Drug mechanisms to help in managing resistant hypertension in obesity

Obesity is a major risk factor for the development of hypertension. Because the prevalence of obesity is increasing worldwide, the prevalence of obesity hypertension is also increasing. Importantly, hypertension in obesity is commonly complicated by dyslipidemia and type 2 diabetes mellitus and hence imposes a high cardiovascular disease risk. Furthermore, obesity is strongly associated with resistant hypertension. Activation of the sympathetic nervous system and the renin-angiotensin system, leading to renal sodium and water retention, links obesity with hypertension. There is also evidence for the release of factors by visceral adipose tissue promoting excessive aldosterone production, and a more central role of aldosterone in obesity hypertension is emerging. Randomized studies evaluating the effect of different classes of antihypertensive agents in obesity hypertension are scarce, short-lasting, and small. Considering the emerging role of aldosterone in the pathogenesis of obesity hypertension, mineralocorticoid receptor antagonism may play a more central role in the pharmacologic treatment of obesity hypertension in the near future

Rs964184 (APOA5-A4-C3-A1) Is Related to Elevated Plasma Triglyceride Levels, but Not to an Increased Risk for Vascular Events in Patients with Clinically Manifest Vascular Disease

Background: Single nucleotide polymorphisms in the APOA5-A4-C3-A1 gene complex are associated with elevated plasma triglycerides and elevated vascular risk in healthy populations. In patients with clinically manifest vascular disease, hypertriglyceridemia and metabolic syndrome are frequently present, but the contribution of these single nucleotide polymorphisms to plasma triglycerides, effect modification by obesity and risk of recurrent vascular events is unknown in these patients. Methods: Prospective cohort study of 5547 patients with vascular disease. Rs964184 (APOA5-A4-C3-A1 gene complex) was genotyped, and we evaluated the relation with plasma lipid levels, presence of metabolic syndrome and the risk for new vascular events. Results: The minor allele of rs964184 was strongly associated with log plasma triglycerides (β 0.12; 95%CI 0.10-0.15, p = 1.1*10−19), and was also associated with 0.03 mmol/L lower high-density lipoprotein-cholesterol (95%CI 0.01–0.04), and 0.14 mmol/L higher non-high-density lipoprotein-cholesterol (95%CI 0.09–0.20). The minor allele frequency increased from 10.9% in patients with plasma triglycerides 27 kg/m2, p for interaction = 0.02). The prevalence of the metabolic syndrome increased from 52% for patients with two copies of the major allele to 62% for patients with two copies of the minor allele (p = 0.01). Rs964184 was not related with recurrent vascular events (HR 0.99; 95%CI 0.86–1.13). Conclusion: The single nucleotide polymorphism rs964184 (APOA5-A4-C3-A1) is associated with elevated plasma triglycerides concentrations in patients with clinically manifest vascular disease. In carriers of one minor allele, the effect on plasma triglycerides was modified by body mass index. There is no relation between rs964184 and recurrent vascular events in these patients

A simplified primary aldosteronism surgical outcome score is a useful prediction model when target organ damage is unknown – Retrospective cohort study

Background: Cure of hypertension after adrenalectomy for primary aldosteronism is no certainty and therefore preoperative patient counseling is essential. The Primary Aldosteronism Surgical Outcome (PASO) Score is a useful prediction model with an area under the curve (AUC) of 0.839. The PASO Score includes ‘Target Organ Damage’ (TOD) (i.e., left ventricular hypertrophy and/or microalbuminuria), which is often unavailable during preoperative counseling and might therefore limit its use in clinical practice. We hypothesized that the PASO score would still be useful if TOD is unknown at time of counseling. Therefore, we aimed to examine the predictive performance of the simplified PASO Score, without taking TOD into account. Materials and methods: In this retrospective cohort study, patients who underwent unilateral adrenalectomy between 2010 and 2016 in 16 medical centers from North America, Europe and Australia were included. TOD was unknown in our database and therefore assigned as absent. Patients were classified as complete, partial or absent clinical success using the PASO consensus criteria. Results: A total of 380 (73.9%) patients were eligible for analysis. Complete, partial and absent clinical success were observed in 29.5%, 55.8% and 14.7% of patients, respectively. The simplified PASO Score had an AUC of 0.730 (95% confidence interval 0.674–0.785) in our total cohort. Conclusion: Without taking TOD into account, the simplified PASO Score had a lower predictive value as compared to the original derivation cohort. Ideally, the complete PASO Score should be used, but when data on TOD are not readily available, the simplified PASO Score is a useful and reasonable alternative

Vascular uptake on 18F-sodium fluoride positron emission tomography:precursor of vascular calcification?

