Perinuclear damage from nuclear envelope deterioration elicits stress responses that contribute to LMNA cardiomyopathy.

Mutations in the LMNA gene encoding lamins A/C cause an array of tissue-selective diseases, with the heart being the most commonly affected organ. Despite progress in understanding the perturbations emanating from LMNA mutations, an integrative understanding of the pathogenesis underlying cardiac dysfunction remains elusive. Using a novel conditional deletion model capable of translatome profiling, we observed that cardiomyocyte-specific Lmna deletion in adult mice led to rapid cardiomyopathy with pathological remodeling. Before cardiac dysfunction, Lmna-deleted cardiomyocytes displayed nuclear abnormalities, Golgi dilation/fragmentation, and CREB3-mediated stress activation. Translatome profiling identified MED25 activation, a transcriptional cofactor that regulates Golgi stress. Autophagy is disrupted in the hearts of these mice, which can be recapitulated by disrupting the Golgi. Systemic administration of modulators of autophagy or ER stress significantly delayed cardiac dysfunction and prolonged survival. These studies support a hypothesis wherein stress responses emanating from the perinuclear space contribute to the LMNA cardiomyopathy development.

Ventricular Tachycardia in Patients With Pre-eclampsia: Prevalence, Predictors, and Associated In-Hospital Adverse Events.

Introduction Pre-eclampsia is a pregnancy-associated multisystem disorder; in rare cases, it can be complicated by arrhythmias such as ventricular tachycardia (VT). The purpose of this study was to determine the prevalence and predictors of VT among patients admitted with pre-eclampsia as well as to analyze the independent association of VT with in-hospital outcomes in this population. Methods Data were obtained from the National Inpatient Sample from January 2016 to December 2019. Patients with a primary diagnosis of pre-eclampsia were selected using International Classification of Diseases, 10th Revision, Clinical Modification (ICD-10-CM) codes. Subsequently, the study population was divided into patients who developed VT versus patients who did not develop this complication. We then assessed the predictors of VT in women with pre-eclampsia as well as the independent association of VT with outcomes taking into account confounders such as age, race, and comorbidities. Results Of 255,946 patients with pre-eclampsia, 92 developed VT (0.04%) during their hospital stay. Multivariate logistic regression showed that patients with VT were far more likely to develop cardiac arrest (adjusted odds ratio, or aOR: 92.582, 95% CI: 30.958-276.871, p=0.001), require permanent pacemaker implantation (aOR: 41.866, 95% CI: 14.800-118.432, p=0.001), develop postpartum hemorrhage (aOR: 2.932, 95% CI: 1.655-5.196, p=0.001), and require left heart catheterization (aOR: 19.508, 95% CI: 3.261-116.708, p=0.001). Predictors of VT included being African American (aOR: 1.939, 95% CI: 1.183-3.177, p=0.009), cerebrovascular disease (aOR: 23.109, 95% CI: 6.953-76.802, p=0.001), congestive heart failure (aOR: 50.340, 95% CI: 28.829-87.901, p=0.001), atrial fibrillation (aOR: 20.148, 95% CI: 6.179-65.690, p=0.001), and obstructive sleep apnea, or OSA (aOR: 3.951, 95% CI: 1.486-10.505, p=0.006). Patients in the VT cohort were found to have an increased length of hospital stay compared to the non-VT cohort (7.16 vs. 4.13 days, p=0.001). Conclusion In a large cohort of women admitted with pre-eclampsia, we found the prevalence of VT to be <1%. Predictors of VT included conditions such as atrial fibrillation, congestive heart failure, and OSA and being African American. VT was found to be independently associated with several adverse outcomes as well as an increased length of hospital stay.

Med25 Limits Master Regulators That Govern Adipogenesis.

