Inhibition of DYRK1a Enhances Cardiomyocyte Cycling After Myocardial Infarction.

BACKGROUND: DYRK1a (dual-specificity tyrosine phosphorylation-regulated kinase 1a) contributes to the control of cycling cells, including cardiomyocytes. However, the effects of inhibition of DYRK1a on cardiac function and cycling cardiomyocytes after myocardial infarction (MI) remain unknown. METHODS: We investigated the impacts of pharmacological inhibition and conditional genetic ablation of DYRK1a on endogenous cardiomyocyte cycling and left ventricular systolic function in ischemia-reperfusion (I/R) MI using αMHC-MerDreMer-Ki67p-RoxedCre::Rox-Lox-tdTomato-eGFP (RLTG) (denoted αDKRC::RLTG) and αMHC-Cre::Fucci2aR::DYRK1aflox/flox mice. RESULTS: We observed that harmine, an inhibitor of DYRK1a, improved left ventricular ejection fraction (39.5±1.6% and 29.1±1.6%, harmine versus placebo, respectively), 2 weeks after I/R MI. Harmine also increased cardiomyocyte cycling after I/R MI in αDKRC::RLTG mice, 10.8±1.5 versus 24.3±2.6 enhanced Green Fluorescent Protein (eGFP)+ cardiomyocytes, placebo versus harmine, respectively, P=1.0×10-3. The effects of harmine on left ventricular ejection fraction were attenuated in αDKRC::DTA mice that expressed an inducible diphtheria toxin in adult cycling cardiomyocytes. The conditional cardiomyocyte-specific genetic ablation of DYRK1a in αMHC-Cre::Fucci2aR::DYRK1aflox/flox (denoted DYRK1a k/o) mice caused cardiomyocyte hyperplasia at baseline (210±28 versus 126±5 cardiomyocytes per 40× field, DYRK1a k/o versus controls, respectively, P=1.7×10-2) without changes in cardiac function compared with controls, or compensatory changes in the expression of other DYRK isoforms. After I/R MI, DYRK1a k/o mice had improved left ventricular function (left ventricular ejection fraction 41.8±2.2% and 26.4±0.8%, DYRK1a k/o versus control, respectively, P=3.7×10-2). RNAseq of cardiomyocytes isolated from αMHC-Cre::Fucci2aR::DYRK1aflox/flox and αMHC-Cre::Fucci2aR mice after I/R MI or Sham surgeries identified enrichment in mitotic cell cycle genes in αMHC-Cre::Fucci2aR::DYRK1aflox/flox compared with αMHC-Cre::Fucci2aR. CONCLUSIONS: The pharmacological inhibition or cardiomyocyte-specific ablation of DYRK1a caused baseline hyperplasia and improved cardiac function after I/R MI, with an increase in cell cycle gene expression, suggesting the inhibition of DYRK1a may serve as a therapeutic target to treat MI.

Prevalence of Helicobacter pylori infection among resettled refugees presenting to a family medicine clinic in the United States.

BACKGROUND: Although endemic to much of the global population, few studies have examined Helicobacter pylori (H. pylori) in US refugee populations. This study investigates the prevalence of H. pylori infection and barriers to treatment in the International Family Medicine Clinic (IFMC), a primary care refugee clinic, in central Virginia. MATERIALS AND METHODS: We conducted a chart review of 188 refugee patients of the IFMC who were referred for an H. pylori test between January 1, 2019, and December 31, 2020. Recorded measures included patient demographics, H. pylori test result, treatment of initial infection, completion of test of cure (TOC), TOC results, salvage therapy, and barriers to treatment. Binary logistic regression was performed to examine the association between demographic factors and H. pylori test results. RESULTS: Of the 171 patients who completed an H. pylori test, 94 tested positive (54.9%). Of the 93 patients that were subsequently treated, 76 were treated with clarithromycin triple therapy (82%). Forty-eight patients (52%) completed a TOC after completing treatment, and 21 (43%) of these patients remained positive, indicating persistent infection. Eighteen patients (90%) who remained positive for H. pylori were subsequently treated with quadruple therapy. Patients under 18 (OR = 0.25, p < 0.01) and patients with a history of previous H. pylori (OR = 0.44, p < 0.05) were less likely to have positive results on initial H. pylori testing. Common barriers to treatment included pregnancy, religious observance (e.g., fasting), and health system complications (e.g., prior authorization for medications, cost of treatment). CONCLUSIONS: The prevalence of H. pylori among refugees at the IFMC was higher than the overall prevalence estimate for the United States, which is consistent with previous studies. This work represents an updated picture of H. pylori prevalence among refugees in the United States and contributes to the identification of treatment barriers.

Impact of a Center of Excellence in Confirming or Excluding a Diagnosis of Hypertrophic Cardiomyopathy.

Tertiary hospitals with expertise in hypertrophic cardiomyopathy (HCM) are assuming a greater role in confirming and correcting HCM diagnoses at referring centers. The objectives were to establish the frequency of alternate diagnoses from referring centers and identify predictors of accuracy of an HCM diagnosis from the referring centers. Imaging findings from echocardiography, cardiac computed tomography, and cardiac magnetic resonance imaging (CMR) in 210 patients referred to an HCM Center of Excellence between September 2020 and October 2022 were reviewed. Clinical and imaging characteristics from pre-referral studies were used to construct a model for predictors of ruling out HCM or confirming the diagnosis using machine learning methods (least absolute shrinkage and selection operator logistic regression). Alternative diagnoses were found in 38 of the 210 patients (18.1%) (median age 60 years, 50% female). A total of 17 of the 38 patients (44.7%) underwent a new CMR after their initial visit, and 14 of 38 patients (36.8%) underwent review of a previous CMR. Increased left ventricular end-diastolic volume, indexed, greater septal thickness measurements, greater left atrial size, asymmetric hypertrophy on echocardiography, and the presence of an implantable cardioverter-defibrillator were associated with higher odds ratios for confirming a diagnosis of HCM, whereas increasing age and the presence of diabetes were more predictive of rejecting a diagnosis of HCM (area under the curve 0.902, p <0.0001). In conclusion, >1 in 6 patients with presumed HCM were found to have an alternate diagnosis after review at an HCM Center of Excellence, and both clinical findings and imaging parameters predicted an alternate diagnosis.