Michael Resl

The Relationship between Insulin Resistance and the Cardiovascular Biomarker Growth Differentiation Factor-15 in Obese Patients

BACKGROUND Growth differentiation factor-15 (GDF-15) is a stress-responsive cytokine linked to obesity comorbidities such as cardiovascular disease, inflammation, and cancer. GDF-15 also has adipokine properties and recently emerged as a prognostic biomarker for cardiovascular events. METHODS We evaluated the relationship of plasma GDF-15 concentrations with parameters of obesity, inflammation, and glucose and lipid metabolism in a cohort of 118 morbidly obese patients [mean (SD) age 37.2 (12) years, 89 females, 29 males] and 30 age- and sex-matched healthy lean individuals. All study participants underwent a 75-g oral glucose tolerance test; 28 patients were studied before and 1 year after Roux-en-Y gastric bypass surgery. RESULTS Obese individuals displayed increased plasma GDF-15 concentrations (P < 0.001), with highest concentrations observed in patients with type 2 diabetes. GDF-15 was positively correlated with age, waist-to-height ratio, mean arterial blood pressure, triglycerides, creatinine, glucose, insulin, C-peptide, hemoglobin A(1c), and homeostatic model assessment insulin resistance index and negatively correlated with oral glucose insulin sensitivity. Age, homeostatic model assessment index, oral glucose insulin sensitivity, and creatinine were independent predictors of GDF-15 concentrations. Roux-en-Y gastric bypass led to a significant reduction in weight, leptin, insulin, and insulin resistance, but further increased GDF-15 concentrations (P < 0.001). CONCLUSIONS The associations between circulating GDF-15 concentrations and age, insulin resistance, and creatinine might account for the additional cardiovascular predictive information of GDF-15 compared to traditional risk factors. Nevertheless, GDF-15 changes following bariatric surgery suggest an indirect relationship between GDF-15 and insulin resistance. The clinical utility of GDF-15 as a biomarker might be limited until the pathways directly controlling GDF-15 concentrations are better understood.

Plasma NT-proBNP increases in response to LPS administration in healthy men

Circulating levels of B-type natriuretic peptide (BNP) and NH(2)-terminal-proBNP (NT-proBNP) increase in response to volume overload and help in the differential diagnosis of acute heart failure. Elevated plasma BNP levels are observed also in sepsis and do not always correspond to left ventricular dysfunction. Here, we investigated plasma NT-proBNP fluctuations in response to human bacterial endotoxinemia, an experimental model of systemic infection and inflammation. Escherichia coli endotoxin (LPS) (2 ng/kg) was administered to 10 healthy volunteers in a randomized, placebo-controlled, cross-over design. Plasma NT-proBNP, C-reactive protein (CRP), COOH terminal pro-endothelin-1 (CT-proET-1), and midregional-pro-adrenomedullin (MR-proADM) were measured at hourly intervals for 6 h. LPS administration induced a continuous increase in plasma NT-proBNP that reached peak values after 6 h (40.7 +/- 7.9 vs. 16.1 +/- 3.2 pg/ml in placebo days, mean +/- SE; P = 0.023). The profile of changes in NT-proBNP correlated to changes in body temperature (P < 0.001), heart rate (P = 0.005), CRP (P < 0.001), and CT-proET-1 (P = 0.008), but not to blood pressure values. Our results demonstrate that plasma NT-proBNP increases in a model of systemic infection/inflammation in healthy men with normal heart function. This finding emphasizes the necessity to consider concomitant infections when interpreting elevated circulating NT-proBNP concentrations.

