Germline Mutations in CIDEB and Protection against Liver Disease.

BACKGROUND: Exome sequencing in hundreds of thousands of persons may enable the identification of rare protein-coding genetic variants associated with protection from human diseases like liver cirrhosis, providing a strategy for the discovery of new therapeutic targets. METHODS: We performed a multistage exome sequencing and genetic association analysis to identify genes in which rare protein-coding variants were associated with liver phenotypes. We conducted in vitro experiments to further characterize associations. RESULTS: The multistage analysis involved 542,904 persons with available data on liver aminotransferase levels, 24,944 patients with various types of liver disease, and 490,636 controls without liver disease. We found that rare coding variants in APOB, ABCB4, SLC30A10, and TM6SF2 were associated with increased aminotransferase levels and an increased risk of liver disease. We also found that variants in CIDEB, which encodes a structural protein found in hepatic lipid droplets, had a protective effect. The burden of rare predicted loss-of-function variants plus missense variants in CIDEB (combined carrier frequency, 0.7%) was associated with decreased alanine aminotransferase levels (beta per allele, -1.24 U per liter; 95% confidence interval [CI], -1.66 to -0.83; P = 4.8×10-9) and with 33% lower odds of liver disease of any cause (odds ratio per allele, 0.67; 95% CI, 0.57 to 0.79; P = 9.9×10-7). Rare coding variants in CIDEB were associated with a decreased risk of liver disease across different underlying causes and different degrees of severity, including cirrhosis of any cause (odds ratio per allele, 0.50; 95% CI, 0.36 to 0.70). Among 3599 patients who had undergone bariatric surgery, rare coding variants in CIDEB were associated with a decreased nonalcoholic fatty liver disease activity score (beta per allele in score units, -0.98; 95% CI, -1.54 to -0.41 [scores range from 0 to 8, with higher scores indicating more severe disease]). In human hepatoma cell lines challenged with oleate, CIDEB small interfering RNA knockdown prevented the buildup of large lipid droplets. CONCLUSIONS: Rare germline mutations in CIDEB conferred substantial protection from liver disease. (Funded by Regeneron Pharmaceuticals.).

Seasonal variation of vasopressin and its relevance for the winter peak of cardiometabolic disease: A pooled analysis of five cohorts.

BACKGROUND: Vasopressin concentration is typically higher at night, during stress, and in males, but readily lowered by water intake. Vasopressin is also a causal candidate for cardiometabolic disease, which shows seasonal variation. OBJECTIVE: To study whether vasopressin concentration varies by season in a temperate climate. METHODS: The vasopressin surrogate marker copeptin was analyzed in fasting plasma samples from five population-based cohorts in Malmö, Sweden (n = 25,907, 50.4% women, age 18-86 years). We investigated seasonal variation of copeptin concentration and adjusted for confounders in sinusoidal models. RESULTS: The predicted median copeptin level was 5.81 pmol/L (7.18 pmol/L for men and 4.44 pmol/L for women). Copeptin exhibited a distinct seasonal pattern with a peak in winter (mid-February to mid-March) and nadir in late summer (mid-August to mid-September). The adjusted absolute seasonal variation in median copeptin was 0.62 pmol/L (95% confidence interval [CI] 0.50; 0.74, 0.98 pmol/L [95% CI 0.73; 1.23] for men and 0.46 pmol/L [95% CI 0.33; 0.59] for women). The adjusted relative seasonal variation in mean log copeptin z-score was 0.20 (95% CI 0.17; 0.24, 0.18 [95% CI 0.14; 0.23] in men and 0.24 [95% CI 0.19; 0.29] in women). The observed seasonal variation of copeptin corresponded to a risk increase of 4% for incident diabetes mellitus and 2% for incident coronary artery disease. CONCLUSION: The seasonal variation of the vasopressin marker copeptin corresponds to increased disease risk and mirrors the known variation in cardiometabolic status across the year. Moderately increased water intake might mitigate the winter peak of cardiometabolic disease.

High water intake and low urine osmolality are associated with favorable metabolic profile at a population level: low vasopressin secretion as a possible explanation.

