Protocols were in accord with institutional guidelines and were approved by the local institutional review board. All participants gave written informed consent. Consecutive, self-defined white and African-Dutch women undergoing an abdominal procedure for fibroid enucleation or hysterectomy for fibroids were eligible for inclusion.Abstract-Hypertension remains the main risk factor for cardiovascular death. Environmental and biological factors are known to contribute to the condition, and circulating creatine kinase was reported to be the main predictor of blood pressure in the general population. This was proposed to be because of high resistance artery creatine kinase-BB rapidly regenerating ATP for vascular contractility. Therefore, we assessed whether creatine kinase isoenzyme mRNA levels in human resistance arteries are associated with blood pressure. We isolated resistance-sized arteries from omental fat donated by consecutive women undergoing uterine fibroid surgery. Blood pressure was measured in the sitting position. Vessels of 13 women were included, 6 normotensive and 7 hypertensive, mean age 42.9 years (SE, 1.6) and mean systolic/ diastolic blood pressure, 144.8 (8.0)/86.5 (4.3) mm Hg. Arteriolar creatine kinase isoenzyme mRNA was assessed using quantitative real-time polymerase chain reaction. Normalized creatine kinase B mRNA copy numbers, ranging from 5.2 to 24.4 (mean, 15.0; SE, 1.9), showed a near-perfect correlation with diastolic blood pressure (correlation coefficient, 0.9; 95% confidence interval, 0.6-1.0) and were well correlated with systolic blood pressure, with a 90% relative increase in resistance artery creatine kinase B mRNA in hypertensives compared with normotensives, normalized copy numbers were, respectively, 19.3 (SE, 2.0) versus 10.1 (SE, 2.1), P=0.0045. To our knowledge, this is the first direct evidence suggesting that resistance artery creatine kinase mRNA expression levels concur with blood pressure levels, almost doubling with hypertension. These findings add to the evidence that creatine kinase might be involved in the vasculature's pressor responses. (Hypertension. 2014;63:68-73.)

To our knowledge, this is the first report on the BP-lowering effect of creatine kinase inhibition. Our data indicate that modulation of the creatine kinase system is a potential novel treatment target for hypertension.

This study extends on our previous findings in pregnant normotensive women of CK-dependent microvascular contractility, indicating that CK contributes significantly to resistance artery contractility across human normotension and primary hypertension outside the context of pregnancy. Further studies should explore the effect of CK inhibitors on clinical blood pressure.

Aims/hypothesis South Asians have a disproportionately high risk of developing abdominal obesity, insulin resistance and type 2 diabetes. Brown adipose tissue (BAT) has been identified as a possible target to fight obesity and protect against metabolic disturbance. We explored whether lower BAT activity in South Asians compared with Europids may contribute to the high risk of metabolic disturbance. Methods We studied 20 healthy men (ten Europids/ten South Asians, BMI 19-25 kg/m 2 , age 18-32 years). Following 2 h of cold exposure (16-18°C) after an overnight fast, 18 F-fluorodeoxyglucose ( 18 F-FDG) positronemission tomography-computed tomography (CT) and 123 I-metaiodobenzylguanidine ( 123 I-MIBG) single-photon emission computed tomography-CT were performed to visualise metabolic BAT activity and sympathetic stimulation of BAT. Metabolic BAT activity was defined as maximal standardised uptake value (SUV max ) of 18 F-FDG, and sympathetic stimulation of BAT as semiquantitative uptake value (SQUV) of 123 I-MIBG. We performed hyperinsulinaemic-euglycaemic clamps to assess insulin sensitivity. Spearman's correlations for SUV max of 18 F-FDG and both SQUV of 123 I-MIBG and insulin sensitivity were determined. Results The median (interquartile range) SUV max of 18 F-FDG in South Asians (7.5 [2.2-10.6] g/ml) was not different from the median SUV max obtained in Europids (4.5 [2.2-8.4] g/ml; p=0.59). There was no correlation between BAT activity and insulin sensitivity. Correlations between SQUV of 123 I-MIBG and SUV max of 18 F-FDG were positive, both in the total population (ρ=0.80, p<0.001) and after stratification by ethnicity (Europids, ρ =0.65, p = 0.04; South Asians, ρ=0.83, p=0.01). Conclusions/interpretation This is the first study to prospectively investigate ethnic differences in metabolic BAT activity during cold exposure. We did not find differences in BAT activity between South Asians and Europids. Therefore, it seems unlikely that BAT plays an important role in the development of unfavourable metabolic profiles in South Asians.

