Andreas Meinitzer

Homoarginine, Cardiovascular Risk, and Mortality

Background— Homoarginine is an amino acid derivative that may increase nitric oxide availability and enhance endothelial function. The effect of the level of homoarginine on cardiovascular outcome and mortality is unknown. Methods and Results— We assessed cardiovascular and all-cause mortality according to homoarginine levels in a cohort of 3305 subjects referred for coronary angiography from the LUdwigshafen RIsk and Cardiovascular Health (LURIC) Study. After investigating the relation of homoarginine with kidney function and markers of endothelial dysfunction, we explored its effects on adverse outcomes in a second high-risk cohort of 1244 patients with type 2 diabetes mellitus receiving maintenance hemodialysis (4D study [Die Deutsche Diabetes Dialyse Studie]). In the LURIC study, mean serum homoarginine levels were 2.6±1.1 &mgr;mol/L. During a median follow-up of 7.7 years, 766 patients died. After adjustments for age and sex, patients in the lowest quartile (<1.85 &mgr;mol/L) had a >4-fold higher rate of dying of cardiovascular disease (hazard ratio 4.1, 95% confidence interval 3.0 to 5.7) than patients in the highest quartile (>3.1 &mgr;mol/L). Lower homoarginine levels were associated with lower estimated glomerular filtration rate and higher levels of intercellular adhesion molecule-1 and vascular cell adhesion molecule-1. Hemodialysed patients had lower mean homoarginine levels of 1.2±0.5 &mgr;mol/L and experienced a 5-fold increased mortality rate compared with LURIC patients (608 deaths during a median follow-up of 4 years). Homoarginine consistently affected mortality, which was 2-fold higher in 4D study patients in the lowest quartile (<0.87 &mgr;mol/L) than in patients in the highest quartile (>1.4 &mgr;mol/L). Conclusions— Homoarginine levels are independently associated with cardiovascular and all-cause mortality in patients referred for coronary angiography and in patients undergoing hemodialysis. Future studies are needed to elucidate the underlying pathomechanisms.

Cardioprotection and lifespan extension by the natural polyamine spermidine

Aging is associated with an increased risk of cardiovascular disease and death. Here we show that oral supplementation of the natural polyamine spermidine extends the lifespan of mice and exerts cardioprotective effects, reducing cardiac hypertrophy and preserving diastolic function in old mice. Spermidine feeding enhanced cardiac autophagy, mitophagy and mitochondrial respiration, and it also improved the mechano-elastical properties of cardiomyocytes in vivo, coinciding with increased titin phosphorylation and suppressed subclinical inflammation. Spermidine feeding failed to provide cardioprotection in mice that lack the autophagy-related protein Atg5 in cardiomyocytes. In Dahl salt-sensitive rats that were fed a high-salt diet, a model for hypertension-induced congestive heart failure, spermidine feeding reduced systemic blood pressure, increased titin phosphorylation and prevented cardiac hypertrophy and a decline in diastolic function, thus delaying the progression to heart failure. In humans, high levels of dietary spermidine, as assessed from food questionnaires, correlated with reduced blood pressure and a lower incidence of cardiovascular disease. Our results suggest a new and feasible strategy for protection against cardiovascular disease.

Plasma aldosterone levels are associated with increased cardiovascular mortality: the Ludwigshafen Risk and Cardiovascular Health (LURIC) study

AIMS Evidence has accumulated that elevated aldosterone levels are associated with increased risks of fatal cardiovascular (CV) events. With the present analysis, we aimed at evaluating prospectively whether plasma aldosterone correlates with all-cause and CV disease (CVD) mortality in a large cohort of patients. METHODS AND RESULTS Median plasma aldosterone concentration (PAC) was 79.0 (48.0-124.0) pg/mL (normal range: 30-160) in 3153 patients [median age: 63.5 (56.3-70.6) years; 30.1% women] who had undergone coronary angiography. After a median follow-up of 7.7 (7.2-8.5) years, a total of 716 participants died [22.7%; 454 (14.4%) due to CV causes and 262 (8.3%) due to non-CV causes]. In multivariable Cox proportional hazard analysis, adjusted for age, gender, antihypertensive treatment, and established CV risk factors, PAC levels stratified in quartiles were significantly associated with all-cause and CVD mortality. Compared with the reference (first) PAC quartile, hazard ratios (confidence interval 95%) for the fourth, third, and second PAC quartiles were 1.30 (1.02-1.65, P = 0.033), 1.32 (1.04-1.68, P = 0.021), and 1.20 (0.93-1.54, P = 0.155) for total mortality and 1.58 (1.15-2.16, P = 0.004), 1.39 (1.01-1.90, P = 0.041), and 1.63 (1.20-2.20, P = 0.002) for CVD mortality, respectively. Analyses for specific causes of CV death revealed strong associations between PAC levels and higher risk for fatal stroke and sudden cardiac death. CONCLUSION In a large cohort of patients scheduled for coronary angiography, variation in PAC levels within the normal range is associated with increased all-cause and CVD mortality independent of major established CV risk factors.

