Heiner K. Berthold

Low vitamin D status: A contributing factor in the pathogenesis of congestive heart failure?

OBJECTIVES This study was designed to evaluate the association between vitamin D status and congestive heart failure (CHF). BACKGROUND Impaired intracellular calcium metabolism is an important factor in the pathogenesis of CHF. The etiology of CHF, however, is not well understood. METHODS Twenty patients age <50 years and 34 patients age >/=50 years with New York Heart Association classes >/=2 and 34 control subjects age >/=50 years were recruited. N-terminal pro-atrial natriuretic peptide (NT-proANP), a predictor of CHF severity; vitamin D metabolites; and parameters of calcium metabolism were measured in fasting blood samples collected between November 2000 and March 2001. RESULTS Both groups of CHF patients had markedly increased serum levels of NT-proANP (p < 0.001), increased serum phosphorus levels (p < 0.001), and reduced circulating levels of both 25-hydroxyvitamin D (p < 0.001) and calcitriol (p < 0.001). Albumin-corrected calcium levels were reduced and parathyroid hormone levels were increased in the younger CHF patients compared with the controls (both p values <0.001). Moreover, parathyroid hormone levels tended to be higher in the elderly CHF patients than in the controls (p = 0.074). In a nonlinear regression analysis 25-hydroxyvitamin D and calcitriol were inversely correlated with NT-proANP (r(2) = 0.16; p < 0.001 and r(2) = 0.12; p < 0.01, respectively). The vitamin D genotype at the BmsI restriction site did not differ between the study groups. CONCLUSIONS The low vitamin D status can explain alterations in mineral metabolism as well as myocardial dysfunction in the CHF patients, and it may therefore be a contributing factor in the pathogenesis of CHF.

Vitamin D supplementation enhances the beneficial effects of weight loss on cardiovascular disease risk markers

BACKGROUND High blood concentrations of parathyroid hormone and low concentrations of the vitamin D metabolites 25-hydroxyvitamin D [25(OH)D] and calcitriol are considered new cardiovascular disease risk markers. However, there is also evidence that calcitriol increases lipogenesis and decreases lipolysis. OBJECTIVE We investigated the effect of vitamin D on weight loss and traditional and nontraditional cardiovascular disease risk markers in overweight subjects. DESIGN Healthy overweight subjects (n = 200) with mean 25(OH)D concentrations of 30 nmol/L (12 ng/mL) received vitamin D (83 microg/d) or placebo in a double-blind manner for 12 mo while participating in a weight-reduction program. RESULTS Weight loss was not affected significantly by vitamin D supplementation (-5.7 +/- 5.8 kg) or placebo (-6.4 +/- 5.6 kg). However, mean 25(OH)D and calcitriol concentrations increased by 55.5 nmol/L and 40.0 pmol/L, respectively, in the vitamin D group but by only 11.8 nmol/L and 9.3 pmol/L, respectively, in the placebo group (P < 0.001), whereas a more pronounced decrease occurred in the vitamin D group than in the placebo group in blood concentrations of parathyroid hormone (-26.5% compared with -18.7%; P = 0.014), triglycerides (-13.5% compared with +3.0%; P < 0.001), and the inflammation marker tumor necrosis factor-alpha (-10.2% compared with -3.2%; P = 0.049). The beneficial biochemical effects were independent of the loss in body weight, fat mass, and sex. However, compared with placebo, vitamin D supplementation also increased LDL-cholesterol concentrations (+5.4% compared with -2.5%; P < 0.001). CONCLUSIONS The results indicate that a vitamin D supplement of 83 microg/d does not adversely affect weight loss and is able to significantly improve several cardiovascular disease risk markers in overweight subjects with inadequate vitamin D status participating in a weight-reduction program. This trial was registered at clinicaltrials.gov as NCT00493012.

