Heidrun Mehling

Randomized comparison of reduced fat and reduced carbohydrate hypocaloric diets on intrahepatic fat in overweight and obese human subjects

Obesity‐related hepatic steatosis is a major risk factor for metabolic and cardiovascular disease. Fat reduced hypocaloric diets are able to relieve the liver from ectopically stored lipids. We hypothesized that the widely used low carbohydrate hypocaloric diets are similarly effective in this regard. A total of 170 overweight and obese, otherwise healthy subjects were randomized to either reduced carbohydrate (n = 84) or reduced fat (n = 86), total energy restricted diet (−30% of energy intake before diet) for 6 months. Body composition was estimated by bioimpedance analyses and abdominal fat distribution by magnetic resonance tomography. Subjects were also submitted to fat spectroscopy of liver and oral glucose tolerance testing. In all, 102 subjects completed the diet intervention with measurements of intrahepatic lipid content. Both hypocaloric diets decreased body weight, total body fat, visceral fat, and intrahepatic lipid content. Subjects with high baseline intrahepatic lipids (>5.56%) lost ≈7‐fold more intrahepatic lipids compared with those with low baseline values (<5.56%) irrespective of diet composition. In contrast, changes in visceral fat mass and insulin sensitivity were similar between subgroups, with low and high baseline intrahepatic lipids. Conclusion: A prolonged hypocaloric diet low in carbohydrates and high in fat has the same beneficial effects on intrahepatic lipid accumulation as the traditional low‐fat hypocaloric diet. The decrease in intrahepatic lipids appears to be independent of visceral fat loss and is not tightly coupled with changes in whole body insulin sensitivity during 6 months of an energy restricted diet. (HEPATOLOGY 2011)

Dietary omega-3 fatty acids modulate the eicosanoid profile in man primarily via the CYP-epoxygenase pathway

Cytochrome P450 (CYP)-dependent metabolites of arachidonic acid (AA) contribute to the regulation of cardiovascular function. CYP enzymes also accept EPA and DHA to yield more potent vasodilatory and potentially anti-arrhythmic metabolites, suggesting that the endogenous CYP-eicosanoid profile can be favorably shifted by dietary omega-3 fatty acids. To test this hypothesis, 20 healthy volunteers were treated with an EPA/DHA supplement and analyzed for concomitant changes in the circulatory and urinary levels of AA-, EPA-, and DHA-derived metabolites produced by the cyclooxygenase-, lipoxygenase (LOX)-, and CYP-dependent pathways. Raising the Omega-3 Index from about four to eight primarily resulted in a large increase of EPA-derived CYP-dependent epoxy-metabolites followed by increases of EPA- and DHA-derived LOX-dependent monohydroxy-metabolites including the precursors of the resolvin E and D families; resolvins themselves were not detected. The metabolite/precursor fatty acid ratios indicated that CYP epoxygenases metabolized EPA with an 8.6-fold higher efficiency and DHA with a 2.2-fold higher efficiency than AA. Effects on leukotriene, prostaglandin E, prostacyclin, and thromboxane formation remained rather weak. We propose that CYP-dependent epoxy-metabolites of EPA and DHA may function as mediators of the vasodilatory and cardioprotective effects of omega-3 fatty acids and could serve as biomarkers in clinical studies investigating the cardiovascular effects of EPA/DHA supplementation.

The effect of CCR2 inhibitor CCX140-B on residual albuminuria in patients with type 2 diabetes and nephropathy: a randomised trial.