Symmetrical and Asymmetrical Dimethylarginine as Predictors for Mortality in Patients Referred for Coronary Angiography: The Ludwigshafen Risk and Cardiovascular Health Study

BACKGROUND Asymmetrical dimethylarginine (ADMA), an endogenous nitric oxide synthase inhibitor, has been linked to cardiovascular risk. The clinical role of its structural isomer symmetrical dimethylarginine (SDMA) remains largely unclear. METHODS We measured SDMA and ADMA in 3229 patients undergoing coronary angiography at baseline (1997-2000) and recorded total and cardiovascular mortality during a median follow-up time of 7.7 years. We investigated associations of SDMA with cardiovascular risk factors and mortality and compared its role as a cardiovascular risk factor with ADMA, which predicted mortality in previous analyses of our study. RESULTS In linear regression analyses including common cardiovascular risk factors as covariates, SDMA and ADMA were significantly associated with cystatin C, N-terminal pro-B-type natriuretic peptide, New York Heart Association classification, and homocysteine. The regression coefficients were higher for SDMA than for ADMA. In Cox proportional-hazards models adjusted for cardiovascular risk factors, the hazard ratios (HRs) (with 95% CI) in the second, third, and fourth SDMA quartile compared to the lowest quartile were 0.77 (0.60-0.99), 0.99 (0.78-1.25), and 1.51 (1.20-1.91) for total mortality and 0.92 (0.68-1.25), 0.93 (0.68-1.26), and 1.54 (1.14-2.01) for cardiovascular mortality. The same calculations for ADMA quartiles revealed HRs of 1.05 (0.83-1.32), 1.19 (0.95-1.50), and 1.61 (1.30-1.99) for total mortality and HR of 1.00 (0.74-1.34), 1.26 (0.95-1.68), and 1.54 (1.18-2.02) for cardiovascular mortality. CONCLUSIONS Serum concentrations of SDMA are independently associated with increased cardiovascular and all-cause mortality in patients undergoing coronary angiography. The pattern of risk linked to SDMA is different from that linked to ADMA, suggesting different pathophysiological roles of these 2 methylarginine metabolites.

Effects of vitamin D on blood pressure and cardiovascular risk factors: a randomized controlled trial.

Vitamin D deficiency is a risk factor for arterial hypertension, but randomized controlled trials showed mixed effects of vitamin D supplementation on blood pressure (BP). We aimed to evaluate whether vitamin D supplementation affects 24-hour systolic ambulatory BP monitoring values and cardiovascular risk factors. The Styrian Vitamin D Hypertension Trial is a single-center, double-blind, placebo-controlled study conducted from June 2011 to August 2014 at the endocrine outpatient clinic of the Medical University of Graz, Austria. We enrolled 200 study participants with arterial hypertension and 25-hydroxyvitamin D levels below 30 ng/mL. Study participants were randomized to receive either 2800 IU of vitamin D3 per day as oily drops (n=100) or placebo (n=100) for 8 weeks. Primary outcome measure was 24-hour systolic BP. Secondary outcome measures were 24-hour diastolic BP, N-terminal-pro-B-type natriuretic peptide, QTc interval, renin, aldosterone, 24-hour urinary albumin excretion, homeostasis model assessment-insulin resistance, triglycerides, high-density lipoprotein cholesterol, and pulse wave velocity. A total of 188 participants (mean [SD] age, 60.1 [11.3] years; 47% women; 25-hydroxyvitamin D, 21.2 [5.6] ng/mL) completed the trial. The mean treatment effect (95% confidence interval) for 24-hour systolic BP was −0.4 (−2.8 to 1.9) mm Hg (P=0.712). Triglycerides increased significantly (mean change [95% confidence interval], 17 [1–33] mg/dL; P=0.013), but no further significant effects were observed for secondary outcomes. Vitamin D supplementation in hypertensive patients with low 25-hydroxyvitamin D has no significant effect on BP and several cardiovascular risk factors, but it was associated with a significant increase in triglycerides. Clinical Trial Registration— URL: http://www.clinicaltrials.gov. Unique identifier: NCT02136771.

