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.

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.

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.

Resistance artery creatine kinase mRNA and blood pressure in humans.

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.

Creatine kinase is associated with failure of hypertension treatment.

BACKGROUND: Failure of hypertension treatment is a major clinical issue because of the high prevalence and the associated mortality risk. We have reported evidence that creatine kinase increases blood pressure through greater sodium retention and cardiovascular contractility, by rapidly providing ATP for these functions. Therefore, we hypothesized that high creatine kinase is associated with failure of antihypertensive treatment. METHOD: We analyzed a cross-sectional, random multiethnic sample of the general population (N = 1444), aged 34-60 years. The primary outcome was the independent association between resting serum creatine kinase and treated uncontrolled hypertension in the population, using multinomial logistic regression analysis. RESULTS: Hypertension prevalence was, respectively, 26.8; 30.8; and 41.2% for the lowest (<88  IU/l) through the highest population creatine kinase tertile (>145  IU/l; P < 0.001). Treatment failed in 72.9% of participants within the highest creatine kinase tertile vs. 46.7% within the lowest tertile (P = 0.004). In logistic regression analysis, creatine kinase was the main predictor of treatment failure (adjusted odds ratio 3.7; 95% confidence interval 1.2-10.9), independent of age, sex, BMI, fasting glucose, ethnicity, or education level. CONCLUSION: Creatine kinase is associated with failure of antihypertensive therapy. Further investigations concerning this association might help improve treatment strategies for difficult-to-treat hypertension.

The effect of the creatine analogue beta-guanidinopropionic acid on energy metabolism: a systematic review.

BACKGROUND: Creatine kinase plays a key role in cellular energy transport. The enzyme transfers high-energy phosphoryl groups from mitochondria to subcellular sites of ATP hydrolysis, where it buffers ADP concentration by catalyzing the reversible transfer of the high-energy phosphate moiety (P) between creatine and ADP. Cellular creatine uptake is competitively inhibited by beta-guanidinopropionic acid. This substance is marked as safe for human use, but the effects are unclear. Therefore, we systematically reviewed the effect of beta-guanidinopropionic acid on energy metabolism and function of tissues with high energy demands. METHODS: We performed a systematic review and searched the electronic databases Pubmed, EMBASE, the Cochrane Library, and LILACS from their inception through March 2011. Furthermore, we searched the internet and explored references from textbooks and reviews. RESULTS: After applying the inclusion criteria, we retrieved 131 publications, mainly considering the effect of chronic oral administration of beta-guanidinopropionic acid (0.5 to 3.5%) on skeletal muscle, the cardiovascular system, and brain tissue in animals. Beta-guanidinopropionic acid decreased intracellular creatine and phosphocreatine in all tissues studied. In skeletal muscle, this effect induced a shift from glycolytic to oxidative metabolism, increased cellular glucose uptake and increased fatigue tolerance. In heart tissue this shift to mitochondrial metabolism was less pronounced. Myocardial contractility was modestly reduced, including a decreased ventricular developed pressure, albeit with unchanged cardiac output. In brain tissue adaptations in energy metabolism resulted in enhanced ATP stability and survival during hypoxia. CONCLUSION: Chronic beta-guanidinopropionic acid increases fatigue tolerance of skeletal muscle and survival during ischaemia in animal studies, with modestly reduced myocardial contractility. Because it is marked as safe for human use, there is a need for human data.

Creatine and creatine analogues in hypertension and cardiovascular disease.