BACKGROUND Patients with type 2 diabetes and nephropathy have high cardiorenal morbidity and mortality despite optimum treatment including angiotensin-converting enzyme (ACE) inhibitors or angiotensin receptor blockers (ARBs). Residual risk is related to residual albuminuria. We assessed whether CCX140-B, a selective inhibitor of C-C chemokine receptor type 2 (CCR2), could further reduce albuminuria when given in addition to standard care, including ACE inhibitors or ARBs. METHODS In this randomised, double-blind, placebo-controlled clinical trial, we recruited patients from 78 research centres in Belgium, Czech Republic, Germany, Hungary, Poland, and the UK. We enrolled patients with type 2 diabetes aged 18-75 years with proteinuria (first morning void urinary albumin to creatinine ratio [UACR] 100-3000 mg/g), estimated glomerular filtration rate of 25 mL/min per 1·73 m(2) or higher, and taking stable antidiabetic treatment and ACE inhibitors or ARBs, for at least 8 weeks before study entry. Patients were stratified based on baseline UACR and renal function (estimated glomerular filtration rate), and then randomly assigned (1:1:1) via an interactive web response system with a minimisation algorithm to oral placebo, 5 mg CCX140-B, or 10 mg CCX140-B once a day. The 12-week dosing period in the initial protocol was extended to 52 weeks by protocol amendment. The primary efficacy measure was change from baseline in UACR during 52 weeks in the modified intention-to-treat population (all patients with uninterrupted dosing, excluding patients who stopped dosing at week 12 either permanently under the original protocol, or temporarily because of delay in approval of the protocol amendment). We did safety analyses on all randomly assigned patients who received at least one dose of study drug. According to a prespecified analysis plan, we analysed the primary endpoint with one-sided statistical testing with calculation of upper 95% confidence limits of the differences between active and control. This trial is registered with ClinicalTrials.gov, number NCT01447147. FINDINGS The study ran from Dec 7, 2011 (first patient enrolled), until Aug 4, 2014. We enrolled 332 patients: 111 were assigned to receive placebo, 110 to 5 mg CCX140-B, and 111 to 10 mg CCX140-B. Of these, 192 were included in the modified intention-to-treat population. UACR changes from baseline during 52 weeks were -2% for placebo (95% CI -11% to 9%), -18% for 5 mg CCX140-B (-26% to -8%), and -11% for 10 mg CCX140-B (-20% to -1%). We recorded a -16% difference between 5 mg CCX140-B and placebo (one-sided upper 95% confidence limit -5%; p=0·01) and a -10% difference between 10 mg CCX140-B and placebo (upper 95% confidence limit 2%; p=0·08). Adverse events occurred in 81 (73%) of 111 patients in the placebo group versus 71 (65%) of 110 patients in the CCX140-B 5 mg group and 68 (61%) of 111 patients in the CCX140-B 10 mg group; there were no renal events during the study. INTERPRETATION Our data suggest that CCR2 inhibition with CCX140-B has renoprotective effects on top of current standard of care in patients with type 2 diabetes and nephropathy. FUNDING ChemoCentryx.

Niacin Lowers Serum Phosphate and Increases HDL Cholesterol in Dialysis Patients

BACKGROUND AND OBJECTIVES Adverse effects complicate the use of drugs that are prescribed for phosphate control in dialysis patients. Alternative treatment options are needed. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS Nicotinic acid inhibits intestinal phosphate reabsorption and increases HDL cholesterol. This study tested the phosphate-lowering and HDL-increasing effect of Niaspan (prolonged-release nicotinic acid) in patients who were undergoing dialysis. Efficacy, safety, and tolerability of Niaspan were prospectively studied. Twenty dialysis patients, who were receiving a stable dosage of a calcium salt-containing drug for phosphate control, received after a 2-wk washout period Niaspan for 12 wk. Patients were started on 375 mg/d, and the dosage was increased every 2 wk to achieve 500, 1000, 1500, and 2000 mg/d, respectively. Clinical and laboratory parameters were prospectively recorded in patients who tolerated a target dosage of > or = 1000 mg/d. RESULTS Seventeen patients tolerated > or = 1000 mg/d Niaspan (mean dosage 1470 +/- 110 mg/d). Niaspan treatment for 12 wk decreased serum phosphate values from 7.2 +/- 0.5 to 5.9 +/- 0.6 mg/dl (P < 0.015). In contrast, Niaspan did not affect serum calcium levels. A significant increase in HDL cholesterol from 40 +/- 3.2 to 59 +/- 5.5 mg/dl (34%) was also observed with Niaspan (P = 0.0005). CONCLUSIONS Niaspan effectively lowered serum phosphate levels and significantly increased HDL cholesterol. Niaspan may provide an alternative or adjunctive treatment option in dialysis patients.