Low to moderate sugar-sweetened beverage consumption impairs glucose and lipid metabolism and promotes inflammation in healthy young men: a randomized controlled trial

BACKGROUND Sugar-sweetened beverages (SSBs) have unfavorable effects on glucose and lipid metabolism if consumed in high quantities by obese subjects, but the effect of lower doses in normal-weight subjects is less clear. OBJECTIVE The aim was to investigate the effects of SSBs consumed in small to moderate quantities for 3 wk on LDL particle distribution and on other parameters of glucose and lipid metabolism as well as on inflammatory markers in healthy young men. DESIGN Twenty-nine subjects were studied in a prospective, randomized, controlled crossover trial. Six 3-wk interventions were assigned in random order as follows: 600 mL SSBs containing 1)40 g fructose/d [medium fructose (MF)], 2) 80 g fructose/d [high fructose (HF)], 3) 40 g glucose/d [medium glucose (MG)], 4) 80 g glucose/d [high glucose (HG)], 5) 80 g sucrose/d [high sucrose (HS)], or 6) dietary advice to consume low amounts of fructose. Outcome parameters were measured at baseline and after each intervention. RESULTS LDL particle size was reduced after HF by -0.51 nm (95% CI: -0.19, -0.82 nm) and after HS by -0.43 nm (95% CI: -0.12, -0.74; P < 0.05 for both). Similarly, a more atherogenic LDL subclass distribution was seen when fructose-containing SSBs were consumed (MF, HF, and HS: P < 0.05). Fasting glucose and high-sensitivity C-reactive protein (hs-CRP) increased significantly after all interventions (by 4-9% and 60-109%, respectively; P < 0.05); leptin increased during interventions with SSBs containing glucose only (MG and HG: P < 0.05). CONCLUSION The present data show potentially harmful effects of low to moderate consumption of SSBs on markers of cardiovascular risk such as LDL particles, fasting glucose, and hs-CRP within just 3 wk in healthy young men, which is of particular significance for young consumers. This trial was registered at clinicaltrials.gov as NCT01021969.

Sex Disparities in the Treatment and Control of Cardiovascular Risk Factors in Type 2 Diabetes

OBJECTIVE—To assess whether sex differences exist in the effective control and medication treatment intensity of cardiovascular disease (CVD) risk factors. RESEARCH DESIGN AND METHODS—We performed a cross-sectional analysis including 44,893 patients with type 2 diabetes (51% women). End points included uncontrolled CVD risk factors (LDL cholesterol ≥130 mg/dl, systolic blood pressure [SBP] ≥140 mmHg, and A1C ≥8%) and the intensity of medical management in patients with uncontrolled CVD risk factors. Multiple-adjusted odds ratios were calculated after stratification for the presence of CVD (present in 39% of the patients). RESULTS—Women with CVD were less likely to have SBP, LDL cholesterol, and A1C controlled and less likely to receive intensive lipid-lowering treatment. Women without CVD were less likely than men to have LDL cholesterol controlled with no differences in SBP or A1C control. CONCLUSIONS—Women with diabetes and CVD have poorer control of important modifiable risk factors than men and receive less intensified lipid-lowering treatment.

Comparison of the hepatic clearances of campesterol, sitosterol, and cholesterol in healthy subjects suggests that efflux transporters controlling intestinal sterol absorption also regulate biliary secretion

Background: Recently identified ABCG5/8 transporters are responsible in part for the different absorption rates of campesterol, sitosterol, and cholesterol. These transporters are also expressed in the liver and might regulate biliary sterol secretion. Aims: This study was therefore conducted to determine the biliary secretion rates and hepatic clearances of campesterol, sitosterol, and cholesterol. Subjects: Six healthy, male volunteers. Methods: Deuterium labelled sitosterol and campesterol, and unlabelled sitostanol were constantly infused together with a liquid formula using a duodenal perfusion technique. Biliary secretion and hepatic clearance rates were calculated from hourly bile and plasma samples. Results: Plasma concentrations of cholesterol, campesterol, and sitosterol averaged 167.5 (50) mg/dl (SD), 0.50 (0.22) mg/dl, and 0.30 (0.10) mg/dl, respectively. Sitosterol showed a significantly higher biliary secretion rate (1.23 (0.87) mg/h) than campesterol (0.76 (0.54) mg/h, p=0.0321), but both plant sterols had significantly lower biliary secretion rates compared with cholesterol (47.7 (17.5) mg/h; p=0.001 for both). Hepatic clearance of cholesterol (0.31 (0.18) dl/h) was significantly lower compared with campesterol (2.11 (2.51) dl/h) and sitosterol (4.97 (4.70) dl/h; p=0.028 for both), and the clearance of campesterol was significant lower compared with sitosterol (p=0.028). Conclusion: The observed inverse relation between hepatic clearance and known intestinal absorption of cholesterol, campesterol, and sitosterol supports the hypothesis that the ABCG5/8 transporters regulating intestinal sterol absorption might also be involved in biliary sterol excretion.

