Hypertension
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Randomized Controlled Trial
Substance P increases sympathetic activity during combined angiotensin-converting enzyme and dipeptidyl peptidase-4 inhibition.
Dipeptidyl peptidase-4 inhibitors prevent the degradation of incretin hormones and reduce postprandial hyperglycemia in patients with type 2 diabetes mellitus. Dipeptidyl peptidase-4 degrades other peptides with a penultimate proline or alanine, including bradykinin and substance P, which are also substrates of angiotensin-converting enzyme (ACE). During ACE inhibition, substance P is inactivated primarily by dipeptidyl peptidase-4, whereas bradykinin is first inactivated by aminopeptidase P. This study tested the hypothesis that dipeptidyl peptidase-4 inhibition potentiates vasodilator and fibrinolytic responses to substance P when ACE is inhibited. Twelve healthy subjects participated in this randomized, double-blinded, placebo-controlled crossover study. On each study day, subjects received sitagliptin 200 mg by mouth or placebo. Substance P and bradykinin were infused via brachial artery before and during intra-arterial enalaprilat. Sitagliptin and enalaprilat each reduced forearm vascular resistance and increased forearm blood flow without affecting mean arterial pressure, but there was no interactive effect of the inhibitors. Enalaprilat increased bradykinin-stimulated vasodilation and tissue plasminogen activator release; sitagliptin did not affect these responses to bradykinin. The vasodilator response to substance P was unaffected by sitagliptin and enalaprilat; however, substance P increased heart rate and vascular release of norepinephrine during combined ACE and dipeptidyl peptidase-4 inhibition. In women, sitagliptin diminished tissue plasminogen activator release in response to substance P both alone and during enalaprilat. Substance P increases sympathetic activity during combined ACE and dipeptidyl peptidase-4 inhibition. ⋯ - URL: http://www.clinicaltrials.gov. Unique identifier: NCT01413542.
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Renal sympathetic denervation (RSD) is a treatment option for patients with resistant arterial hypertension, but in some patients it is not successful. Predictive parameters on the success of RSD remain unknown. The angiogenic factors soluble fms-like tyrosine kinase-1 (sFLT-1), intercellular cell adhesion molecule-1 (ICAM-1), and vascular cell adhesion molecule-1 (VCAM-1) are known to be associated with endothelial dysfunction, vascular remodeling, and hypertension. ⋯ The areas under the curve for sFLT-1, ICAM-1, and VCAM-1 were 0.82 (interquartile range, 0.718-0.921; P<0.001), 0.754 (0.654-0.854; P<0.001), and 0.684 (0.564-804; P=0.01), respectively, demonstrating prediction of an RSD response. Responders showed significantly higher serum levels of sFLT-1, ICAM-1, and VCAM-1 at baseline compared with nonresponders. Thus, this study identified for the first time potential biomarkers with a predictive value indicating a responder or nonresponder before renal denervation.
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Maternal prepregnancy obesity is associated with impaired cardiometabolic health in offspring. Whether these associations reflect direct intrauterine causal mechanisms remains unclear. In a population-based prospective cohort study among 4871 mothers, fathers, and their children, we examined the associations of both maternal and paternal prepregnancy body mass index (BMI) with childhood body fat distribution and cardiometabolic outcomes and explored whether any association was explained by pregnancy, birth, and childhood factors. ⋯ Smaller effect estimates for these outcomes were observed for paternal obesity. In conclusion, higher maternal and paternal prepregnancy BMI were associated with an adverse cardiometabolic profile in offspring, with stronger associations present for maternal prepregnancy BMI. These findings suggest that maternal prepregnancy BMI may influence the cardiometabolic health of offspring through direct intrauterine mechanisms.
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Blood pressure is a critical determinant of cardiovascular morbidity and mortality. It is affected by environmental factors, but has a strong heritable component. Despite recent large genome-wide association studies, few genetic risk factors for blood pressure have been identified. ⋯ Applying the conditional false discovery rate method to the enriched phenotypes, we identified 62 loci associated with SBP (false discovery rate <0.01), including 42 novel loci. The observed polygenic overlap between SBP and several related disorders indicates that the epidemiological associations are not mediated solely via lifestyle factors but also reflect an etiologic relation that warrants further investigation. The new gene loci identified implicate novel genetic mechanisms related to lipid biology and the immune system in SBP.