PURPOSE: Elevated plasma concentration of the vasopressin marker copeptin and low water intake are associated with elevated blood glucose and diabetes risk at a population level. Moreover, in individuals with low urine volume and high urine osmolality (u-Osm), water supplementation reduced fasting plasma (fp) copeptin and fp-glucose. In this observational study, we investigated if low total water intake or high u-Osm correlated with high fp-copeptin and components of the metabolic syndrome at the population level. METHODS: In the population-based Malmö Offspring Study (MOS, n = 2599), fp-copeptin and u-Osm from morning urine samples were measured, and diet and total water intake (from beverages and food moisture) was assessed by a 4-day web-based record. RESULTS: Increasing water intake by tertile was after adjustment for age and sex associated with low fp-triglycerides (p = 0.002) and high fp-HDL (p = 0.004), whereas there was no association with the other investigated metabolic traits (HbA1c, fp-glucose, BMI or waist circumference). Increasing u-Osm by tertile was, after adjustment for age and sex, associated with high fp-glucose (p = 0.007), and borderline significantly associated with high HbA1c (p = 0.053), but no association was observed with fp-HDL, fp-triglycerides, BMI or waist circumference. Fp-copeptin concentration correlated significantly with water intake (r = - 0.13, p < 0.001) and u-Osm (r = 0.27, p < 0.001). High copeptin was associated with all investigated metabolic traits (p < 0.001 for all). CONCLUSION: Low concentrations of the vasopressin marker copeptin is linked to high water intake, low u-Osm, and a favorable metabolic profile, suggesting that vasopressin lowering lifestyle interventions, such as increased water intake, may promote metabolic health.

Elevated plasma copeptin levels identify the presence and severity of non-alcoholic fatty liver disease in obesity.

INTRODUCTION: Copeptin is the stable surrogate marker of vasopressin (VP), which is released in response to elevated plasma osmolality or low blood pressure. Elevated plasma copeptin levels are associated with higher risk of insulin resistance-related disorders, such as type 2 diabetes (T2DM), metabolic syndrome (MS), and cardiovascular disease, and experimental reduction of circulating VP levels is shown to significantly decrease hepatic fat content in obese rats, independently from body adiposity. However, the association between copeptin and non-alcoholic fatty liver disease and steatohepatitis (NAFLD/NASH) in humans has not been explored yet. The aim of this study was to explore the relationship between plasma copeptin and the presence/severity of NAFLD/NASH. METHODS: For this study, we recruited 60 obese patients candidate to bariatric surgery for clinical purposes in which intraoperative liver biopsies were performed for diagnosing NAFLD/NASH. Circulating copeptin levels were also assessed in 60 age- and sex-comparable non-obese individuals without NAFLD at liver ultrasonography. Plasma copeptin was measured by sandwich immunoluminometric assay (Thermo Fisher Scientific). RESULTS: Obese patients with biopsy-proven NAFLD (53%) had significantly higher copeptin levels than both obese individuals without NAFLD and non-obese subjects (ob/NAFLD+ 9.5 ± 4.9; ob/NAFLD- 6.4 ± 2.6; and non-ob/NAFLD- 7.4 ± 5.1 pmol/L; p = 0.004 and p = 0.01 respectively). Plasma copeptin concentration positively correlated with hepatic macro- and micro-vesicular steatosis (r = 0.36, p = 0.026; r = 0.31, p = 0.05), lobular inflammation (r = 0.37, p = 0.024) and significantly increased throughout degrees of NASH severity, as expressed as absence, borderline, and overt NASH at the liver biopsy (r = 0.35, p = 0.01). Greater circulating copeptin predicted the presence of NASH with OR = 1.73 (95% CI = 1.02-2.93) after multivariate adjustment for age, sex, renal function and presence of T2DM and MS components. CONCLUSIONS: Increased plasma copeptin is independently associated with the presence and severity of NAFLD and NASH, pointing to a novel mechanism behind human fatty liver disease potentially modifiable by pharmacological treatment and lifestyle intervention.

Plasma copeptin as a predictor of kidney disease.