BACKGROUND: The creatine kinase system, the central regulatory system of cellular energy metabolism, provides ATP in situ at ATP-ases involved in ion transport and muscle contraction. Furthermore, the enzyme system provides relative protection from tissue ischaemia and acidosis. The system could therefore be a target for pharmacologic intervention. OBJECTIVES: To systematically evaluate evidence regarding the effectiveness of interventions directly targeting the creatine kinase system as compared to placebo control in adult patients with essential hypertension or cardiovascular disease. SEARCH METHODS: Electronic databases searched: Medline (1950 - Feb 2011), Embase (up to Feb 2011), the Cochrane Controlled Trials Register (issue 3, Aug 2009), Latin-American/Caribbean databank Lilacs; references from textbooks and reviews; contact with experts and pharmaceutical companies; and searching the Internet. There was no language restriction. SELECTION CRITERIA: Randomized controlled trials comparing creatine, creatine phosphate, or cyclocreatine (any route, dose or duration of treatment) with placebo; in adult patients with essential hypertension, heart failure, or myocardial infarction. We did not include papers on the short-term use of creatine during cardiac surgery. DATA COLLECTION AND ANALYSIS: The outcomes assessed were death, total myocardial infarction (fatal or non-fatal), hospitalizations for congestive heart failure, change in ejection fraction, and changes in diastolic and systolic blood pressure in mm Hg or as percent change. MAIN RESULTS: Full reports or abstracts from 1164 papers were reviewed, yielding 11 trials considering treatment with creatine or creatine analogues in 1474 patients with heart failure, ischemic heart disease or myocardial infarction. No trial in patients with hypertension was identified. Eleven trials (1474 patients, 35 years or older) comparing add-on therapy of the creatine-based drug on standard treatment to placebo control in patients with heart failure (6 trials in 1226 / 1474 patients ), or acute myocardial infarction (4 trials in 220 / 1474 patients) or 1 in ischemic heart disease (28 / 1474 patients) were identified. The drugs used were either creatine, creatine phosphate (orally, intravenously, or intramuscular) or phosphocreatinine. In the trials considering heart failure all three different compounds were studied; creatine orally (Gordon 1995, Kuethe 2006), creatine phosphate via intravenous infusion (Ferraro 1996, Grazioli 1992), and phosphocreatinine orally (Carmenini 1994, Maggi 1990). In contrast, the acute myocardial infarction trials studied intravenous creatine phosphate only. In the ischemic heart disease trial (Pedone 1984) creatine phosphate was given twice daily through an intramuscular injection to outpatients and through an intravenous infusion to inpatients. The duration of the study intervention was shorter for the acute patients, from a two hour intravenous infusion of creatine phosphate in acute myocardial infarction (Ruda 1988, Samarenko 1987), to six months in patients with heart failure on oral phosphocreatinine therapy (Carmenini 1994). In the acute myocardial infarction patients the follow-up period varied from the acute treatment period (Ruda 1988) to 28 days after start of the symptoms (Samarenko 1987) or end of the hospitalization period (Zochowski 1994). In the other trials there was no follow-up after discontinuation of treatment, except for Gordon 1995 which followed the patients until four days after stopping the intervention.Only two out of four trials in patients with acute myocardial infarction reported mortality outcomes, with no significant effect of creatine or creatine analogues (RR 0.73, CI: 0.22 - 2.45). In addition, there was no significance on the progression of myocardial infarction or improvement on ejection fraction. The main effect of the interventions seems to be on improvement of dysrhythmia. AUTHORS' CONCLUSIONS: This review found inconclusive evidence to decide on the use of creatine analogues in clinical practice. In particular, it is not clear whether there is an effect on mortality, progression of myocardial infarction and ejection fraction, while there is some evidence that dysrhythmia and dyspnoea might improve. However, it is not clear which analogue, dose, route of administration, and duration of therapy is most effective. Moreover, given the small sample size of the discussed trials and the heterogeneity of the population included in these reports, larger clinical studies are needed to confirm these observations.

Cerebral palsy and the application of the international criteria for acute intrapartum hypoxia.

OBJECTIVE: To apply objective criteria for the identification of acute intrapartum hypoxia in a cohort of cerebral palsy cases and to identify other cerebral palsy-related pathologies. METHODS: A cohort of all 235 neonates with cerebral palsy from a single Australian tertiary care center born between 1986 and 2003. Cases were identified from the South Australian Cerebral Palsy Register. Maternal and pediatric case notes were audited with application of the 2003 American College of Obstetricians and Gynecologists/American Academy of Pediatrics criteria to identify acute intrapartum hypoxia. RESULTS: Data were available for analysis in 213 cases (91%). Major antenatal or pediatric cerebral palsy-related pathologies were identified in 98.1% of all these cases. An isolated acute intrapartum hypoxic event was defined as likely in only 2 of the 46 neonates born at term and none born preterm. Neonatal nucleated red blood cell counts were often high in neonates born preterm and following antenatal pathologies. CONCLUSION: Cerebral palsy was seldom preceded by acute intrapartum hypoxia but antenatal cerebral palsy-related pathologies are often detectable. The objective American College of Obstetricians and Gynecologists/American Academy of Pediatrics criteria are useful to audit cerebral palsy causation and exclude primary intrapartum hypoxia. LEVEL OF EVIDENCE: II-3.