Yentl C. Haan

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.

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 High Creatine Kinase Phenotype is Hypertension- and Obesity-Prone

Dear Editor: In a recent publication, Johnsen and colleagues reported that baseline serum creatine kinase (CK) was correlated with blood pressure at follow-up, but the authors indicated that this association was attenuated when adjusted for body mass index (BMI). The authors concluded that the association between CK and blood pressure was modified by BMI. However, existing data indicate a causal role for CK in both hypertension and obesity, rendering the analysis with BMI as a confounding variable potentially invalid. CK rapidly regenerates adenosine triphosphate from phosphocreatine near highly energy-demanding processes such as ion transport and muscle contractility. Thus, the enzyme is thought to promote hypertension by enhancing sodium retention and cardiovascular contractility. In line with this, a recent study showed a near-perfect correlation between expression of CK in human resistance arteries and systemic arterial blood pressure. In addition, skeletal muscle CK, the main determinant of serum CK, is associated with type II fiber predominance, resistance artery rarefaction, and hypertension. Furthermore, the high CK, type II fiber–predominant skeletal muscle phenotype is obesity-prone. These fast type II fibers designed for sprinting typically rely on glycolysis and cytoplasmic CK, and display an attenuated mitochondrial capacity for oxidation of glucose and fatty acids. Thus, the glucose and fatty acid uptake and utilization is limited, promoting the storage of lipid as fat tissue and obesity. Importantly, CK inhibition leads to a shift from type II to type I fiber predominance and weight loss, providing further evidence for a causal role of CK in obesity. Causal knowledge is a prerequisite for confounding analysis, and confounder identification must be grounded on an understanding of the causal network linking the variables under study. Thus, adding BMI as a confounder to the regression analysis to assess the contribution of CK to blood pressure creates overadjustment bias, as the authors attempt to control for a variable that is causally related to the exposure. Thus, we contend that since CK is known to promote obesity, BMI should not be included as a confounder to explain the association between CK and blood pressure.

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.

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 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.

Health literacy in Suriname

ABSTRACT 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.

[OP.1A.01] MORE CARDIOVASCULAR EVENTS AMONG WOMEN WITH UTERINE FIBROIDS: DATA OF 11,858 WOMEN FROM THE MULTI-ETHNIC NHANES SURVEY

Objective: We recently showed that women with uterine fibroids have a higher hypertension risk compared to women without fibroids, independent of age, body mass index and ethnicity. Whether this translates into more cardiovascular events is unknown. Therefore, we assessed the risk of cardiovascular events in women with fibroids. Design and method: Data of the multi-ethnic, cross-sectional National Health and Nutrition Examination Surveys (NHANES) 1999–2006 were analyzed including 11,858 women, aged 18–85 years. Presence of uterine fibroids and previous cardiovascular events (i.e. any cardiovascular event, congestive heart failure, coronary heart disease or stroke) were self-reported. Physical examination included assessment for obesity (BMI >=30.0 kg/m2), hypertension (SBP/DBP >=140/90 mmHg, or antihypertensive treatment), diabetes (fasting glucose >6.9 mmol/L, or antidiabetic medication), and hypercholesterolemia (cholesterol >6.1 mmol/L, or receiving cholesterol-lowering medication). The primary outcome was the independent odds ratio of cardiovascular events in women with and without uterine fibroids. Results: We included 700 women with and 11,158 women without self-reported fibroids. Women with fibroids were younger (43.6 (SD 7.4) vs 46.4 (21.4) years, p < 0.001) and more often African (38.0 vs 19.8%, p < 0.001). In the different age groups, the prevalence of obesity, hypertension and cardiovascular disease was significantly higher in women with fibroids (Figure 1). Figure. No caption available. As expected, women with fibroids had more hypertension (adjusted OR 1.49, 95%CI 1.13–1.97) and obesity (adjusted OR 1.49, 95%CI 1.17–1.89). Importantly, women with fibroids had more stroke (OR 2.25, 95%CI 1.10–4.57), and total cardiovascular disease (OR 2.27, 95%CI 1.42–3.62), adjusted for age, BMI, ancestry, use of hormones, educational level, SBP, fasting glucose and cholesterol. Diabetes and hypercholesterolemia did not differ significantly between women with and without fibroids. Conclusions: We found that women with fibroids have more cardiovascular events than women without fibroids. Further research regarding the underlying pathophysiology is needed. In addition, currently uterine fibroids are classified as a benign condition. However, these data indicate that fibroids may be considered as a marker for cardiovascular risk, warranting early screening and monitoring of the cardiovascular risk profile in women with fibroids.

[OP.LB03.09] THE ACUTE EFFECT OF THE SPECIFIC CREATINE KINASE INHIBITOR BETA- GPA IN HEALTHY MAN (ABC-TRIAL): A RANDOMIZED PLACEBO AND ACTIVE CONTROLLED FIRST-IN-HUMAN TRIAL

Objective: There is increasing evidence that the ATP generating enzyme creatine kinase (CK) is involved in hypertension. The enzyme is central to the regeneration of ATP by using creatine phosphate and ADP, thereby forming creatine and ATP. We recently showed that beta-guanidinopropionic acid (GPA), a creatine analogue and competitive CK inhibitor, effectively and safely reduced blood pressure in the spontaneously hypertensive rat. This renders GPA to be potentially beneficial for blood pressure lowering. However, no human data are available. Therefore, according to FDA and EMEA guidelines, we assessed the tolerability of a subtherapeutic GPA dose in man. Figure. No caption available. Design and method: In this randomized, placebo and active controlled, triple blind, single center trial (randomization 1:1:1), we included healthy male volunteers, 18 to 50 years old, BMI 18.5–29.9 kg/m2, recruited in the Netherlands. The interventions consisted of one week daily oral administration of GPA in a subtherapeutic dose of 100 mg, creatine 5 gram, or placebo. The primary outcome was the tolerability of GPA as a descriptive measure, in an intent-to-treat analysis. Results: Twenty four randomized participants received the allocated intervention (8 in each treatment arm) and 23 completed the study. One participant in the placebo arm dropped out because of an external event in his family. He experienced no side effects, including not during a re-challenge with the assigned drug. GPA was well tolerated. There were no serious or severe adverse events with GPA, creatine and placebo after 1 week of active treatment, and no significant differences in safety measures including self-reported data obtained with structured and unstructured questionnaires. No abnormalities were reported from physical examination, laboratory determined toxicity including kidney and liver parameters, or cardiovascular safety including QT interval between treatment arms (Table 1). Conclusions: To our knowledge, these are the first human data of the specific CK inhibitor and potential new blood pressure lowering agent GPA. We found no evidence of toxicity with subtherapeutic doses, and will proceed to assess safety and tolerance in a dose-escalation trial in humans. Clinical trial registration number The Netherlands National Trial Register (NTR) number 4444, registered March 9, 2014.