Effects of hydration on plasma copeptin, glycemia and gluco-regulatory hormones: a water intervention in humans.

PURPOSE: High plasma copeptin, a marker of vasopressin, predicts diabetes mellitus. We tested if copeptin could be suppressed by increased water intake in healthy individuals, and if a water-induced change in copeptin was accompanied by altered concentrations of glucose, insulin or glucagon. METHODS: Thirty-nine healthy individuals underwent, in random order, 1 week of high water intake (3 L/day on top of habitual intake) and 1 week of normal (habitual) fluid intake (control). Fasting plasma concentrations of copeptin, glucose, insulin and glucagon were compared between the ends of both periods. Furthermore, acute copeptin kinetics were mapped for 4 h after ingestion of 1 L of water. RESULTS: After acute intake of 1 L water, copeptin was significantly reduced within 30 min, and reached maximum reduction within 90 min with on average 39% reduction (95% confidence interval (95 CI) 34-45) (p < 0.001) and remained low the entire test period (4 h). One week of increased water intake led to a 15% reduction (95 CI 5-25) (p = 0.003) of copeptin compared to control week. The greatest reduction occurred among subjects with habitually high copeptin and concentrated urine ("water-responders"). Water-responders had significant water-induced reduction of glucagon, but glucose and insulin were unaffected. CONCLUSIONS: Both acute and 1 week extra water intake potently reduced copeptin concentration. In those with the greatest decline (water-responders), who are typically low drinkers with high baseline copeptin, water induced a reduction in fasting glucagon. Long-term trials assessing the effect of water on glucometabolic traits should focus on low-water drinkers with high copeptin concentration.

Orthostatic Changes in Hemodynamics and Cardiovascular Biomarkers in Dysautonomic Patients.

BACKGROUND: Impaired autonomic control of postural homeostasis results in orthostatic intolerance. However, the role of neurohormones in orthostatic intolerance has not been explained. METHODS: Six-hundred-and-seventy-one patients (299 males; 55 ± 22 years) with unexplained syncope underwent head-up tilt (HUT) with serial blood sampling. Systolic blood pressure (SBP) and heart rate (HR) supine, after 3 min, and lowest BP/highest HR during HUT were recorded. Plasma levels of epinephrine, norepinephrine, renin, C-terminal-pro-arginine-vasopressin (CT-proAVP), C-terminal- endothelin-1 (CT-proET-1), and mid-regional-fragment of pro-atrial-natriuretic-peptide (MR-proANP) were determined at supine and 3 min of HUT. Multivariate-adjusted logistic regression model was applied to compare 1st (reference) with 4th quartile of 3 min and maximal ΔSBP/ΔHR (i.e. pronounced hypotension or tachycardia) vs. changes in neuroendocrine biomarkers, respectively. RESULTS: Higher resting CT-proET-1 predicted BP fall at 3 min (Odds ratio (OR) per 1 SD: 1.62, 95%CI 1.18-2.22; p = 0.003), and max BP fall during HUT (1.82, 1.28-2.61; p = 0.001). Higher resting CT-proAVP predicted BP fall at 3 min (1.33, 1.03-1.73; p = 0.03), which was also associated with increase in CT-proAVP (1.86, 1.38-2.51; p = 0.00005) and epinephrine (1.47, 1.12-1.92; p = 0.05) during HUT. Lower resting MR-proANP predicted tachycardia at 3 min (0.37, 0.24-0.59; p = 0.00003), and max tachycardia during HUT (0.47, 0.29-0.77; p = 0.002). Further, tachycardia during HUT was associated with increase in epinephrine (1.60, 1.15-2.21; p = 0.005), and norepinephrine (1.87, 1.38-2.53; p = 0.005). CONCLUSIONS: Resting CT-proET-1 and CT-proAVP are increased in orthostatic hypotension, while resting MR-proANP is decreased in postural tachycardia. Moreover, early BP fall during orthostasis evokes increase in CT-proAVP and epinephrine, while postural tachycardia is associated with increase in norepinephrine and epinephrine.

High salt intake increases copeptin but salt sensitivity is associated with fluid induced reduction of copeptin in women.

