A deleterious gene-by-environment interaction imposed by calcium channel blockers in Marfan syndrome.

Calcium channel blockers (CCBs) are prescribed to patients with Marfan syndrome for prophylaxis against aortic aneurysm progression, despite limited evidence for their efficacy and safety in the disorder. Unexpectedly, Marfan mice treated with CCBs show accelerated aneurysm expansion, rupture, and premature lethality. This effect is both extracellular signal-regulated kinase (ERK1/2) dependent and angiotensin-II type 1 receptor (AT1R) dependent. We have identified protein kinase C beta (PKCß) as a critical mediator of this pathway and demonstrate that the PKCß inhibitor enzastaurin, and the clinically available anti-hypertensive agent hydralazine, both normalize aortic growth in Marfan mice, in association with reduced PKCß and ERK1/2 activation. Furthermore, patients with Marfan syndrome and other forms of inherited thoracic aortic aneurysm taking CCBs display increased risk of aortic dissection and need for aortic surgery, compared to patients on other antihypertensive agents.

Association of chronic kidney disease (CKD) and failure to monitor renal function with adverse outcomes in people with diabetes: a primary care cohort study.

BACKGROUND: Chronic kidney disease (CKD) is a known risk factor for cardiovascular events and all-cause mortality. We investigate the relationship between CKD stage, proteinuria, hypertension and these adverse outcomes in the people with diabetes. We also study the outcomes of people who did not have monitoring of renal function. METHODS: A cohort of people with type 1 and 2 diabetes (N = 35,502) from the Quality Improvement in Chronic Kidney Disease (QICKD) cluster randomised trial was followed up over 2.5 years. A composite of all-cause mortality, cardiovascular events, and end stage renal failure comprised the outcome measure. A multilevel logistic regression model was used to determine correlates with this outcome. Known cardiovascular and renal risk factors were adjusted for. RESULTS: Proteinuria and reduced estimated glomerular filtration rate (eGFR) were independently associated with adverse outcomes in people with diabetes. People with an eGFR < 60 ml/min, proteinuria, and hypertension have the greatest odds ratio (OR) of adverse outcome; 1.58 (95% CI 1.36-1.83). Renal function was not monitored in 4460 (12.6%) people. Unmonitored renal function was associated with adverse events; OR 1.35 (95% CI 1.13-1.63) in people with hypertension and OR 1.32 (95% CI 1.07-1.64) in those without. CONCLUSIONS: Proteinuria, eGFR < 60 ml/min, and failure to monitor renal function are associated with cardiovascular and renal events and mortality in people with diabetes.