Vitamin D and Cardiovascular Disease

Cardiovascular disease (CVD) is a major cause of morbidity and mortality worldwide. Recently vitamin D deficiency has been identified as a potential risk factor for many diseases not traditionally associated with vitamin D, such as cancer and CVD. This review discusses the evidence suggesting an association between low 25-hydroxyvitamin D levels and CVD and the possible mechanisms mediating it. Vitamin D deficiency has been associated with CVD risk factors such as hypertension and diabetes mellitus, with markers of subclinical atherosclerosis such as intima-media thickness and coronary calcification as well as with cardiovascular events such as myocardial infarction and stroke as well as congestive heart failure. It could be suggested that vitamin D deficiency contributes to the development of CVD through its association with risk factors, such as diabetes and hypertension. However, direct effects of vitamin D on the cardiovascular system may also be involved. Vitamin D receptors are expressed in a variety of tissues, including cardiomyocytes, vascular smooth muscle cells and endothelial cells and vitamin D has been shown to affect inflammation and cell proliferation and differentiation. While much evidence supports a potential antiatherosclerotic effect of vitamin D, prospective, placebo-controlled randomized as well as mechanistic studies are needed to confirm this association. Since vitamin D deficiency is easy to screen for and treat, the confirmation of such an association could have important implications for both, patient care and health policy.

Ezetimibe alone or in combination with simvastatin increases small dense low-density lipoproteins in healthy men: a randomized trial

AIMS The predominance of small dense low-density lipoproteins (sdLDLs) has been associated with increased cardiovascular risk. The effect of ezetimibe on LDL subfraction distribution has not been fully elucidated. This study assessed by gradient gel electrophoresis the effects of ezetimibe alone, simvastatin alone, and their combination on sdLDL subfraction distribution. METHODS AND RESULTS A single-centre, randomized, parallel three-group open-label study was performed in 72 healthy men with a baseline LDL-cholesterol (LDL-C) concentration of 111 +/- 30 mg/dL (2.9 +/- 0.8 mmol/L). They were treated with ezetimibe (10 mg/day, n = 24), simvastatin (40 mg/day, n = 24), or their combination (n = 24) for 14 days. Blood was drawn before and after the treatment period. Generalized estimating equations were used to assess the influence of drug therapy on LDL subfraction distribution, controlling for within-subject patterns (clustering). We adjusted for age, body mass index, and baseline concentrations of LDL-C and triglycerides. Ezetimibe alone changed LDL subfraction distribution towards a more atherogenic profile by significantly increasing sdLDL subfractions (LDL-IVA +14.2%, P = 0.0216 and LDL-IVB +16.7%, P = 0.039; fully adjusted Wald chi(2) test). In contrast, simvastatin alone significantly decreased the LDL-IVB subfraction (-16.7%, P = 0.002). This effect was offset when simvastatin was combined with ezetimibe (LDL-IVB +14.3%, P = 0.44). All three treatments decreased the large, more buoyant LDL-I subfraction, the effects of ezetimibe being the most pronounced (ezetimibe -13.9%, P < 0.0001; combination therapy -7.3%, P = 0.0743; simvastatin -4.6%, P < 0.0001). CONCLUSION In healthy men, treatment with ezetimibe alone is associated with the development of a pro-atherogenic LDL subfraction profile. Potentially atheroprotective effects of simvastatin are offset by ezetimibe. This study is registered with ClinicalTrials.gov, identifier no. NCT00317993.

