CK (Creatine Kinase) Is Associated With Cardiovascular Hemodynamics: The HELIUS Study.

The ATP-regenerating enzyme CK (creatine kinase) is strongly associated with blood pressure, which lowers upon experimental CK inhibition. The enzyme is thought to affect cardiovascular hemodynamics through enhanced systemic vascular resistance, stroke volume, and cardiac contractility, but data on these parameters are lacking. We hereby report hemodynamics by CK levels in the multiethnic, cross-sectional HELIUS study (Healthy Life in an Urban Setting). Physical examination included sitting brachial blood pressure and noninvasively assessed supine systemic vascular resistance, stroke volume, cardiac output, and cardiac contractility, which we associated with resting plasma CK. Data from 14 937 men and women (mean age, 43.3; SD, 12.9) indicated that per log CK increase, blood pressure increased with 20.2 (18.9-21.4) mm Hg systolic/13.0 (12.2-13.7) diastolic, an odds ratio for hypertension of 6.1 (5.1-7.2). Outcomes were similar by sex, body mass index, and ancestry, although higher blood pressures in men, with overweight/obesity, and West-African ancestry were partially explained by higher CK, with an adjusted increase in systolic/diastolic pressure of 10.5 (10.0-10.9)/6.4 (6.0-6.7) mm Hg per log CK increase. Systemic vascular resistance, stroke volume, cardiac output, and cardiac contractility (n=7876), increased by respectively 20%, 39%, 14%, and 23% SD per log CK increase. This study indicates that the association of CK with blood pressure likely results from an increase in systemic vascular resistance and stroke volume. These data expand the knowledge on the nature of hypertension associated with CK and may inform further experiments on CK inhibition as a means to lower blood pressure.

Aortic pulse wave velocity in individuals of Asian and African ancestry: the HELISUR study.

Aortic pulse wave velocity has emerged as an important predictor of cardiovascular events, but data on ethnic differences in pulse wave velocity remain scarce. We explored differences in pulse wave velocity between people of Asian and African ancestry. Data were used from the cross-sectional Healthy Life in Suriname (HELISUR) study. Pulse wave velocity was estimated oscillometrically with the Arteriograph. We included 353 Asians and 364 Africans, aged respectively 44.9 (SD 13.5) and 42.8 (SD 14.1) years (p = 0.05). Crude median PWV was higher in Asians than in Africans (8.1 [IQR 6.9-10.1] m/s vs. 7.7 [IQR 6.5-9.3] m/s, p = 0.03), which was mainly attributable to an increased PWV in Asians ≥ 50 years (10.1 [IQR 8.7-11.8] m/s vs. 9.1 [IQR 7.9-11.3] m/s in Africans ≥50 years, p < 0.01). After adjustment for age and MAP in multivariable linear regression, Asians had a 1.044 [95% CI 1.019-1.072] m/s higher PWV compared to Africans. Additional adjustment for sex, glucose, total cholesterol, HDL cholesterol, triglycerides, BMI, and waist circumference did not substantially change the difference in pulse wave velocity between Asians and Africans (+1.044 [95% CI 1.016-1.074] m/s for Asians vs. Africans). In conclusion, persons of Asian ancestry have a higher pulse wave velocity than those of African ancestry. This persisted after adjustment for important cardiovascular risk parameters, including age and blood pressure. The higher PWV found in Asians could be consistent with their increased coronary heart disease risk.

The risk of hypertension and cardiovascular disease in women with uterine fibroids.

Women with fibroids have a notably high hypertension risk. However, adjusted data regarding other cardiovascular disease (CVD) risk factors are scarce. In this cross-sectional study, CVD risk factors, hemodynamic parameters, and asymptomatic organ damage were analyzed between women with uterine fibroids and controls in a multi-ethnic population. In total, 104 women with self-reported fibroids and 624 controls were included. Women with fibroids had significantly higher odds to have hypertension (OR 3.4; 95% CI 2.2-5.2), diabetes (1.7; 1.0-2.9), and hypercholesterolemia (1.8; 1.1-3.2). After adjustment for confounders, only the odds ratio for hypertension was significant (1.8; 1.1-3.1). Asymptomatic organ damage occurred significantly more often in women with fibroids (66.7%; 95% CI 55.8%-77.6% vs 42.9%; 38.0-47.8 in controls), especially in the younger age group (respectively 48.5%; 31.1%-65.9% vs 22.1%; 17.0-27.2). In this study, women with fibroids had a remarkably high hypertension risk compared to controls, with more asymptomatic organ damage, in particular young women.

Creatine kinase and renal sodium excretion in African and European men on a high sodium diet.