Background: Plasma copeptin, a marker of vasopressin, is associated with renal function decline in the general population. Our aim was to study the links between elevated copeptin and future risk of kidney disease. Methods: Copeptin was measured in a sample of the Malmö Preventive Project (MPP) Reinvestigation (n = 5158) and in the Malmö Diet and Cancer Cardiovascular Cohort (MDC-CC) (n = 5162). According to national registers, 89 subjects in MPP and 180 in MDC-CC developed chronic kidney disease (CKD) during follow-up (8.7 and 19.6 years, respectively). Results: After multivariate adjustment (gender, age, body mass index, smoking status, estimated glomerular filtration rate, prevalent diabetes, systolic blood pressure and prevalent antihypertensive treatment), copeptin (beta-coefficient per 1 standard deviation increment of ln copeptin) was independently associated with increased risk of CKD during follow-up in both cohorts (MPP: (HR) 1.46, 95% confidence interval (CI) 1.18-1.80, P < 0.001; MDC-CC: HR 1.25, 95% CI 1.02-1.54, P = 0.03) among subjects free from prevalent kidney disease at baseline. Furthermore, in MPP, elevated copeptin predicted a specified diagnosis of kidney disease other than CKD (HR 1.31, 95% CI 1.08-1.59, P = 0.006) after multivariate adjustment. In a corresponding analysis in MDC-CC, copeptin was associated with a 10% increased risk, which, however, was non-significant (P = 0.25). A meta-analysis of the MPP and MDC-CC data showed significant association between elevated copeptin and a specified diagnosis of kidney disease other than CKD (HR 1.18, 95% CI 1.05-1.34, P = 0.008). Conclusion: An increased level of copeptin independently predicts development of both CKD and other specified kidney diseases, suggesting that copeptin can be used to identify individuals at risk for kidney disease development.

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.

Effect of increased water intake on plasma copeptin in healthy adults.

PURPOSE: Inter-individual variation in median plasma copeptin is associated with incident type 2 diabetes mellitus, progression of chronic kidney disease, and cardiovascular events. In this study, we examined whether 24-h urine osmolality was associated with plasma copeptin and whether increasing daily water intake could impact circulating plasma copeptin. METHODS: This trial was a prospective study conducted at a single investigating center. Eighty-two healthy adults (age 23.6 ± 2.9 years, BMI 22.2 ± 1.5 kg/m2, 50% female) were stratified based upon habitual daily fluid intake volumes: arm A (50-80% of EFSA dietary reference values), arm B (81-120%), and arm C (121-200%). Following a baseline visit, arms A and B increased their water intake to match arm C for a period of 6 consecutive weeks. RESULTS: At baseline, plasma copeptin was positively and significantly associated with 24-h urine osmolality (p = 0.002) and 24-h urine specific gravity (p = 0.003) but not with plasma osmolality (p = 0.18), 24-h urine creatinine (p = 0.09), and total fluid intake (p = 0.52). Over the 6-week follow-up, copeptin decreased significantly from 5.18 (3.3;7.4) to 3.90 (2.7;5.7) pmol/L (p = 0.012), while urine osmolality and urine specific gravity decreased from 591 ± 206 to 364 ± 117 mOsm/kg (p < 0.001) and from 1.016 ± 0.005 to 1.010 ± 0.004 (p < 0.001), respectively. CONCLUSIONS: At baseline, circulating levels of copeptin were positively associated with 24-h urine concentration in healthy young subjects with various fluid intakes. Moreover, this study shows, for the first time, that increased water intake over 6 weeks results in an attenuation of circulating copeptin. CLINICAL TRIAL REGISTRATION NUMBER: NCT02044679.

The Vasopressin System in the Risk of Diabetes and Cardiorenal Disease, and Hydration as a Potential Lifestyle Intervention.