B-Type Natriuretic Peptide Modulates Ghrelin, Hunger, and Satiety in Healthy Men

Chronic heart failure is accompanied by anorexia and increased release of B-type natriuretic peptide (BNP) from ventricular cardiomyocytes. The pathophysiological mechanisms linking heart failure and appetite regulation remain unknown. In this study, we investigated the impact of intravenous BNP administration on appetite-regulating hormones and subjective ratings of hunger and satiety in 10 healthy volunteers. Participants received in a randomized, placebo-controlled, crossover, single-blinded study (subject) placebo once and 3.0 pmol/kg/min human BNP-32 once administered as a continuous infusion during 4 h. Circulating concentrations of appetite-regulating peptides were measured hourly. Subjective ratings of hunger and satiety were evaluated by visual analog scales. BNP inhibited the fasting-induced increase in total and acylated ghrelin concentrations over time (P = 0.043 and P = 0.038, respectively). In addition, BNP decreased the subjective rating of hunger (P = 0.009) and increased the feeling of satiety (P = 0.012) when compared with placebo. There were no significant changes in circulating peptide YY, glucagon-like peptide 1, oxyntomodulin, pancreatic polypeptide, leptin, and adiponectin concentrations. In summary, our results demonstrate that BNP exerts anorectic effects and reduces ghrelin concentrations in men. These data, taken together with the known cardiovascular properties of ghrelin, support the existence of a heart–gut–brain axis, which could be therapeutically targeted in patients with heart failure and obesity.

Endothelial Markers May Link Kidney Function to Cardiovascular Events in Type 2 Diabetes

OBJECTIVE The increased cardiovascular risk in diabetes has been linked to endothelial and renal dysfunction. The aim of this study was to investigate the role of stable fragments of the precursors of adrenomedullin, endothelin-1, vasopressin, and atrial natriuretic peptide in progression of cardiovascular disease in patients with diabetes. RESEARCH DESIGN AND METHODS This was a prospective, observational study design with a composite end point (death or unexpected admission to hospital due to a cardiovascular event) on 781 patients with type 2 diabetes (54 events, median duration of observation 15 months). The four stable precursor peptides midregional adrenomedullin (MR-proADM), midregional proatrial natriuretic peptide (MR-proANP), COOH-terminal proendothelin-1 (CT-proET-1), and COOH-terminal provasopressin or copeptin (CT-proAVP) were determined at baseline, and their association to renal function and cardiovascular events was studied using stepwise linear and Cox logistic regression analysis and receiver operating characteristic analysis, respectively. RESULTS MR-proADM, CT-proET-1, CT-proAVP, and MR-proANP were all elevated in patients with future cardiovascular events and independently correlated to serum creatinine. MR-proADM and MR-proANP were significant predictors of a future cardiovascular event, with MR-proANP being the stronger (area under the curve 0.802 ± 0.034, sensitivity 0.833, specificity 0.576, positive predictive value 0.132, and negative predictive value 0.978 with a cutoff value of 75 pmol/l). CONCLUSIONS The four serum markers of vasoactive and natriuretic peptides are related to both kidney function and cardiovascular events, thus linking two major complications of diabetes, diabetic nephropathy and cardiovascular disease.

Systemic administration of oxytocin reduces basal and lipopolysaccharide-induced ghrelin levels in healthy men

Oxytocin (OXT) and ghrelin have several common properties such as the involvement in the first phase response to stressors, in appetite regulation, and in the modulation of neural functions. Despite a recent study showing that intraventricular administration of ghrelin activates OXT neurons, little is known on the cross-talk between these two peptides. Here, we investigated the role of the i.v. administration of OXT on circulating ghrelin concentrations under fasting conditions and during the lipopolysaccharide (LPS)-induced endotoxemia. A randomized placebo-controlled cross-over study was performed in ten healthy men. In four study sessions, the participants received once placebo, once OXT (1 pmol/kg per min over 90 min), once LPS (2 ng/kg), and once both OXT and LPS. Plasma ghrelin, glucose, and free fatty acid (FFA) levels were measured at regular intervals during the first 6 h following the LPS bolus. Systemic administration of OXT decreased within 1 h plasma ghrelin levels (611+/-54 vs 697+/-52 pg/ml in placebo days, P=0.013) and increased plasma glucose and FFA concentrations (P=0.002 and P=0.005 respectively). OXT also reduced the LPS-induced surge in ghrelin at time point 2 h (P=0.021). In summary, i.v. administration of OXT decreases circulating levels of ghrelin during fasting, as well as following LPS-induced endotoxemia in healthy men. The cross-talk between OXT and ghrelin might be important in the regulation of energy homeostasis and stress responses.