Left Ventricular Mass and Function With Reduced-Fat or Reduced-Carbohydrate Hypocaloric Diets in Overweight and Obese Subjects

In animals, carbohydrate and fat composition during dietary interventions influenced cardiac metabolism, structure, and function. Because reduced-carbohydrate and reduced-fat hypocaloric diets are commonly used in the treatment of obesity, we investigated whether these interventions differentially affect left ventricular mass, cardiac function, and blood pressure. We randomized 170 overweight and obese subjects (body mass index, 32.9±4.4; range, 26.5–45.4 kg/m2) to 6-month hypocaloric diets with either reduced carbohydrate intake or reduced fat intake. We obtained cardiac MRI and ambulatory blood pressure recordings over 24 hours before and after 6 months. Ninety subjects completing the intervention period had a full cardiac MRI data set. Subjects lost 7.3±4.0 kg (7.9±3.8%) with reduced-carbohydrate diet and 6.2±4.2 kg (6.7±4.4%) with reduced-fat diet (P<0.001 within each group; P=not significant between interventions). Caloric restriction led to similar significant decreases in left ventricular mass with low-carbohydrate diets (5.4±5.4 g) or low-fat diets (5.2±4.8 g; P<0.001 within each group; P=not significant between interventions). Systolic and diastolic left ventricular function did not change with either diet. The 24-hour systolic blood pressure decreased similarly with both interventions. Body weight change (&bgr;=0.33; P=0.02) and percentage of ingested n-3 polyunsaturated fatty acids (&bgr;=−0.27; P=0.03) predicted changes in left ventricular mass. In conclusion, weight loss induced by reduced-fat diets or reduced-carbohydrate diets similarly improved left ventricular mass in overweight and obese subjects over a 6-month period. However, n-3 polyunsaturated fatty acid ingestion may have an independent beneficial effect on left ventricular mass.

A pilot study of chronic, low-dose epoetin-β following percutaneous coronary intervention suggests safety, feasibility, and efficacy in patients with symptomatic ischaemic heart failure

Low‐dose epoetin‐β improved neo‐angiogenesis and cardiac regeneration in experimental models of ischaemic cardiomyopathy without raising haemoglobin. No clinical study has tested this approach to date.

Significant Reduction in Helicobacter pylori Load in Humans with Non-viable Lactobacillus reuteri DSM17648: A Pilot Study.

Abstract Reducing the amount of Helicobacter pylori in the stomach by selective bacterial–bacterial cell interaction was sought as an effective and novel method for combating the stomach pathogen. Lactobacillus reuteri DSM17648 was identified as a highly specific binding antagonist to H. pylori among more than 700 wild-type strains of Lactobacillus species. Applying a stringent screening procedure, the strain DSM17648 was identified as selective binder to H. pylori cells under in vivo gastric conditions. The strain DSM17648 co-aggregates the pathogen in vivo and in vitro. The specific co-aggregation occurs between Lact. reuteri DSM17648 and different H. pylori strains and serotypes, as well as H. heilmannii, but not with Campylobacter jejuni or other commensal oral and intestinal bacteria. Lact. reuteri DSM17648 was shown in a proof-of-concept single-blinded, randomized, placebo-controlled pilot study to significantly reduce the load of H. pylori in healthy yet infected adults. Reducing the amount of H. pylori in the stomach by selective bacterial–bacterial cell interaction might be an effective and novel method for combating the stomach pathogen. Lact. reuteri DSM17648 might prove useful as an adhesion blocker in antibiotic-free H. pylori therapies.