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BackgroundDespite adequate treatment, up to 30% of treated antihypertensive patients with primary, uncomplicated hypertension remain uncontrolled. We proposed that high intracellular activity of the ATP regenerating enzyme creatine kinase (CK) increases pressor responses and hypertension risk. In line with this, we found that plasma CK activity after rest, a surrogate measure of tissue activity, is the main predictor of blood pressure levels and failure of antihypertensive therapy in the general population. In addition, the creatine analog and competitive oral creatine kinase inhibitor beta-guanidinopropionic acid effectively and safely reduced blood pressure in the spontaneously hypertensive rat. However, to our knowledge there are no human data on the safety of oral supplementation with this substance. Therefore, we will assess the tolerability of beta-guanidinopropionic acid in men, compared to creatine and placebo.Methods/DesignThis is a randomized, active and placebo controlled, triple blind, double dummy, single center clinical intervention trial in 24 healthy male volunteers, 18 to 50 years old, recruited in the Netherlands. The intervention consists of one week of daily oral administration of beta-guanidinopropionic acid 100 mg, creatine 5 gram, or placebo. The primary outcome is the tolerability of beta-guanidinopropionic acid as a descriptive measure, in an intent-to-treat analysis. Other outcomes include the placebo-adjusted differences with baseline in biochemical and hemodynamic parameters, including plasma markers of muscle tissue damage, urine sodium excretion, resting sitting systolic and diastolic brachial blood pressure, supine systolic and diastolic central blood pressure, pulse wave velocity and augmentation index, heart rate, cardiac contractility, cardiac output, and total peripheral resistance.DiscussionThere is an unfulfilled need for new conservative options to treat resistant hypertension. This study will provide first-in-men data on creatine kinase inhibition as a potential new class of antihypertensive drugs.Trial registrationThe Netherlands National Trial Register Trialregister.nl (identifier NTR 4444), registered 9 March 2014.

AimsIncreasing evidence indicates that the ATP‐generating enzyme creatine kinase (CK) is involved in hypertension. CK rapidly regenerates ATP from creatine phosphate and ADP. Recently, it has been shown that beta‐guanidinopropionic acid (GPA), a kidney‐synthesized creatine analogue and competitive CK inhibitor, reduced blood pressure in spontaneously hypertensive rats. To further develop the substance as a potential blood pressure‐lowering agent, we assessed the tolerability of a sub‐therapeutic GPA dose in healthy men.MethodsIn this active and placebo‐controlled, triple‐blind, single‐centre trial, we recruited 24 healthy men (18–50 years old, BMI 18.5–29.9 kg m−2) in the Netherlands. Participants were randomized (1:1:1) to one week daily oral administration of GPA 100 mg, creatine 5 g, or matching placebo. The primary outcome was the tolerability of GPA, in an intent‐to‐treat analysis.ResultsTwenty‐four randomized participants received the allocated intervention and 23 completed the study. One participant in the placebo arm dropped out for personal reasons. GPA was well tolerated, without serious or severe adverse events. No abnormalities were reported with GPA use in clinical safety parameters, including physical examination, laboratory studies, or 12‐Lead ECG. At day 8, mean plasma GPA was 213.88 (SE 0.07) in the GPA arm vs. 32.75 (0.00) nmol l−1 in the placebo arm, a mean difference of 181.13 (95% CI 26.53–335.72).ConclusionIn this first‐in‐human trial, low‐dose GPA was safe and well‐tolerated when used during 1 week in healthy men. Subsequent studies should focus on human pharmacokinetic and pharmacodynamic assessments with different doses.

In this first extensive cardiovascular assessment in the general population of this middle-income Caribbean country, high prevalence of hypertension with inadequate levels of treatment and control was predominant. The findings emphasize the need for collaborative effort from national and international bodies to prioritize the implementation of affordable and sustainable public health programs that combat the escalating hypertension and cardiovascular risk factor burden.