This study investigated if copeptin is affected by high salt intake and whether any salt-induced changes in copeptin are related to the degree of salt sensitivity. The study was performed on 20 men and 19 women. In addition to meals containing 50 mmol NaCl daily, capsules containing 100 mmol NaCl and corresponding placebo capsules were administered during 4 weeks each, in random order. Measurements of 24 h blood pressure, body weight, 24 h urinary volume, and fasting plasma copeptin were performed at high and low salt consumption. Copeptin increased after a high compared to low dietary salt consumption in all subjects 3,59 ± 2,28 versus 3,12 ± 1,95 (P = 0,02). Copeptin correlated inversely with urinary volume, at both low (r = -0,42; P = 0,001) and high (r = -0,60; P < 0,001) salt consumption, as well as with the change in body weight (r = -0,53; P < 0,001). Systolic salt sensitivity was inversely correlated with salt-induced changes of copeptin, only in females (r = -0,58; P = 0,017). As suppression of copeptin on high versus low salt intake was associated with systolic salt sensitivity in women, our data suggest that high fluid intake and fluid retention may contribute to salt sensitivity.

A clinically confirmed family history for early myocardial infarction is associated with increased risk of obesity, insulin resistance and metabolic syndrome.

OBJECTIVE: The risk factor pattern underlying a parental history of myocardial infarction (MI) is incompletely understood. We examined whether a parental history of clinically verified early MI may promote development of insulin resistance, obesity and the metabolic syndrome (MetS). METHODS: One hundred and seventy-four offspring to patients with clinically verified MI before 60 years of age in the population-based prospective Malmo Diet and Cancer (MDC) study were recruited (positive parental history). As controls, we included 174 offspring of MDC participants without MI during 14 years of follow-up in the MDC (negative parental history). MetS was defined according to the National Cholesterol Education Program Adult Treatment Panel III (NCEP ATP III) guidelines, obesity as BMI greater than 30  kg/m and insulin resistance as the top quartile of homeostasis model assessment index in the 348 included offspring (mean age 44 years, 49% women). RESULTS: The odds ratio, 95% confidence interval, for MetS in positive parental history as compared with negative parental history was 2.05, 1.06-4.00 (P = 0.034) after adjustment for age, sex, low-density lipoprotein cholesterol (LDL) and smoking. positive parental history was also independently associated with obesity 2.50, 1.34-4.66 (P = 0.003), abdominal obesity 2.01, 1.21-3.33 (P = 0.007) and insulin resistance 1.97, 1.14-3.40 (P = 0.014), whereas there was no association with LDL and smoking. All of these relationships were stronger in men than in women. CONCLUSION: Parental history of clinically verified early MI is associated with MetS, obesity and insulin resistance rather than with traditional cardiovascular disease risk factors such as LDL and smoking, suggesting that primary preventive interventions targeted at weight reduction and improvement of insulin sensitivity may be particularly beneficial in this subset of the population.

A dedicated investigation unit improves management of syncopal attacks (Syncope Study of Unselected Population in Malmo--SYSTEMA I).

AIMS: To investigate whether a systematic approach to unexplained syncopal attacks based on the European Society of Cardiology guidelines would improve the diagnostic and therapeutic outcomes. METHODS AND RESULTS: Patients presenting with transient loss of consciousness to the Emergency Department of Skåne University Hospital in Malmö were registered by triage staff. Those with established cardiac, neurological, or other definite aetiology and those with advanced dementia were excluded. The remaining patients were offered evaluation based on an expanded head-up tilt test protocol, which included carotid sinus massage, and nitroglycerine challenge if needed. Out of 201 patients registered over a period of 6 months, 129 (64.2%) were found to be eligible; of these, 101 (38.6% men, mean age 66.3 +/- 18.4 years) decided to participate in the study. Head-up tilt test allowed diagnoses in 91 cases (90.1%). Vasovagal syncope (VVS) was detected in 45, carotid sinus hypersensitivity (CSH) in 27, and orthostatic hypotension (OH) in 51 patients. Twelve patients with VVS and 15 with CSH also had OH, whereas 25 were diagnosed with OH only. In a multivariate logistic regression, OH was independently associated with age [OR (per year): 1.05, 95% CI 1.02-1.08, P = 0.001], history of hypertension (2.73, 1.05-7.09, P = 0.039), lowered estimated glomerular filtration rate (per 10 mL/min/1.73 m(2): 1.17, 1.01-1.33, P = 0.032), use of loop diuretics (10.44, 1.22-89.08, P = 0.032), and calcium-channel blockers (5.29, 1.03-27.14, P = 0.046), while CSH with age [(per year) 1.12, 1.05-1.19, P < 0.001), use of angiotensin-converting enzyme inhibitor/angiotensin receptor blocker (4.46, 1.22-16.24, P = 0.023), and nitrates (27.88, 1.99-389.81, P = 0.013). CONCLUSION: A systematic approach to patients presenting with unexplained syncopal attacks considerably increased diagnostic efficacy and accuracy. Potential syncope diagnoses have a tendency to overlap and show diversity in demographic, anamnestic, and pharmacological determinants.