BACKGROUND: Type 2 diabetes, chronic kidney disease (CKD) and its cardiovascular complications are increasing as health problems worldwide. These diseases are interrelated with overlapping occurrence and once diabetes is established, the risk of cardiorenal disease is dramatically elevated. Thus, a search for unifying modifiable risk factors is key for effective prevention. SUMMARY: Elevated fasting plasma concentration of vasopressin, measured with the marker copeptin, predicts new onset type 2 diabetes as well as renal function decline. Furthermore, we recently showed that increased plasma copeptin concentration independently predicts the development of both CKD and other specified kidney diseases. In consequence, high copeptin is an independent risk factor for cardiovascular disease and premature mortality in both diabetes patients and in the general population. Vasopressin is released when plasma osmolality is high, and the easiest way to lower plasma vasopressin and copeptin concentration is to increase water intake. In a human water intervention experiment with 1 week of 3 L/day increased water intake, the one third of the participants with the greatest copeptin reduction (water responders) were those with a phenotype of low water intake (high habitual plasma copeptin and urine osmolality, and low urine volume). The water-responders had a copeptin reduction of 41% after 1 week of increased water intake compared to a control week; in contrast, a 3% reduction occurred in the other two thirds of the study participants. Among water responders, increased water intake also induced a reduction in fasting glucagon concentration. Key Messages: Elevated copeptin, a measure of vasopressin, is a risk marker of metabolic and cardiorenal diseases and may assist in the detection of individuals at higher risk for these diseases. Furthermore, individuals with high copeptin and other signs of low water intake may experience beneficial glucometabolic effects of increased water intake. Future randomized control trials investigating effects of hydration on glucometabolic and renal outcomes should focus on individuals with signs of low water intake including high plasma copeptin concentration.

Increased Levels of Copeptin, a Surrogate Marker of Arginine Vasopressin, Are Associated with an Increased Risk of Chronic Kidney Disease in a General Population.

BACKGROUND: Our aim was to test if plasma copeptin, a stable surrogate marker of arginine vasopressin, predicts decline of glomerular filtration rate (GFR) and risk of chronic kidney disease (CKD). METHODS: We measured copeptin and renal function at the Malmö Diet and Cancer Cardiovascular Cohort baseline exam and reassessed renal function after a follow-up time of 16.6 ± 1.5 years (n = 3,186). Furthermore, we defined CKD based on an estimated GFR (eGFR) calculated by the Modification of Diet in Renal Disease (MDRD) <60 (CKD_60MDRD), <45 (CKD_45MDRD) and <30 (CKD_30MDRD) ml/min/1.73 m2. RESULTS: After multivariate adjustment (gender, age, baseline eGFR, smoking status, systolic blood pressure, antihypertensive treatment and follow-up time), copeptin (beta-coefficient per 1 SD increment of copeptin) was independently associated with significantly greater annual decline of eGFR (ml/min/1.73 m2) according to the MDRD formula (OR 0.057, 95% CI 0.022-0.093; p = 0.001) as well as according to the CKD Epidemiology Collaboration (CKD-EPI) formula (OR 0.050, 95% CI 0.022-0.077; p < 0.001). Each SD increment of copeptin independently predicted incident CKD_60MDRD (OR 1.19, 95% CI 1.04-1.36; p = 0.010), CKD_45MDRD (OR 1.33, 95% CI 1.04-1.71; p = 0.026) and CKD_30MDRD (OR 3.69, 95% CI 1.41-9.66; p = 0.008). The relationship between copeptin and CKD defined by CKD-EPI gave similar results. CONCLUSION: Our data suggest that increased levels of copeptin independently predict decline in eGFR and greater risk of new-onset CKD.

Vasopressin and hydration play a major role in the development of glucose intolerance and hepatic steatosis in obese rats.

AIMS/HYPOTHESIS: High plasma copeptin, a marker of vasopressin (VP) secretion, has been shown to be associated with the metabolic syndrome and development of type 2 diabetes in humans. The present study was designed to determine the long-term influence of plasma VP concentration in a rodent model prone to metabolic dysfunction. METHODS: Obese Zucker rats and their lean counterparts were submitted for 4 weeks to one of three protocols inducing different levels of VP. Circulating VP was either reduced by increasing the daily water intake (low-VP), or increased by a chronic i.p. infusion of VP (high-VP). The control rats had normal VP levels that depended on their own regulation of water intake and VP secretion. RESULTS: Compared with controls with normal VP, lean rats with high-VP had a higher fasting glycaemia after 4 weeks. In obese rats, high-VP promoted hyperinsulinaemia, glucose intolerance, assessed by glucose and insulin tolerance tests, and an impaired response to a pyruvate challenge. Conversely, treatment with a selective arginine vasopressin receptor 1A (V1aR) antagonist reduced glucose intolerance. Low-VP obese rats had unchanged glucose tolerance but exhibited a drastic decrease in liver steatosis compared with control obese rats, associated with low hepatic triacylglycerol and cholesterol content, and reduced expression of hepatic lipogenic genes. These effects were independent of changes in body adiposity, and plasma sodium and osmolality did not differ among groups. CONCLUSION/INTERPRETATION: These findings show a causal relationship between the VP-hydration axis and the metabolic risk. Therapeutic perspectives include diet recommendations regarding hydration, but also potential pharmacological interventions targeting the VP V1aR.