Serum uric acid is related to cardiovascular events and correlates with N-terminal pro-B-type natriuretic peptide and albuminuria in patients with diabetes mellitus

Diabet. Med. 29, 721–725 (2012)

Targeted multiple biomarker approach in predicting cardiovascular events in patients with diabetes

Objective We hypothesised that biomarkers representing different pathophysiological pathways of atherosclerosis namely growth differentiation factor 15 (GDF-15), N-terminal pro B-type natriuretic peptide (NT-proBNP) and high-sensitive troponin T (hs-TnT) could enhance cardiovascular risk prediction in patients with type 2 diabetes mellitus. Methods This is a prospective study in 746 patients with type 2 diabetes mellitus, who were followed up for 60 months. The primary endpoint was defined as unplanned hospitalisation for cardiovascular disease or death. The prognostic performance of the biomarkers of interest (GDF-15 in comparison with NT-proBNP and hs-TnT) was evaluated in univariate as well as in stepwise Cox regression models. HRs are presented per standard unit increase. Results The primary endpoint was registered in 171 patients (22.9%). In univariate Cox regression models, GDF-15 as well as hs-TnT provided significant prognostic information. Even after adjusting for established cardiovascular risk factors, GDF-15, hs-TnT and NT-proBNP remained strong independent predictors of the endpoint (logGDF-15: HR 1.37, p<0.01, CI 1.12 to 1.68; loghs-TnT: HR 1.43, p<0.01, CI 1.13 to 1.1.82; logNT-proBNP: HR 1.45, p<0.01, CI 1.26 to 1.66). The number of elevated markers showed a strong complementarity to predict future long-term risk. Adding hs-TnT and GDF-15 to a zero model already including NT-proBNP led to a net reclassification improvement (NRI) of 33.6% (CI 16.0% to 50.8%, NRI for patients with event: 11.1% CI −4.7% to 26.6%, for patients without event: 22.5% CI 13.6% to 30.5%). Conclusions GDF-15 and hs-TnT are strong independent cardiovascular biomarkers augmenting the predictive value of NT-proBNP in patients with diabetes.

A comparison of NT-proBNP and albuminuria for predicting cardiac events in patients with diabetes mellitus.

Aims: Cardiovascular events are the most relevant events in patients with diabetes mellitus. We aimed to compare the predictive values of N-terminal pro-brain natriuretic peptide (NT-proBNP) and the state-of-the-art marker, albuminuria, for cardiac events in diabetic patients. Methods: In this prospective observational study we recruited 1071 patients with diabetes mellitus. NT-proBNP and albuminuria ⊟ defined as a urinary albumin/creatinine ratio >30 mg/g ⊟ were measured at baseline. Patients were followed during a mean observation period of 33.1 months. A total of 103 patients reached the defined endpoint (unplanned hospitalization due to a cardiac event or death). Results: The mean duration of diabetes was 15 ± 12 years and the mean HbA1c was 7.5 ± 3.1%. At baseline, 23.7% of the patients presented with albuminuria and 36.6% had plasma NT-proBNP values >125 pg/ml. Multiple Cox regression analysis including age, gender, duration of diabetes HbA1c, albuminuria, and lnNT-proBNP revealed that lnNT-proBNP (hazard ratio 2.314; 95% CI 1.914⊟2.798, p < 0.001) was a better predictor than albuminuria (HR 1.544; 95% CI 1.007⊟2.368, p = 0.047) or age (HR 1.030; 95% CI 1.008⊟1.053, p = 0.007). Calculating different Cox-models with (A) albuminuria, (B) NT-proBNP, or (C) both in the model revealed that the C-index was best if NT-proBNP was entered in the model (C-index for A 0.735, for B 0.809, and for C 0.786). Kaplan⊟Meier analysis demonstrated that albuminuria does not add substantial information if NT-proBNP is entered into the model. Conclusion: NT-proBNP was superior to albuminuria for predicting cardiac events.

