A Crossover Trial Using High‐Fidelity Cardiovascular Phenotyping

Background Sympathetic and parasympathetic influences on heart rate (HR), which are governed by baroreflex mechanisms, are integrated at the cardiac sinus node through hyperpolarization‐activated cyclic nucleotide–gated channels (HCN4). We hypothesized that HCN4 blockade with ivabradine selectively attenuates HR and baroreflex HR regulation, leaving baroreflex control of muscle sympathetic nerve activity intact. Methods and Results We treated 21 healthy men with 2×7.5 mg ivabradine or placebo in a randomized crossover fashion. We recorded electrocardiogram, blood pressure, and muscle sympathetic nerve activity at rest and during pharmacological baroreflex testing. Ivabradine reduced normalized HR from 65.9±8.1 to 58.4±6.2 beats per minute (P<0.001) with unaffected blood pressure and muscle sympathetic nerve activity. On ivabradine, cardiac and sympathetic baroreflex gains and blood pressure responses to vasoactive drugs were unchanged. Ivabradine aggravated bradycardia during baroreflex loading. Conclusions HCN4 blockade with ivabradine reduced HR, leaving physiological regulation of HR and muscle sympathetic nerve activity as well as baroreflex blood pressure buffering intact. Ivabradine could aggravate bradycardia during parasympathetic activation

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

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Abstract 618: Dietary Omega-3 Fatty Acid Compete With Arachidonic Acid For The Formation Of Physiologically Active Cyp-eicosanoids In Man

Cytochrome P450 (CYP)-dependent metabolites of arachidonic acid (AA; 20:4 n-6) regulate vascular, renal, and cardiac function. However, the same CYP isoforms that metabolize AA also accept eicosapentaenoic acid (EPA; 20:5 n-3) and docosahexaenoic acid (DHA; 22:6 n-3) as alternative substrates, suggesting that the profile of physiologically active CYP-eicosanoids can be modulated in vivo by changing the dietary fatty acid composition. After we proved this hypothesis in rodents, we now expanded our studies to humans. The trial included 10 healthy men and 10 women aged 18 to 45 years (EudraCT: 2009-013458-33). They ingested 1 Omacor® capsule (480 mg EPA + 360 mg DHA) daily for the first 4 weeks, and two capsules daily in the subsequent 4 weeks, followed by 8 weeks of wash-out. Fatty acids and CYP-dependent metabolites were determined in blood and urine samples by gas chromatography and LC-MS/MS, respectively. The Omega-3 Index (% EPA + DHA of total fatty acids in red blood cells) increased from 4.98±0.80 to 8.03±1.06 at week 8 (p &lt;0.001 vs. week 0), and declined to 6.33±1.44 at week 16. Concomitantly, the plasma CYP-epoxyeicosanoid index, defined as the ratio of EPA- plus DHA- vs. AA-derived epoxymetabolites ((EEQs+EDPs)/EETs), increased almost 3-fold from 0.83±0.05 to 2.35±0.17 (p &lt;0.001; week 0 vs. week 8), and declined to 1.58±0.53 at week 16. In urine, the corresponding hydrolysis products were detectable and their ratio increased from 1.57±1.19 to 4.74±2.61 after 2g Omacor ® , and returned to baseline (1.38±0.75) after cessation of supplementation. Among the individual regioisomeric epoxymetabolites, AA-derived 14,15-EET predominated at baseline but was clearly exceeded by the EPA-derived 17,18-EEQ after EPA/DHA supplementation (3.24±0.26 vs.1.88±0.22 at week 0 and 2.96±0.24 vs. 6.15±0.43 ng/ml plasma at week 8). The plasma level of DHA-derived 19,20-EDP increased from 1.23±0.11 at week 0 to 2.52±0.19 at week 8. These results demonstrate that the human CYP-eicosanoid profile is highly susceptible to changes in dietary fatty acids. In particular, EPA/DHA supplementation promotes the formation of 17,18-EEQ that we previously identified as a candidate for mediating vasodilatory and antiarrhythmic effects of omega-3 fatty acids. </jats:p

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

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.status: publishe

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

Hydrojet-based delivery of footprint-free iPSC-derived cardiomyocytes into porcine myocardium

AbstractThe reprogramming of patient´s somatic cells into induced pluripotent stem cells (iPSCs) and the consecutive differentiation into cardiomyocytes enables new options for the treatment of infarcted myocardium. In this study, the applicability of a hydrojet-based method to deliver footprint-free iPSC-derived cardiomyocytes into the myocardium was analyzed. A new hydrojet system enabling a rapid and accurate change between high tissue penetration pressures and low cell injection pressures was developed. Iron oxide-coated microparticles were ex vivo injected into porcine hearts to establish the application parameters and the distribution was analyzed using magnetic resonance imaging. The influence of different hydrojet pressure settings on the viability of cardiomyocytes was analyzed. Subsequently, cardiomyocytes were delivered into the porcine myocardium and analyzed by an in vivo imaging system. The delivery of microparticles or cardiomyocytes into porcine myocardium resulted in a widespread three-dimensional distribution. In vitro, 7 days post-injection, only cardiomyocytes applied with a hydrojet pressure setting of E20 (79.57 ± 1.44%) showed a significantly reduced cell viability in comparison to the cells applied with 27G needle (98.35 ± 5.15%). Furthermore, significantly less undesired distribution of the cells via blood vessels was detected compared to 27G needle injection. This study demonstrated the applicability of the hydrojet-based method for the intramyocardial delivery of iPSC-derived cardiomyocytes. The efficient delivery of cardiomyocytes into infarcted myocardium could significantly improve the regeneration.</jats:p