Low homoarginine concentration is a novel risk factor for heart disease

Background Homoarginine is an amino acid which may play a role in nitric oxide and energy metabolism. Low homoarginine concentrations have previously been linked to increased mortality, but the underlying mechanisms remain unknown. Objectives To investigate whether serum homoarginine concentrations are associated with myocardial function, energy metabolism and fatal events. Design and patients Serum homoarginine concentrations were measured in 3305 Caucasian patients who were referred for coronary angiography at a tertiary care centre in Germany. After baseline examinations (1997–2000), patients were followed-up with respect to specific causes of death. Results Homoarginine concentration correlated positively with angiographic ejection fraction and was inversely associated with N-terminal pro-B-type natriuretic peptide (p<0.001 for both). Variables of energy metabolism (guanidinoacetate and creatine) were significantly associated with homoarginine concentration (p<0.001 for both). Over a median follow-up time of 9.9 years, 991 patients died, including 258 sudden cardiac deaths, 148 heart failure deaths and 105 fatal myocardial infarctions. Multivariable adjusted Cox proportional HRs (with 95% CI) for the first versus the fourth homoarginine quartile were 2.44 (1.60 to 3.73) for sudden cardiac deaths, 3.44 (1.89 to 6.24) for heart failure deaths, and 3.78 (1.77 to 8.06) for fatal myocardial infarctions. Conclusions Homoarginine deficiency is associated with myocardial dysfunction and significantly increased risk of fatal cardiovascular events and may be related to poor energy metabolism. Further studies are warranted to explore the significance of homoarginine metabolism in risk stratification and treatment of heart diseases.

Obesity-related dysregulation of the tryptophan-kynurenine metabolism: role of age and parameters of the metabolic syndrome.

Obesity‐related immune mediated systemic inflammation was associated with the development of the metabolic syndrome by induction of the tryptophan (TRP)–kynurenine (KYN) pathway. The study aimed to assess whether this holds true across the lifespan from juvenility to adulthood.

Homoarginine, heart failure, and sudden cardiac death in haemodialysis patients

Sudden cardiac death (SCD) is a major contributor to the excess mortality of patients on maintenance dialysis. Homoarginine deficiency may lead to decreased nitric oxide availability and endothelial dysfunction. Based on this rationale we assessed whether homoarginine deficiency is a risk factor for SCD in dialysis patients.

Asymmetrical dimethylarginine is associated with renal and cardiovascular outcomes and all-cause mortality in renal transplant recipients.

Increased plasma levels of asymmetric dimethylarginine (ADMA) are associated with endothelial dysfunction and predict the progression to dialysis and death in patients with chronic kidney disease. The effects of these increased ADMA levels in renal transplant recipients, however, are unknown. We used the data from ALERT, a randomized, double-blind, placebo-controlled study of the effect of fluvastatin on cardiovascular and renal outcomes in 2102 renal transplant recipients with stable graft function on enrollment. Patients who were initially randomized to fluvastatin or placebo in the 5- to 6-year trial were offered open-label fluvastatin in a 2-year extension of the original study. After adjustment for baseline values for established factors in this post hoc analysis, ADMA was found to be a significant risk factor for graft failure or doubling of serum creatinine (hazard ratio 2.78), major cardiac events (hazard ratio 2.61), cerebrovascular events (hazard ratio 6.63), and all-cause mortality (hazard ratio 4.87). In this trial extension, the number of end points increased with increasing quartiles of plasma ADMA levels. All end points were significantly increased in the fourth compared to the first quartile. Our study shows that elevated plasma levels of ADMA are associated with increased morbidity, mortality, and the deterioration of graft function in renal transplant recipients.

Hyperparathyroidism in Patients with Primary Aldosteronism: Cross-Sectional and Interventional Data from the GECOH Study

CONTEXT Experimental studies suggest that aldosterone induces hypercalciuria and might contribute to hyperparathyroidism. OBJECTIVE We aimed to test for differences in PTH levels and parameters of calcium and vitamin D metabolism in patients with primary aldosteronism (PA) compared with patients with essential hypertension (EH) and to evaluate the impact of PA treatment on these laboratory values. DESIGN, SETTING, AND PARTICIPANTS The Graz Endocrine Causes of Hypertension study includes hypertensive patients referred for screening for endocrine hypertension at a tertiary care center in Graz, Austria. MAIN OUTCOME MEASURES Differences in PTH levels between patients with PA and EH. RESULTS Among 192 patients, we identified 10 patients with PA and 182 with EH. PTH levels (mean ± sd in picograms per milliliter) were significantly higher in PA patients compared with EH (67.8 ± 26.9 vs. 46.5 ± 20.9; P = 0.002). After treatment of PA with either adrenal surgery (n = 5) or mineralocorticoid receptor antagonists (n = 5), PTH concentrations decreased to 43.9 ± 14.9 (P = 0.023). Serum 25-hydroxyvitamin D concentrations were similar in both groups. Compared with EH, serum calcium concentrations were significantly lower (2.35 ± 0.10 vs. 2.26 ± 0.10 mmol/liter; P = 0.013), and there was a nonsignificant trend toward an increased spot urine calcium to creatinine ratio in PA [median (interquartile range) 0.19 (0.11-0.31) vs. 0.33 (0.12-0.53); P = 0.094]. CONCLUSIONS Our results suggest that PA contributes to secondary hyperparathyroidism. Further studies are warranted to evaluate whether PTH has implications for PA diagnostics and whether mineralocorticoid receptor antagonists have a general impact on PTH and calcium metabolism.