Creatine kinase (CK) rapidly regenerates ATP for Na+ /K+ -ATPase driven sodium retention throughout the kidney. Therefore, we assessed whether resting plasma CK is associated with sodium retention after a high sodium diet. Sixty healthy men (29 European and 31 African ancestry) with a mean age of 37.2 years (SE 1.2) were assigned to low sodium intake (< 50 mmol/d) during 7 days, followed by 3 days of high sodium intake (> 200 mmol/d). Sodium excretion (mmol/24-h) after high sodium was 260.4 (28.3) in the high CK tertile versus 415.2 (26.3) mmol/24-h in the low CK tertile (P < .001), with a decrease in urinary sodium excretion of 98.4 mmol/24-h for each increase in log CK, adjusted for age and African ancestry. These preliminary results are in line with the energy buffering function of the CK system, but more direct assessments of kidney CK will be needed to further establish whether this enzyme enhances sodium sensitivity.

Hypertension and Cardiovascular Risk Profile in a Middle-Income Setting: The HELISUR Study.

BACKGROUND: Hypertension is the leading risk factor responsible for premature death worldwide, but its burden has shifted to low- and middle-income countries. Therefore, we studied hypertension and cardiovascular risk in the population of Suriname, a middle-income country with a predominantly urban population of African and Asian ancestry. METHODS: A random sample of 1,800 noninstitutionalized men and women aged 18-70 years was selected to be interviewed at home and examined at the local hospital for cardiovascular risk factors, asymptomatic organ damage, and cardiovascular disease. RESULTS: The 1,157 participants examined (37% men) were mainly of self-defined Asian (43%) or African (39%) ancestry, mean age 43 years (SD 14). The majority of the population (71%) had hypertension or prehypertension, respectively, 40% and 31%. Furthermore, 72% was obese or overweight, while 63% had diabetes or prediabetes. Only 1% of the adult population had an optimal cardiovascular risk profile. Hypertension awareness, treatment, and control were respectively 68%, 56%, and 20%. In line with this, 22% of the adult population had asymptomatic organ damage, including increased arterial stiffness, left ventricular hypertrophy, microalbuminuria, or asymptomatic chronic kidney disease. CONCLUSIONS: 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.

The acute effect of beta-guanidinopropionic acid versus creatine or placebo in healthy men (ABC-Trial): A randomized controlled first-in-human trial.

AIMS: Increasing 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. METHODS: In 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. RESULTS: Twenty-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). CONCLUSION: In 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.

Health literacy in Suriname.

BACKGROUND: Low health literacy is an independent predictor of cardiovascular mortality. However, data on health literacy in low- and middle-income countries are scarce. Therefore, we assessed the level of health literacy in Suriname, a middle-income country with a high cardiovascular mortality. METHODS: We estimated health literacy in a convenience sample at an urban outpatient center in the capital and at a semirural health center, using the validated Rapid Estimate of Adult Literacy in Medicine adapted for the Dutch language (REALM-D) instrument. REALM-D scores vary from 0 to 66 (all correct). The primary outcome was the level of health literacy. Furthermore, we assessed the effect of age, sex, ethnicity, disease history, research location, and level of education on health literacy with multivariable linear regression. RESULTS: We included 99 volunteers (52% men; 51% urban research location) with a mean age of 44.9 years (SD 13.4). The mean REALM-D score was moderate: 48.6 (SD 8.1). Greater health literacy was associated with male sex, an urban research location, and a higher educational level. CONCLUSION: Health literacy was moderate in these Surinamese participants. Health care workers should take health literacy into account, and targeted interventions should be developed to improve health literacy in Suriname.

Creatine kinase as a marker of obesity in a multi-ethnic population.

OBJECTIVE: Creatine kinase (CK), the central regulatory enzyme of energy metabolism, is particularly high in type II skeletal muscle fibers, which are associated with insulin resistance and obesity. As resting plasma CK is mainly derived from skeletal muscle, we assessed whether plasma CK is associated with markers of obesity. METHODS: In this cross-sectional study, we analyzed a random sample of the multi-ethnic population of Amsterdam, the Netherlands, consisting of 1444 subjects aged 34-60 years. The primary outcome was the independent association between plasma CK after rest and waist circumference. Other outcomes included waist-to-hip ratio and body mass index. RESULTS: Mean waist circumference increased from the first through the third CK tertile, respectively 90.3 (SD 13.4), 93.2 (SD 14.3), and 94.4 (SD 13.3) cm (p < 0.001 for differences between tertiles). The increase in waist circumference was 8.91 (95% CI 5.35 to 12.47) cm per log CK increase after adjustment for age, sex, African ethnicity, educational level, physical activity and plasma creatinine. Similarly, CK was independently associated with waist-to-hip ratio and body mass index, with an increase of respectively 0.05 (95% CI 0.03 to 0.07) and 3.6 (95% CI 2.3 to 5.0) kg/m2 per log CK increase. CONCLUSIONS: Plasma CK is independently associated with measures of obesity in a multi-ethnic population. This is in line with the central role of type II skeletal muscle fibers in energy metabolism and obesity. Prospective studies should assess whether resting plasma CK could be an easy accessible marker of CK rich type II fiber predominance that helps identify individuals at risk for obesity.

Creatine kinase inhibition lowers systemic arterial blood pressure in spontaneously hypertensive rats: a randomized controlled trial.