Copeptin is an independent predictor of diabetic heart disease and death.

BACKGROUND: We previously discovered that high copeptin is associated with incidence of diabetes mellitus (diabetes), abdominal obesity, and albuminuria. Furthermore, copeptin predicts cardiovascular events after myocardial infarction in diabetic patients, but whether it is associated with heart disease and death in individuals without diabetes and prevalent cardiovascular disease is unknown. In this study, we aim to test whether plasma copeptin (copeptin), the C-terminal fragment of arginine vasopressin prohormone, predicts heart disease and death differentially in diabetic and nondiabetic individuals. METHODS: We related plasma copeptin to a combined end point composed of coronary artery disease (CAD), heart failure (HF), and death in diabetes (n = 895) and nondiabetes (n = 4187) individuals of the Malmö Diet and Cancer Study-Cardiovascular cohort. RESULTS: Copeptin significantly interacted with diabetes regarding the combined end point (P = .006). In diabetic individuals, copeptin predicted the combined end point (hazard ratio [HR] 1.32 per SD, 95% CI 1.10-1.58, P = .003) after adjustment for conventional risk factors, prevalent HF and CAD, and remained significant after additional adjustment for either fasting glucose (P = .02) or hemoglobin A1c (P = .02). Furthermore, in diabetic individuals, copeptin predicted CAD (HR 1.33 per SD, 95% CI 1.04-1.69, P = .02), HF (HR 1.62 per SD, 95% CI 1.09-2.41, P = .02), and death (HR 1.32 per SD, 95% CI 1.04-1.68, P = .02). Interestingly, among nondiabetic individuals, copeptin was not associated with any of the end points. CONCLUSIONS: Copeptin predicted heart disease and death, specifically in diabetes patients, suggesting copeptin and the vasopressin system as a prognostic marker and therapeutic target for diabetic heart disease and death.

High total carbon dioxide predicts 1-year readmission and death in patients with acute dyspnea.

RATIONALE: Patients with acute dyspnea are a large heterogeneous patient group where initial management is important for outcome. OBJECTIVES: The objective of the study is to investigate if venous blood gas parameters predict 1-year risk of readmission or death in patients admitted to the emergency department due to acute dyspnea. METHODS: We studied 283 patients with acute dyspnea and followed them up for 1 year regarding incidence of readmission or death. MEASUREMENTS AND MAIN RESULTS: In venous blood obtained immediately upon admission levels of total carbon dioxide (TCO2), base excess (BE), potential hydrogen (pH), and partial pressure of carbon dioxide (pCO2) were measured. In Cox proportional hazards models, patients belonging to top and bottom quartiles of TCO2, BE, pH, and pCO2 were compared to patients belonging to the 2 central quartiles and assessed for end point. After adjustment, top (hazard ratio [HR], 1.48; 95% confidence interval [CI], 1.08-2.04; P=.016) and bottom (HR, 1.54; 95% CI, 1.08-2.18; P=.017) quartiles of BE were associated with increased risk of readmission or death. The strongest predictor was top quartile of TCO2 (HR, 1.68; 95% CI, 1.21-2.35; P=.002). In the combined analysis, top quartile of TCO2 remained significantly related to the end point (HR, 1.59; 95% CI, 1.03-2.45; P=.035), whereas BE became nonsignificant. Comorbidities, for example, prevalent chronic obstructive pulmonary disease, did not explain the association. Neither pCO2 nor pH predicted the end point. CONCLUSIONS: A high value of TCO2 appears to be an easily accessible marker for 1-year readmission or death in patients with acute dyspnea and may thus add clinically important information for risk stratification and follow-up strategies.