On the subjective acceptance during cardiovascular magnetic resonance imaging at 7.0 Tesla

Purpose This study examines the subjective acceptance during UHF-CMR in a cohort of healthy volunteers who underwent a cardiac MR examination at 7.0T. Methods Within a period of two-and-a-half years (January 2012 to June 2014) a total of 165 healthy volunteers (41 female, 124 male) without any known history of cardiac disease underwent UHF-CMR. For the assessment of the subjective acceptance a questionnaire was used to examine the participants experience prior, during and after the UHF-CMR examination. For this purpose, subjects were asked to respond to the questionnaire in an exit interview held immediately after the completion of the UHF-CMR examination under supervision of a study nurse to ensure accurate understanding of the questions. All questions were answered with “yes” or “no” including space for additional comments. Results Transient muscular contraction was documented in 12.7% of the questionnaires. Muscular contraction was reported to occur only during periods of scanning with the magnetic field gradients being rapidly switched. Dizziness during the study was reported by 12.7% of the subjects. Taste of metal was reported by 10.1% of the study population. Light flashes were reported by 3.6% of the entire cohort. 13% of the subjects reported side effects/observations which were not explicitly listed in the questionnaire but covered by the question about other side effects. No severe side effects as vomiting or syncope after scanning occurred. No increase in heart rate was observed during the UHF-CMR exam versus the baseline clinical examination. Conclusions This study adds to the literature by detailing the subjective acceptance of cardiovascular magnetic resonance imaging examinations at a magnetic field strength of 7.0T. Cardiac MR examinations at 7.0T are well tolerated by healthy subjects. Broader observational and multi-center studies including patient cohorts with cardiac diseases are required to gain further insights into the subjective acceptance of UHF-CMR examinations.

Non-Viable Lactobacillus reuteri DSMZ 17648 (Pylopass™) as a New Approach to Helicobacter pylori Control in Humans

Prevalence of infections by Helicobacter pylori, a pathogen involved in a number of gastrointestinal diseases, remains high in developing countries. Management of infections by eradication is not always an option. Lactobacillus reuteri (L. reuteri) DSMZ17648 (Pylopass™/Lonza) specifically co-aggregates H. pylori in vitro and was shown to reduce 13C urea breath test in vivo. In this pilot study, we tried to replicate previous findings in an independent sample and to evaluate effects of spray-drying vs. freeze-drying of cultures. A single-blinded, placebo-controlled study was done in 22 H. pylori positive, asymptomatic adults. H. pylori levels were determined by 13C-urea-breath method after 14 days of supplementation, as well as after 6, 12, and 24 weeks follow-up. In the test group, but not in the placebo group, a significant reduction of H. pylori was observed. For the first time, spray-dried cells of L. reuteri DSMZ17648 have been used in a human study and results are in line with the first study results, supplementing with freeze-dried material. This is of special interest as spray-drying results in dead cell material, meaning that the effect of L. reuteri must be independent of its probiotic activity. These results confirm the potential of Pylopass™ as a novel way to reduce the load of H. pylori.

Pacemaker Current Inhibition in Experimental Human Cardiac Sympathetic Activation: A Double‐Blind, Randomized, Crossover Study

Hyperpolarization‐activated, cyclic nucleotide–gated 4 (HCN4) channels comprise the final pathway for autonomic heart rate (HR) regulation. We hypothesized that HCN4 inhibition could reverse autonomic imbalance in a human model of cardiac sympathetic activation. Nineteen healthy men ingested oral metoprolol+reboxetine, ivabradine+reboxetine, or placebo+reboxetine in a double‐blind, randomized, crossover fashion. We assessed HR, blood pressure (BP), stroke volume, and cardiac output during rest and profound orthostatic stress. HR variability, BP variability, and baroreflex sensitivity were analyzed. Metoprolol, but not ivabradine, decreased resting HR and BP. Ivabradine attenuated the HR increase to orthostatic stress, albeit to a lesser extent than metoprolol. Stroke volume and cardiac output at a given HR were significantly lower with metoprolol. Unlike metoprolol, ivabradine did not affect HR variability, BP variability, or baroreflex sensitivity. Ivabradine attenuates sympathetic influences on HR at the sinus node level, leaving myocardial sympathetic activation unopposed. Reversal of parasympathetic dysfunction by ivabradine appears limited.