Mediator 25 (Med25) is a member of the mediator complex that relays signals from transcription factors to the RNA polymerase II machinery. Multiple transcription factors, particularly those involved in lipid metabolism, utilize the mediator complex, but how Med25 is involved in this context is unclear. We previously identified Med25 in a translatome screen of adult cardiomyocytes (CMs) in a novel cell type-specific model of LMNA cardiomyopathy. In this study, we show that Med25 upregulation is coincident with myocardial lipid accumulation. To ascertain the role of Med25 in lipid accumulation, we utilized iPSC-derived and neonatal CMs to recapitulate the in vivo phenotype by depleting lamins A and C (lamin A/C) in vitro. Although lamin A/C depletion elicits lipid accumulation, this effect appears to be mediated by divergent mechanisms dependent on the CM developmental state. To directly investigate Med25 in lipid accumulation, we induced adipogenesis in Med25-silenced 3T3-L1 preadipocytes and detected enhanced lipid accumulation. Assessment of pertinent mediators driving adipogenesis revealed that C/EBPα and PPARγ are super-induced by Med25 silencing. Our results indicate that Med25 limits adipogenic potential by suppressing the levels of master regulators that govern adipogenesis. Furthermore, we caution the use of early-developmental-stage cardiomyocytes to model adult-stage cells, particularly for dissecting metabolic perturbations emanating from LMNA mutations.

Perinuclear damage from nuclear envelope deterioration elicits stress responses that contribute to LMNA cardiomyopathy.

Mutations in the LMNA gene encoding nuclear lamins A/C cause a diverse array of tissue-selective diseases, with the heart being the most commonly affected organ. Despite progress in understanding the molecular perturbations emanating from LMNA mutations, an integrative understanding of the pathogenesis leading to cardiac dysfunction remains elusive. Using a novel cell-type specific Lmna deletion mouse model capable of translatome profiling, we found that cardiomyocyte-specific Lmna deletion in adult mice led to rapid cardiomyopathy with pathological remodeling. Prior to the onset of cardiac dysfunction, lamin A/C-depleted cardiomyocytes displayed nuclear envelope deterioration, golgi dilation/fragmentation, and CREB3-mediated golgi stress activation. Translatome profiling identified upregulation of Med25, a transcriptional co-factor that can selectively dampen UPR axes. Autophagy is disrupted in the hearts of these mice, which can be recapitulated by disrupting the golgi or inducing nuclear damage by increased matrix stiffness. Systemic administration of pharmacological modulators of autophagy or ER stress significantly improved the cardiac function. These studies support a hypothesis wherein stress responses emanating from the perinuclear space contribute to the development of LMNA cardiomyopathy. Teaser: Interplay of stress responses underlying the development of LMNA cardiomyopathy.

Access to Urological Care for Medicaid-Insured Patients at Urology Practices Acquired by Private Equity Firms.

OBJECTIVE: To characterize appointment access for Medicaid-insured patients seeking care at urology practices affiliated with private equity firms in light of the recent national trends in practice consolidation. METHODS: We identified 214 urology offices affiliated with private equity firms that were geographically matched with 231 non-private equity affiliated urology offices. Using a standardized script, researchers posed as an adult patient with either Medicaid or commercial insurance in the clinical setting of new onset, painless hematuria. The primary outcome was whether the patient's insurance was accepted for an appointment. The secondary outcome was appointment wait time. RESULTS: We conducted 815 appointment inquiry calls to 214 private equity (PE) and 231 non-PE-affiliated urology offices across 12 states. Appointment availability was higher for commercially-insured patients (99.0%; 95% CI: 98.1%-99.9%) vs Medicaid-insured patients (59.8%; 95% confidence interval [CI]: 55.0%-64.6%) (P < .0001). Medicaid acceptance was higher at non-PE affiliated (66.8%; CI 60.4%-73.2%) than PE-affiliated practices (52.1%; 95% CI 45.0%-59.2%) (P = .003). On multivariable logistic regression analysis, state Medicaid expansion status (odds ratio [OR] 2.20; CI 1.14-4.28; P = .020) was independently associated with Medicaid appointment availability, whereas PE-affiliation (OR 0.55; CI 0.37-0.83; P = .004) was independently associated with lower Medicaid access. Appointment wait times did not differ significantly for commercially-insured vs Medicaid patients (19.2 vs 20.1 days; p = .59), but PE-affiliated practices offered shorter mean wait times than non-PE offices (17.5 vs 21.4 days; P = .017). CONCLUSION: Access disparities for urologic evaluation in patients with Medicaid insurance at urology practices and were more pronounced at private equity acquired practices.