Incident Cardiovascular Disease in Women With Type 1 or Type 2 Diabetes Following a Hypertensive Disorder of Pregnancy.

BACKGROUND: The extent to which a history of hypertensive disorders of pregnancy is associated with incident cardiovascular disease also among women with diabetes is unknown. METHODS: In this nationwide register-based cohort study, parous women aged 18 to 69 years with a first delivery in the Swedish Medical Birth Register, regardless of diabetic status at that time, and a subsequent clinical visit in the Swedish National Diabetes Register were included. Time to first cardiovascular disease event (myocardial infarction, stroke, or heart failure) before age 70 years by hypertensive disorders of pregnancy history was separately analyzed by diabetes type using Cox regression models that included conventional risk factors. RESULTS: In total, 1748 (18.9%) of 9230 women with type 1 and 5904 (10.6%) of 55 773 women with type 2 diabetes had their first delivery complicated by a hypertensive disorder of pregnancy. Median time (25-75th percentile) between first delivery and start of follow-up was 3.3 (1.4-13.0) years for women with type 1 and 29.8 (22.4-35.6) years for women with type 2 diabetes. In modeling, the risk for any cardiovascular disease event among women with a history of hypertensive disorders of pregnancy was generally 10% to 20% higher, with main models estimating hazard ratios to 1.20 (95% CI, 0.99-1.47) for women with type 1 and 1.15 (95% CI, 1.02-1.29) for women with type 2 diabetes. CONCLUSIONS: In women with diabetes, a history of hypertensive disorders of pregnancy was associated with an increased risk of incident cardiovascular disease and should be considered as a risk enhancer.

Long-term health outcomes associated with hydration status.

Body water balance is determined by fundamental homeostatic mechanisms that maintain stable volume, osmolality and the composition of extracellular and intracellular fluids. Water balance is maintained by multiple mechanisms that continuously match water losses through urine, the skin, the gastrointestinal tract and respiration with water gains achieved through drinking, eating and metabolic water production. Hydration status is determined by the state of the water balance. Underhydration occurs when a decrease in body water availability, due to high losses or low gains, stimulates adaptive responses within the water balance network that are aimed at decreasing losses and increasing gains. This stimulation is also accompanied by cardiovascular adjustments. Epidemiological and experimental studies have linked markers of low fluid intake and underhydration - such as increased plasma concentration of vasopressin and sodium, as well as elevated urine osmolality - with an increased risk of new-onset chronic diseases, accelerated aging and premature mortality, suggesting that persistent activation of adaptive responses may be detrimental to long-term health outcomes. The causative nature of these associations is currently being tested in interventional trials. Understanding of the physiological responses to underhydration may help to identify possible mechanisms that underlie potential adverse, long-term effects of underhydration and inform future research to develop preventative and treatment approaches to the optimization of hydration status.

The possible role of the vasopressin system in hematopoiesis.

Vasopressin is a pleiotropic hormone that controls body fluid homeostasis. Vasopressin has also been proposed to be involved in erythropoiesis, thrombocyte activity and inflammation. However, whether increasing vasopressin is associated with changes in hematopoietic markers is not known. To evaluate this gap of knowledge we measured the vasopressin marker copeptin and markers of erythropoiesis (erythrocyte count, hemoglobin (Hb), red blood cell distribution width (RDW), mean corpuscular volume (MCV), erythrocyte volume fraction (EVF)), leukocyte count (total count, lymphocytes, neutrophils) and thrombocyte count in 5312 participants from the Swedish CArdioPulmonary bioImage Study (SCAPIS). The associations between increasing copeptin tertile and the hematopoietic markers were analyzed in multivariate linear regression analyses. We found that increasing copeptin tertile was significantly (p < 0.001) associated with increasing erythrocytes, RDW, EVF, Hb, leukocytes and neutrophils after adjustment for age, sex, current smoking, prevalent diabetes, hypertension, creatinine, body mass index and physical activity. Increasing copeptin tertile was, however, not associated with change in MCV, lymphocyte or thrombocyte count. In conclusion, we found that increasing copeptin levels are positively associated with markers of erythropoiesis and leukocyte count in the general population. These results warrant further research on possible mechanistic effects of vasopressin on hematopoiesis.

