on tens of thousands of patients hospitalized with COVID-19 from at least 122 centers across the United States. From January 2020 through May 2021, there were 709 (2.2%) out of 32,015 patients with a coded diagnosis of T2MI. We performed Wilcoxon tests, chi-squared test, and multivariable logistic regression to (1) identify predictive pre-hospital patient characteristics (Table 1) of T2MI for patients hospitalized with COVID-19 and (2) investigate the impact of T2MI on mortality and morbidity. Results: Patients in the T2MI group were older (71 vs. 63 years, p<0.001), and in forward selection analyses, patients with a diagnosis of T2MI had higher odds of known HTN (OR 1.79 [1.01-3.1], p=0.026) and heart failure (OR 3.46 [2.24-5.34], p<0.001). Increased age, admission troponin, CRP, and d-dimer were also associated with higher odds of T2MI. Hispanic race (OR 0.517 [0.289-0.924], p=0.026) and use of antihyperglycemics (OR 0.562 [0.377-0.836], p=0.005) were both associated with lower odds of T2MI. T2MI led to increased mortality (HR 1.32, [1.17-1.5], P<0.001) and morbidity including cardiac arrest, major bleeding, and stroke. Conclusion: A history of heart failure was the strongest predictor of T2MI in hospitalized COVID19 patients. Patients with a T2MI compared to those without, had significantly higher mortality and morbidity. Limitations include the heterogenous ascertainment of the T2MI diagnosis across sites in this registry.
The most commonly mutated gene in hypertrophic cardiomyopathy (HCM) is cardiac myosin binding protein C (MYBPC3). Over 90% of MYBPC3 mutations are nonsense, but whether these mutations manifest in loss- or gain-of-function is unresolved. Evidence suggests MYBPC3 mutants impact protein quality control mechanisms. The objective of this study was to evaluate interactions of MYBPC3 with proteostatic systems and test the hypothesis that these interactions affect protein homeostasis in cardiomyocytes. WT and mutant MYBPC3 constructs were expressed in neonatal rat ventricular myocytes (NRVMs) via adenovirus. Mutant MYBPC3 induced ubiquitin proteasome system reporter GFPu accumulation (fold increase in GFPu-positive cells vs control: WT 138±14.0%, mutant 198±27.2%, mean±SEM, p<0.05 vs control and WT), indicating proteasome dysfunction. Affinity purification/mass spectrometry identified molecular chaperones Hsp70 and Hsc70 as prominent interactors with MYBPC3. We observed MYBPC3 degradation by cycloheximide chase in response to Hsc70 siRNA knockdown or pharmacological treatment with Hsp70 activator YM-1. Hsc70 knockdown slowed degradation of WT and mutant MYBPC3 (WT control t ½ =5.47±0.70 hr, WT Hsc70 knockdown t ½ =13.5±1.62 hr; mutant control t ½ =3.42±0.61 hr, mutant Hsc70 knockdown t ½ =9.87±0.95 hr), while YM-1 treatment accelerated degradation (WT DMSO t ½ =10.2±3.28 hr, WT YM-1 t ½ =3.16±0.61 hr; mutant DMSO t ½ =11.7±2.67 hr, mutant YM-1 t ½ =1.37±0.16 hr). We then evaluated whether transferrin uptake via clathrin mediated endocytosis, a critical Hsc70-dependent activity, was affected by mutant MYBPC3. Transferrin uptake was significantly decreased in NRVMs expressing mutant MYBPC3 compared to WT and untreated controls (transferrin-positive cells: control 22.93±3.34%, WT 17.47±0.70%, mutant 9.30±1.63%, mean±SEM, p<0.05 vs control and WT). In conclusion, we have demonstrated that Hsp70 chaperones interact with MYBPC3 in cardiomyocytes and affect MYBPC3 degradation, suggesting MYBPC3 is a client of Hsp70 and Hsc70. Additionally, expression of mutant MYBPC3 causes ubiquitin proteasome impairment and interferes with normal Hsc70 function. These results support our hypothesis that mutant MYBPC3 affects protein homeostasis in HCM.
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