Background: Microcalcifications cannot be identified with the present resolution of CT; however, 18F-sodium fluoride (18F-NaF) positron emission tomography (PET) imaging has been proposed for non-invasive identification of microcalcification. The primary objective of this study was to assess whether 18F-NaF activity can assess the presence and predict the progression of CT detectable vascular calcification. Methods and Results: The data of two longitudinal studies in which patients received a 18F-NaF PET-CT at baseline and after 6 months or 1-year follow-up were used. The target to background ratio (TBR) was measured on PET at baseline and CT calcification was quantified in the femoral arteries at baseline and follow-up. 128 patients were included. A higher TBR at baseline was associated with higher calcification mass at baseline and calcification progression (β = 1.006 [1.005-1.007] and β = 1.002 [1.002-1.003] in the studies with 6 months and 1-year follow-up, respectively). In areas without calcification at baseline and where calcification developed at follow-up, the TBR was.11–.13 (P < .001) higher compared to areas where no calcification developed. Conclusion: The activity of 18F-NaF is related to the amount of calcification and calcification progression. In areas where calcification formation occurred, the TBR was slightly but significantly higher

Blood pressure response to renal denervation is correlated with baseline blood pressure variability: a patient-level meta-analysis

Background: Sympathetic tone is one of the main determinants of blood pressure (BP) variability and treatment-resistant hypertension. The aim of our study was to assess changes in BP variability after renal denervation (RDN). In addition, on an exploratory basis, we investigated whether baseline BP variability predicted the BP changes after RDN. Methods: We analyzed 24-h BP recordings obtained at baseline and 6 months after RDN in 167 treatmentresistant hypertension patients (40% women; age, 56.7 years; mean 24-h BP, 152/90 mmHg) recruited at 11 expert centers. BP variability was assessed by weighted SD [SD over time weighted for the time interval between consecutive readings (SDiw)], average real variability (ARV), coefficient of variation, and variability independent of the mean (VIM). Results: Mean office and 24-h BP fell by 15.4/6.6 and 5.5/ 3.7 mmHg, respectively (P &lt; 0.001). In multivariable-adjusted analyses, systolic/diastolic SDiw and VIM for 24-h SBP/DBP decreased by 1.18/0.63 mmHg (P 0.01) and 0.86/0.42 mmHg (P 0.05), respectively, whereas no significant changes in ARV or coefficient of variation occurred. Furthermore, baseline SDiw (P ¼ 0.0006), ARV (P ¼ 0.01), and VIM (P ¼ 0.04) predicted the decrease in 24-h DBP but not 24-h SBP after RDN. Conclusion: RDN was associated with a decrease in BP variability independent of the BP level, suggesting that responders may derive benefits from the reduction in BP variability as well. Furthermore, baseline DBP variability estimates significantly correlated with mean DBP decrease after RDN. If confirmed in younger patients with less arterial damage, in the absence of the confounding effect of drugs and drug adherence, baseline BP variability may prove a good predictor of BP response to RDN

Genotype-phenotype correlation in pseudoxanthoma elasticum

Background and aims: Pseudoxanthoma elasticum (PXE) is caused by variants in the ABCC6 gene. It results in calcification in the skin, peripheral arteries and the eyes, but has considerable phenotypic variability. We investigated the association between the ABCC6 genotype and calcification and clinical phenotypes in these different organs. Methods: ABCC6 sequencing was performed in 289 PXE patients. Genotypes were grouped as two truncating, mixed, or two non-truncating variants. Arterial calcification mass was quantified on whole body, low dose CT scans; and peripheral arterial disease was measured with the ankle brachial index after treadmill test. The presence of pseudoxanthoma in the skin was systematically scored. Ophthalmological phenotypes were the length of angioid streaks as a measure of Bruchs membrane calcification, the presence of choroidal neovascularizations, severity of macular atrophy and visual acuity. Regression models were built to test the age and sex adjusted genotype-phenotype association. Results: 158 patients (median age 51 years) had two truncating variants, 96 (median age 54 years) a mixed genotype, 18 (median age 47 years) had two non-truncating variants. The mixed genotype was associated with lower peripheral (13: 0.39, 95%CI:-0.62;-0.17) and total (13: 0.28, 95%CI:-0.47;-0.10) arterial calcification mass scores, and lower prevalence of choroidal neovascularizations (OR: 0.41 95%CI:0.20; 0.83) compared to two truncating variants. No association with pseudoxanthomas was found. Conclusions: PXE patients with a mixed genotype have less severe arterial and ophthalmological phenotypes than patients with two truncating variants in the ABCC6 gene. Research into environmental and genetic modifiers might provide further insights into the unexplained phenotypic variability