Orthostatic hypotension in genetically related hypertensive and normotensive individuals.

OBJECTIVES: Prevalence and determinants of orthostatic hypotension remain largely unexplored in younger individuals without significant burden of chronic diseases. METHODS: We investigated frequency and main associations of impaired orthostatic response in a cohort of 469 middle-aged hypertensive patients and 453 of their normotensive first-degree relatives. RESULTS: 13.4% of hypertensive and 5.5% of normotensive study participants were found to have orthostatic hypotension. In a backward logistic regression the following determinants of orthostatic hypotension were identified: sex [female, odds ratio (OR) 2.45, 95% confidence interval (CI) 1.14-5.25, P=0.022], reduced glomerular filtration rate [OR (per ml/min/1.73 m2) 0.97, 95% CI 0.94-0.99, P=0.002], systolic [OR (per mmHg) 1.02, 95% CI 1.00-1.05, P=0.047] and diastolic blood pressure [OR (per mmHg) 1.04, 95% CI 1.00-1.09, P=0.033], and antihypertensive treatment (OR 0.41, 95% CI 0.18-0.93, P=0.034). In hypertensive patients use of angiotensin-converting enzyme inhibitors was related to lower orthostatic hypotension frequency. Percentage of orthostatic hypotension-positive patients in the highest blood pressure stratum (> or = 160 mmHg) decreased from 20.2 to 7.6, when diagnostic criteria of orthostatic hypotension were adjusted for mean systolic orthostatic reaction (2 SD value: 30 mmHg) . During follow-up (t=6.6 years) individuals with impaired orthostatic response showed a trend towards increased total mortality (OR 2.16, 95% CI 0.97-4.80, P=0.06) in a crude model. CONCLUSION: Prevalence of orthostatic hypotension in hypertensive patients is higher than in their normotensive first-degree relatives. Independently of age, sex, and elevated blood pressure, orthostatic hypotension may be additionally determined by impaired renal function. Antihypertensive treatment seems to protect from orthostatic hypotension, in particular, use of angiotensin-converting enzyme inhibitors in hypertensive patients. The diagnostic criteria of orthostatic hypotension may need adjustment for initial supine systolic blood pressure to increase clinical accuracy. The prognostic value of impaired orthostatic response regarding risk of cardiovascular disease and mortality remains uncertain and requires further studies.

The metabolic syndrome and risk of myocardial infarction in familial hypertension (hypertension heredity in Malmö evaluation study).

OBJECTIVES: The aim of this study was to examine whether three main definitions of the metabolic syndrome (MetS)--WHO, National Cholesterol Education Program--Adult Treatment Panel III and International Diabetes Federation--identify the same individuals and are able to predict incident myocardial infarction (MI) in families with essential hypertension. METHODS: The tested definitions were prospectively related to data on MI in a cohort of approximately 1700 individuals with overt essential hypertension and their normotensive first-degree relatives. RESULTS: At baseline, 616 participants had MetS, yet only 209 of them (33.9%) were identified by all definitions, and compatibility rate for each pair of definitions was approximately 50%. During follow-up (Tmean approximately 6.6 years) 53 participants developed MI and they were generally older and more dysmetabolic than the rest of the cohort. There were also more men, smokers and diabetic individuals in this group. After adjustment for all conventional cardiovascular risk factors, including hypertension and diabetes, only the National Cholesterol Education Program definition could predict the increased risk of MI [odds ratio (OR) = 2.2, confidence interval (CI) = 1.2-4.0, P = 0.01]. Among individual MetS components, incident MI was independently associated with three of them: low high-density lipoprotein-cholesterol (OR = 2.03, CI = 1.09-3.78, P = 0.025) insulin resistance (OR = 2.02, CI = 1.08-3.78, P = 0.028) and increased albumin excretion rate (OR = 1.24, CI = 0.99-1.55, P = 0.060). CONCLUSION: The presence of MetS in hypertensive and genetically hypertension prone individuals may signal the increased risk of future MI. However, only the National Cholesterol Education Program criteria appear to have a sufficient predictive accuracy.