OBJECTIVE: Creatine kinase is reported to be a main predictor of blood pressure (BP) in the general population, with a strong correlation between resistance artery creatine kinase expression and clinical BP in humans. The enzyme rapidly regenerates ATP near cytoplasmic ATPases involved in pressor responses, including resistance artery contractility and renal sodium retention. Therefore, we assessed whether creatine kinase inhibition reduces BP. METHODS: We implemented the 'Animal Research: Reporting of In Vivo Experiments' guideline. In a 4-week randomized controlled trial, male 16-week-old spontaneously hypertensive rats (N = 16) were randomly assigned to the specific competitive creatine kinase inhibitor beta-guanidinopropionic acid (3%)-supplemented chow vs. standard chow. BP measured by the tail-cuff method was the main outcome. Other outcomes included vasodilation in isolated arteries and renal renin expression. RESULTS: Creatine kinase inhibition reduced BP safely and reversibly. Mean baseline BP of, respectively, 191.5 (standard error 4.3) mmHg SBP and 143.1 (4.1) mmHg DBP was reduced by, respectively, 42.7 (5.5) mmHg SBP and 35.6 (5.0) mmHg DBP (P < 0.001) compared with controls, with evidence of enhanced vasodilation and a diuretic effect. CONCLUSION: 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.

The acute effect of beta-guanidinopropionic acid versus creatine or placebo in healthy men (ABC Trial): study protocol for a randomized controlled trial.

BACKGROUND: Despite 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/DESIGN: This 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. DISCUSSION: There 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 REGISTRATION: The Netherlands National Trial Register Trialregister.nl (identifier NTR 4444) , registered 9 March 2014.

Hypertension risk in Dutch women with symptomatic uterine fibroids.

BACKGROUND: Female-specific risk factors for cardiovascular disease are understudied. We assessed whether women with uterine fibroids have a greater hypertension risk, independent of the shared risk factors for both conditions. METHODS: Blood pressure was measured in women scheduled for fibroid surgery compared to women scheduled for nonfibroid gynecological surgery and women randomly sampled from the general population. We used multivariable binary logistic regression to assess whether hypertension was more common with surgically treated fibroids, independent of age, body mass index, and African ancestry. RESULTS: We included 1,342 women (542 of African ancestry), of which 272 scheduled for fibroid surgery, 385 controls scheduled for nonfibroid gynecological surgery, and 685 random population controls, with a mean age (SD) of, respectively, 43.4 (6.6), 41.3 (10.2), and 45.1 (6.6) years; and a mean body mass index (SD) of, respectively, 27.4 (5.3), 25.7 (5.7), and 28.2 (5.6) kg/m(2). Hypertension was found more frequently with surgically treated fibroids, with an occurrence of 41.9% in women with fibroids vs. 27.5% in surgical controls, and 28.3% in population controls (P < 0.001 for fibroids vs. controls). The association with hypertension was independent of age, body mass index, and African ancestry (odds ratio, 2.4; 95% confidence interval, 1.7-3.4). CONCLUSIONS: Hypertension risk is higher in Dutch women with surgically treated fibroids than in surgery or population controls, independent of age, body mass index, and African ancestry. Our data add to the body of evidence indicating that women with uterine fibroids are eligible for hypertension screening.

Accuracy for optical diagnosis of small colorectal polyps in nonacademic settings.

BACKGROUND & AIMS: When small colorectal lesions are accurately characterized, adenomas can be removed and discarded without formal histopathology analysis. Previous studies in an academic setting showed that many lesions can be managed accurately on the basis of their endoscopic image (optical diagnosis). We performed a prospective study to assess the accuracy of optical diagnosis of small colorectal polyps in a nonacademic setting (the DISCOUNT trial) by using high-resolution endoscopy (HRE) and narrow-band imaging (NBI). METHODS: During colonoscopy, 1 of 3 nonacademic endoscopists characterized small lesions and declared whether this was done with low or high confidence. In cases of high confidence, the endoscopists decided whether lesions should be removed and discarded or whether they could be left in situ. A surveillance interval was then recommended on-site. RESULTS: Of 215 patients in the study, 108 were found to have 281 small lesions. Of these lesions, 231 were characterized with high confidence by using HRE or NBI; the level of corresponding sensitivity was 77.0% (95% confidence interval, 68.4-83.8), and specificity was 78.8% (95% confidence interval, 70.6-85.2). Of these lesions, 164 were assigned for removal, and 67 were assigned to remain in situ, including 9 adenomas. In 54 patients, a surveillance interval could be recommended on-site that was in line with Dutch guidelines for 44 patients. CONCLUSIONS: Even though many lesions were characterized by HRE or NBI with high confidence, optical diagnosis in a nonacademic setting proved to be disappointing, with a sensitivity of 77.0% and a specificity of 78.8%. Many lesions were accurately assigned to be removed or remain in situ, although few adenomas were assigned to remain in situ. Also, 19% of on-site recommendations for a surveillance interval proved to be inaccurate.