The association between water intake and future cardiometabolic disease outcomes in the Malmö Diet and Cancer cardiovascular cohort.

The aim of this study was to explore the longitudinal association between reported baseline water intake and incidence of coronary artery disease (CAD) and type 2 diabetes in the Malmö Diet and Cancer Cohort (n = 25,369). Using cox proportional hazards models, we separately modelled the effect of plain and total (all water, including from food) water on CAD and type 2 diabetes risk, whilst adjusting for age, sex, diet collection method, season, smoking status, alcohol intake, physical activity, education level, energy intake, energy misreporting, body mass index, hypertension, lipid lowering medication, apolipoprotein A, apolipoprotein B, and dietary variables. Sensitivity analyses were run to assess validity. After adjustment, no association was found between tertiles of plain or total water intake and type 2 diabetes risk. For CAD, no association was found comparing moderate to low intake tertiles from plain or total water, however, risk of CAD increased by 12% (95% CI 1.03, 1.21) when comparing high to low intake tertiles of plain water, and by 17% (95% CI 1.07, 1.27) for high versus low tertiles of total water. Sensitivity analyses were largely in agreement. Overall, baseline water intake was not associated with future type 2 diabetes risk, whilst CAD risk was higher with higher water intakes. Our findings are discordant with prevailing literature suggesting higher water intakes should reduce cardiometabolic risk. These findings may be an artefact of limitations within the study, but future research is needed to understand if there is a causal underpinning.

The association of copeptin with metabolic risk markers is modified by region of origin.

Iraqi born immigrants in Sweden have higher prevalence of metabolic diseases compared to native Swedes. Copeptin, a marker for vasopressin, is associated with increased risk of metabolic disease. In this cross-sectional population study based on the MEDIM cohort we investigated differences in copeptin levels between Iraqi and Swedish born individuals and if the association between copeptin and cardiometabolic risk markers differed by region of origin. We included 1109 Iraqi and 613 Swedish born participants (58% men, mean age 47 years). The Swedish participants had a higher concentration of copeptin compared to the Iraqi born group after age and sex adjustment (p < 0.001). This difference existed only among male individuals with the highest copeptin concentrations, i.e. belonging to copeptin quartile 4 (median (25th; 75th percentile) 20.07 (15.27;33.28) pmol/L for the Swedish born versus 15.57 (13.91;19.00) pmol/L for the Iraqi born, p < 0.001). We found a significant interaction between copeptin (continuous ln-transformed) and being born in Iraq regarding the association with plasma triglycerides (Pinteraction = 0.006). The association between copeptin and BMI was stronger amongst the Iraqi born individuals compared to the Swedish born. Together, this could indicate that copeptin is a more potent marker of metabolic disease among individuals born in Iraq compared to Sweden.

Short-term association between outdoor temperature and the hydration-marker copeptin: a pooled analysis in five cohorts.

BACKGROUND: Whereas outdoor temperature is linked to both mortality and hydration status, the hormone vasopressin, measured through the surrogate copeptin, is a marker of cardiometabolic risk and hydration. We recently showed that copeptin has a seasonal pattern with higher plasma concentration in winter. Here, we aimed to investigate the association between outdoor temperature and copeptin. METHODS: Copeptin was analysed in fasting plasma from five cohorts in Malmö, Sweden (n = 26,753, 49.7% men, age 18-86 years). We utilized a multivariable adjusted non-linear spline model with four knots to investigate the association between short-term temperature (24 h mean apparent) and log copeptin z-score. FINDINGS: We found a distinct non-linear association between temperature and log copeptin z-score, with both moderately low and high temperatures linked to higher copeptin concentration (p < 0.0001). Between 0 °C and nadir at the 75th temperature percentile (corresponding to 14.3 °C), log copeptin decreased 0.13 z-scores (95% CI 0.096; 0.16), which also inversely corresponded to the increase in z-score log copeptin between the nadir and 21.3 °C. INTERPRETATION: The J-shaped association between short-term temperature and copeptin resembles the J-shaped association between temperature and mortality. Whereas the untangling of temperature from other seasonal effects on hydration warrants further study, moderately increased water intake constitutes a feasible intervention to lower vasopressin and might mitigate adverse health effects of both moderately cold and hot outdoor temperatures. FUNDING: Swedish Research Council, Å Wiberg, M Stephen, A Påhlsson, Crafoord and Swedish Heart-Lung Foundations, Swedish Society for Medical Research and Swedish Society of Medicine.