Effects of Lipid-Lowering Drugs on Irisin in Human Subjects In Vivo and in Human Skeletal Muscle Cells Ex Vivo

Context and Objective The myokine irisin has been proposed to regulate energy homeostasis. Little is known about its association with metabolic parameters and especially with parameters influencing pathways of lipid metabolism. In the context of a clinical trial, an exploratory post hoc analysis has been performed in healthy subjects to determine whether simvastatin and/or ezetimibe influence serum irisin levels. The direct effects of simvastatin on irisin were also examined in primary human skeletal muscle cells (HSKMCs). Design and Participants A randomized, parallel 3-group study was performed in 72 men with mild hypercholesterolemia and without apparent cardiovascular disease. Each group of 24 subjects received a 14-day treatment with either simvastatin 40 mg, ezetimibe 10 mg, or their combination. Results Baseline irisin concentrations were not significantly correlated with age, BMI, estimated GFR, thyroid parameters, glucose, insulin, lipoproteins, non-cholesterol sterols, adipokines, inflammation markers and various molecular markers of cholesterol metabolism. Circulating irisin increased significantly in simvastatin-treated but not in ezetimibe-treated subjects. The changes were independent of changes in LDL-cholesterol and were not correlated with changes in creatine kinase levels. In HSKMCs, simvastatin significantly increased irisin secretion as well as mRNA expression of its parent peptide hormone FNDC5. Simvastatin significantly induced cellular reactive oxygen species levels along with expression of pro- and anti-oxidative genes such as Nox2, and MnSOD and catalase, respectively. Markers of cellular stress such as atrogin-1 mRNA and Bax protein expression were also induced by simvastatin. Decreased cell viability and increased irisin secretion by simvastatin was reversed by antioxidant mito-TEMPO, implying in part that irisin is secreted as a result of increased mitochondrial oxidative stress and subsequent myocyte damage. Conclusions Simvastatin increases irisin concentrations in vivo and in vitro. It remains to be determined whether this increase is a result of muscle damage or a protective mechanism against simvastatin-induced cellular stress. Trial Registration ClinicalTrials.gov NCT00317993 NCT00317993.

Physician gender is associated with the quality of type 2 diabetes care

Objectives.  Patient gender influences the quality of medical care whilst the role of physician gender is not well established. To investigate the influence of physician gender on quality of care in patients with type 2 diabetes.

A randomized controlled trial on the efficacy of carbohydrate-reduced or fat-reduced diets in patients attending a telemedically guided weight loss program

BackgroundWe investigated whether macronutrient composition of energy-restricted diets influences the efficacy of a telemedically guided weight loss program.MethodsTwo hundred overweight subjects were randomly assigned to a conventional low-fat diet and a low-carbohydrate diet group (target carbohydrate content: >55% energy and <40% energy, respectively). Both groups attended a weekly nutrition education program and dietary counselling by telephone, and had to transfer actual body weight data to our clinic weekly with added Bluetooth® technology by mobile phone. Various fatness and fat distribution parameters, energy and macronutrient intake, and various biochemical risk markers were measured at baseline and after 6, and 12 months.ResultsIn both groups, energy intake decreased by 400 kcal/d compared to baseline values within the first 6 months and slightly increased again within the second 6 months. Macronutrient composition differed significantly between the groups from the beginning to month 12. At study termination, weight loss was 5.8 kg (SD: 6.1 kg) in the low-carbohydrate group and 4.3 kg (SD: 5.1 kg) in the low-fat group (p = 0.065). In the low-carbohydrate group, triglyceride and HDL-cholesterol levels were lower at month 6 and waist circumference and systolic blood pressure were lower at month 12 compared with the low-fat group (P = 0.005–0.037). Other risk markers improved to a similar extent in both groups.ConclusionDespite favourable effects of both diets on weight loss, the carbohydrate-reduced diet was more beneficial with respect to cardiovascular risk factors compared to the fat-reduced diet. Nevertheless, compliance with a weight loss program appears to be even a more important factor for success in prevention and treatment of obesity than the composition of the diet.Trial registrationClinicaltrials.gov as NCT00868387