Determinants of kidney function in Swedish families: role of heritable factors.

The aim of this study was to evaluate the determinants of kidney function and the role of heritable factors in a sample of 249 siblings free from known cardiovascular disease and without antihypertensive drugs belonging to 110 families. Four different measures and estimates of kidney function were considered. Blood pressure was recorded during 24 h by ambulatory blood pressure monitoring. Heritability was estimated with and without adjustment for significant covariates.In multivariate analysis, in addition to age, sex, BMI, HDL-cholesterol, 24-h systolic and mean blood pressure, systolic nocturnal blood pressure dipping resulted independently related to serum creatinine, estimated Cockcroft-Gault-creatinine clearance and estimated by the modification of diet in renal disease-glomerular filtration rate. After full adjustment, the heritability values were 51% for the measured creatinine clearance (P < 0.01), 58% for the estimated Cockcroft-Gault-creatinine clearance (P < 0.001), 40% for the estimated by the modification of diet in renal disease-glomerular filtration rate (P < 0.001), but 8% (P = 0.34) for serum creatinine.Our data confirm that kidney function is partially under genetic control and that genetic variants of importance for this trait could be mapped. The association of the circadian rhythm of blood pressure with kidney function in this sample deserves further investigation.

Novel mutations in the SLC12A3 gene causing Gitelman's syndrome in Swedes.

PURPOSE: Gitelman's syndrome (GS) is an inherited autosomal recessive disorder due to loss of function mutations in the SLC12A3 gene encoding the Na-Cl co-transporter (NCCT), the target of thiazide diuretics. The defective function of the NCCT, which normally is expressed in the apical membrane of the distal convolute tubule in the kidney, leads to mild hypotension, hypokalemia, hyperreninemic hyperaldosteronism, mild metabolic alkalosis, hypomagnesemia and hypocalciuria. Up to now, more than 100 mutations of the SLC12A3 gene have been described in GS patients. METHODS: We have collected 30 patients from Sweden with a clinical diagnosis of GS and undertaken a mutation screening by SSCP and successive sequencing of the 26 exons and intronic boundaries. Both mutations were identified in most (n = 28, 93%) and at least one mutation was identified in all patients. RESULTS: We found 22 different mutations evenly distributed throughout the gene, 11 of which have not been described previously. The new variants include 8 missense mutations (Glu68Lys, His69Asn, Argl45His, Vall53Met, Gly230Asp, Gly342Ala, Val677Leu and Gly867Ser), 1 insertion (c.834_835insG on exon 6) and 2 splice-site mutations (c.2667 + lT>G substitution in splicing donor site after exon 22, c.1569-1G>A substitution in the splicing acceptor site before exon 13). CONCLUSION: In Swedish patients with the clinical features of GS, disease-causing mutations in the SLC12A3 gene were identified in most patients. The spectrum of GS mutations is wide making full mutation screening of the SLC12A3 gene necessary to confirm the diagnosis.

Moderate salt restriction effectively lowers blood pressure and degree of salt sensitivity is related to baseline concentration of renin and N-terminal atrial natriuretic peptide in plasma.

OBJECTIVE: The effect of salt restriction on blood pressure is under intense debate. We tested the effect of 100 mmol salt reduction on ambulatory blood pressure (ABP) in 46 Swedish individuals, 39 of whom completed the study, using a double-blind, placebo-controlled, cross-over design. Furthermore, we tested whether the basal plasma concentration of renin or N-terminal atrial natriuretic peptide (Nt-proANP) predict the degree of salt sensitivity. METHODS: Participants received all meals and drinks with a total daily NaCl content of 50 mmol during 8 weeks. In addition, NaCl capsules (100 mmol/day) and corresponding placebo capsules were administered for 4 weeks each in random order. ABP after high-salt intake (150 mmol/day) was compared with ABP after low-salt intake (50 mmol/day). Salt sensitivity was defined as the difference between 24-h systolic ABP at the high-salt versus the low-salt periods. Baseline renin and Nt-proANP were related to salt sensitivity. RESULTS: Lowering of salt intake from 150 to 50 mmol/day induced significant blood pressure reductions (mean reduction, 95% confidence interval) in systolic and diastolic 24-h ABP (5.8, 3.4-8.2 and 2.6, 0.91-4.4 mmHg), daytime ABP (5.5, 2.9-8.1 and 2.3, 0.42-4.1 mmHg) and night-time ABP (6.4, 3.5-9.3 and 3.4, 1.4-5.5 mmHg). Baseline ln(renin) correlated inversely with salt sensitivity (r = -0.50, P = 0.001) whereas baseline ln(Nt-proANP) correlated directly (r = 0.33, P = 0.04). CONCLUSION: Lowering of salt intake with 100 mmol/day induces clinically relevant ABP reductions. Renin and Nt-proANP, measured with individuals on their habitual diet, could be useful biomarkers to identify individuals with the greatest blood pressure-lowering benefit from reduced salt intake.