Plasma copeptin and the risk of diabetes mellitus.

BACKGROUND: Animal studies suggest that the arginine vasopressin system may play a role in glucose metabolism, but data from humans are limited. METHODS AND RESULTS: We analyzed plasma copeptin (copeptin), a stable C-terminal fragment of the arginine vasopressin prohormone. Using baseline and longitudinal data from a Swedish population-based sample (n=4742; mean age, 58 years; 60% women) and multivariable logistic regression, we examined the association of increasing quartiles of copeptin (lowest quartile as reference) with prevalent diabetes mellitus at baseline, insulin resistance (top quartile of fasting plasma insulin among nondiabetic subjects), and incident diabetes mellitus on long-term follow-up. New-onset diabetes mellitus was ascertained through 3 national and regional registers. All models were adjusted for clinical and anthropometric risk factors, cystatin C, and C-reactive protein. In cross-sectional analyses, increasing copeptin was associated with prevalent diabetes mellitus (P=0.04) and insulin resistance (P<0.001). During 12.6 years of follow-up, 174 subjects (4%) developed new-onset diabetes mellitus. The odds of developing diabetes mellitus increased across increasing quartiles of copeptin, even after additional adjustment for baseline fasting glucose and insulin (adjusted odds ratios, 1.0, 1.37, 1.79, and 2.09; P for trend=0.004). The association with incident diabetes mellitus remained significant in analyses restricted to subjects with fasting whole blood glucose <5.4 mmol/L at baseline (adjusted odds ratios, 1.0, 1.80, 1.92, and 3.48; P=0.001). CONCLUSIONS: Elevated copeptin predicts increased risk for diabetes mellitus independently of established clinical risk factors, including fasting glucose and insulin. These findings could have implications for risk assessment, novel antidiabetic treatments, and metabolic side effects from arginine vasopressin system modulation.

Copeptin as a predictive marker of incident heart failure.

AIMS: Heart failure (HF) is a common disease with increasing prevalence and poor prognosis. The vasopressin (VP) marker copeptin predicts development of diabetes mellitus, diabetic heart disease, coronary artery disease, and premature mortality. Copeptin is elevated in HF patients and predicts a worse outcome. This study aims to investigate whether copeptin can predict HF development. METHODS: Copeptin was analysed in 5297 individuals (69.6% men) without prevalent HF from the Malmö Preventive Project, a population-based prospective cohort. Cox proportional hazards models were used to analyse risk of incident HF by copeptin levels after adjusting for conventional cardiovascular risk factors. RESULTS: During a median follow-up time of 11.1 years, 350 subjects (6.6%) were diagnosed with HF. Of these events, 99 were classified as myocardial infarction (MI) related HF and 251 as non-MI-related HF. Individuals in the top quartile of copeptin had, after multivariate adjustment for conventional risk factors (age, sex, systolic blood pressure, diabetes mellitus, body mass index, antihypertensive therapy, smoking, low-density lipoprotein cholesterol, and high-density lipoprotein cholesterol), a significantly increased risk of developing HF by 1.63 [confidence interval (CI) 1.20-2.21] for HF compared with the reference quartile 1. After adjustment for conventional risk factors, the hazard ratio (HR) per standard deviation increase of log-transformed copeptin for any HF was 1.30 (95% CI 1.17-1.46), whereas it was 1.39 (CI 1.13-1.71) for MI-related HF and 1.26 (CI 1.11-1.44) for non-MI-related HF. The associations remained after additional adjustment for estimated glomerular filtration rate [HR 1.24 (95% CI: 1.10-1.40)] and for pro atrial natriuretic peptide on top of conventional risk factors [HR 1.14 (95% CI: 1.02-1.28)]. CONCLUSIONS: Elevated copeptin predicts development of HF in older adults. Copeptin is a risk marker of VP-driven HF susceptibility and a candidate to guide prevention efforts of HF targeting the VP system.