Long-Term Efficacy and Safety of ARRY-371797 (PF-07265803) in Patients With Lamin A/C-Related Dilated Cardiomyopathy.

Dilated cardiomyopathy associated with lamin A/C (LMNA) gene variants (LMNA-related dilated cardiomyopathy [DCM]) is a life-threatening condition with a high unmet need, accounting for approximately 6% of idiopathic DCM cases. Currently, no disease-specific treatments target the underlying disease mechanism. ARRY-371797 (PF-07265803), a potent, selective, oral, small-molecule inhibitor of the p38α mitogen-activated protein kinase pathway, improved 6-minute walk test (6MWT) distance in 12 patients with symptomatic LMNA-related DCM in a 48-week, open-label, phase 2 study. This long-term extension study examined the safety and efficacy of ARRY-371797 in patients from the phase 2 study. 6MWT, N-terminal pro-B-type natriuretic peptide concentration, and 12-item Kansas City Cardiomyopathy Questionnaire score were assessed at weeks 48, 72, 96, 120, and 144 from phase 2 study baseline. Eight patients enrolled (mean [SD] age, 51 [10] years, 4 male). Mean 6MWT increased by >30 m (>10%) from phase 2 study baseline up to week 120. The decrease in N-terminal pro-B-type natriuretic peptide observed in the phase 2 study was maintained throughout the present study. Twelve-item Kansas City Cardiomyopathy Questionnaire Physical Limitation increased from baseline at all visits except week 96 (range: -0.8 [week 96] to 13.8 [week 120]); results for other domains were variable. Treatment was generally well tolerated; 2 patients discontinued because of causes not considered treatment-related. There were no deaths. ARRY-371797 was generally well tolerated over median (range) 155.7 (61 to 327)-week exposure; evidence suggested preserved exercise capacity over the study period. The ongoing, pivotal, phase 3, randomized, placebo-controlled study REALM-DCM investigates the efficacy and safety of ARRY-371797 (PF-07265803) in LMNA-related DCM. (ClinicalTrials.gov Identifier: NCT02351856).

Blood pressure variability predicts adverse events and cardiovascular outcomes in SPRINT.

SPRINT (Systolic Blood Pressure Intervention Trial) highlighted the benefits of intensive targeted antihypertensive therapy but resulted in higher rates of treatment-related adverse events. Blood pressure (BP) variability has emerged as a significant predictor of outcomes over and above levels of BP. Using the SPRINT data set, we aimed to determine the relationship of BP variability with cardiovascular outcomes and side effects of antihypertensive therapy. The analyses included all participants randomized in SPRINT who reached the target systolic BP (SBP) for their respective groups (intensive < 120 mm Hg; standard < 140 mm Hg). Coefficients of variation (CV) for SBP, diastolic BP (DBP), and PP for each patient characterized variability. Student t test was used to compare treatment arms for each CV metric. Cox proportional hazards regression was used to identify independent predictors of the SPRINT primary outcome and adverse events. P < .15 on univariate analysis was required to enter the model and P < .05 to remain in it. A total of 8884 patients (4561 standard group; 4323 intensive group) met inclusion criteria. DBP CV differed between the groups (9.12 ± 3.20 standard group; 9.47 ± 3.49 intensive group [P < .0001]). DBP CV predicted a greater hazard for the primary outcome (hazard ratio [HR], 1.14) in the overall model as well as separate analyses by treatment arms (standard group HR, 1.15; intensive group HR, 1.19), each P < .0001. DBP CV also independently predicted a greater hazard for acute kidney injury (HR, 1.12) and hypotensive events (HR, 1.12). Visit-to-visit DBP variability independently predicted worse cardiovascular outcomes and hypoperfusion-related adverse events in SPRINT.

Astrocyte decrease in the subgenual cingulate and callosal genu in schizophrenia.

Decreases in glial cell density and in GFAP mRNA in the anterior cingulate cortex have been reported in schizophrenia, bipolar disorder and major depressive disorder. Our study examines astrocyte and oligodendrocyte density in the white and grey matter of the subgenual cingulate cortex, and at the midline of the genu of the corpus callosum, in schizophrenia, bipolar disorder, depression and normal control cases. Serial coronal sections were stained with H and E for anatomical guidance, cresyl haematoxylin for oligodendrocyte identification and GFAP immunohistochemistry for astrocyte identification. Oligodendrocyte and astrocyte density was measured using systematic anatomical distinctions and randomised counting methods. A significant decrease in astrocyte density was observed in schizophrenia compared with normal controls in the cingulate grey matter, cingulate white matter and the midline of the corpus callosum (p = 0.025). Bipolar disorder and depression cases showed no significant changes in astrocyte density. Oligodendrocytes did not show any changes between diagnostic groups. In subgenual cingulate cortex, the ratio of oligodendrocytes to astrocytes was decreased between the controls and the three disease groups, suggesting a specific glial cell type specific change in schizophrenia.