Dipping and variability of blood pressure and heart rate at night are heritable traits.

BACKGROUND: Blunted nocturnal blood pressure dipping (NBPD) as well as high variability in blood pressure (BPV) and low variability in heart rate (HRV), are associated with increased cardiovascular morbidity and mortality. The aim of this study was to determine whether these traits are heritable. METHODS: We studied 260 healthy siblings without antihypertensive drugs from 118 Swedish families. The BPV and HRV were defined as the standard deviation of BP and heart rate values recorded during 24 h, daytime (6 am to 10 pm), and night-time (10 pm to 6 am). The NBPD was defined as the ratio between night-time and daytime BP. Heritability was estimated with a maximal likelihood method implemented in the Solar software package with and without adjustment for significant covariates. RESULTS: At night, significant heritability was found for systolic (33%, P < .05), diastolic (36%, P < .05), and mean (42%, P < .01) BPV. After covariate adjustment the corresponding heritability values were 23% (P = .08), 29% (P < .05), and 37% (P < .05). Daytime BPV was not heritable. The heritability of NBPD was 38% (P < .05) for systolic, 9% (P = .29) for diastolic, and 36% (P < .05) for mean BP, but after adjustment only systolic NBPD was significant (29%, P < .05). Heart rate was highly heritable both during daytime (57%, P < .001) and night-time (58%, P < .001), but the variability of heart rate, after adjustment, was only significant at night (37%, P < .05). CONCLUSIONS: Our data suggest that BPV and HRV are partially under genetic control and that genetic loci of importance for these traits could be mapped by linkage analysis.

Heritability of ambulatory and office blood pressure phenotypes in Swedish families.

OBJECTIVE: The aim of this study was to estimate the heritability of 24-h ambulatory blood pressure and office blood pressure phenotypes in Swedish families. METHODS: We measured ambulatory and office blood pressure in 260 siblings without antihypertensive treatment from 118 families. Blood pressure heritability was estimated using standard quantitative genetic variance component analysis implemented in the 'SOLAR' software package after adjustment for significant covariates. RESULTS: Heritability values were significant for night-time systolic (37%), diastolic (32%) and mean (32%) ambulatory blood pressure (P < 0.05 for all). During daytime, systolic ambulatory blood pressure was significantly heritable (33%, P < 0.05). Twenty-four-hour systolic (30%) and diastolic (29%) ambulatory blood pressure also had significant values of heritability (P < 0.05). Pulse pressure ambulatory blood pressure was significantly heritable over 24 h (63%, P < 0.01), during daytime (53%, P < 0.01) and at night (34%, P < 0.05). None of the office blood pressure phenotypes had a significant heritability. CONCLUSIONS: We conclude that ambulatory blood pressure, in particular at night, seems better than office blood pressure to capture the heritable part of blood pressure, suggesting that ambulatory blood pressure may be a more exact estimate of an individual's true blood pressure. Genetic studies using ambulatory blood pressure as the phenotype are likely to be more powerful than those using office blood pressure. The high heritability of pulse pressure ambulatory blood pressure indicates that variation in arterial stiffness in subjects free from antihypertensive medication is strongly affected by genetic factors.

A genome wide scan for early onset primary hypertension in Scandinavians.

With the aim of identifying hypertension susceptibility loci, we performed a genome wide scan in Scandinavian sib-pairs with early onset primary hypertension. To be classified as affected, a diagnosis of primary hypertension at age /= 1.0) were fine mapped with additional markers. Multipoint non-parametric linkage analysis was performed using GENEHUNTER v 2.0. Using simulations, a nominal P