Repeat measurements of glycated haemoglobin A1c and N‐terminal pro‐B‐type natriuretic peptide: divergent behaviour in diabetes mellitus

Eur J Clin Invest 2011; 41 (12): 1292–1298

Heart failure in diabetes

SummaryInteractions of glucose metabolism and chronic heart failure have been confirmed by many epidemiologic studies. The association of HbA1c with an increasing risk of heart failure clearly underlines the connection between both diseases. Coronary artery disease (CAD), hypertension and diabetic cardiomyopathy are long-term complications of diabetes mellitus, resulting in diabetic heart failure. Dysfunction of many regulation systems leads to specific diabetic cardiomyopathy, which has been firstly described by Rubler. A reduction in the cardiac expression of the Na-Ca exchanger pump and SERCA2a protein results in an imbalance in cardiac calcium handling. The overactive renin angiotensin aldosteron system (RAAS) also contributes to the impairment of myocardial function. Hyperlipidaemia, hpyerinsulinaemia and hyperglycaemia directly trigger diabetic cardiomyopathy. Generally chronic heart failure is a clinical diagnosis verified by blood tests like NT-proBNP and cardiac ultrasound. Recommendations on treatment of diabetic heart failure are based on subgroup analysis of the large heart failure trials.ZusammenfassungEpidemiologische Daten belegen die wechselseitige Beeinflussung von chronischer Herzinsuffizienz (CHF) und Diabetes mellitus. So ist ein Anstieg des HbA1c mit einem gesteigerten Risiko an einer Herzinsuffizienz zu erkranken verbunden. Koronare Herzkrankheit (KHK), Hypertonie und diabetische Kardiomyopathie sind Spätfolgen des Diabetes, deren gemeinsame Endstrecke die diabetische Herzinsuffizienz darstellt. Das spezifische Krankheitsbild der diabetischen Kardiomyopathie wurde von Rubler erstbeschrieben und ist das Endprodukt zahlreicher Störungen verschiedenster Systeme. So ist beispielsweise die kardiale Expression des Natrium-Kalziumaustauschers und des SERCA2a Proteins reduziert, was eine gestörte myokardiale Kalziumhomöostase zur Folge hat. Auch das überaktive Renin-Angiotensin-Aldosteronsystem (RAAS) spielt eine bedeutende Rolle in der Pathogenese der diabetischen Herzinsuffizienz. Hyperlipidämie, Hyperinsulinämie sowie Hypgerglykämie sind Stoffwechselstörungen, die ebenfalls die Entstehung der diabetische Kardiomyopathie begünstigen. Generell ist die Herzinsuffizienz eine klinische Diagnose, die mit Hilfe von Labortests wie dem NT-proBNP, aber auch apparativ verifiziert werden muss. Die derzeitigen Therapieempfehlungen beruhen auf Subgruppenanalysen der großen Herzinsuffizienzstudien.Interactions of glucose metabolism and chronic heart failure have been confirmed by many epidemiologic studies. The association of HbA1c with an increasing risk of heart failure clearly underlines the connection between both diseases. Coronary artery disease (CAD), hypertension and diabetic cardiomyopathy are long-term complications of diabetes mellitus, resulting in diabetic heart failure. Dysfunction of many regulation systems leads to specific diabetic cardiomyopathy, which has been firstly described by Rubler. A reduction in the cardiac expression of the Na-Ca exchanger pump and SERCA2a protein results in an imbalance in cardiac calcium handling. The overactive renin angiotensin aldosteron system (RAAS) also contributes to the impairment of myocardial function. Hyperlipidaemia, hpyerinsulinaemia and hyperglycaemia directly trigger diabetic cardiomyopathy. Generally chronic heart failure is a clinical diagnosis verified by blood tests like NT-proBNP and cardiac ultrasound. Recommendations on treatment of diabetic heart failure are based on subgroup analysis of the large heart failure trials.