Sex-specific differences in trimethylamine N-oxide (TMAO) concentrations before and after cardiac rehabilitation in acute myocardial infarction patients.

Trimethylamine N-oxide (TMAO) is a biomarker of cardiovascular risk and may enhance the progression of atherosclerosis. The aim of the study was to determine whether there are sex-specific differences in TMAO concentrations before and after cardiac rehabilitation in acute myocardial infarction (AMI) patients. A total of 56 participants [45/56 (80.4 %) males, 11/56 (19.6 %) females] were drawn from AMI inpatients hospitalized at the Division of Cardiology, Medical University of Graz, Austria. For the assessment of TMAO, serum samples were collected within the first day after hospital admission due to AMI and at the start and end of cardiac rehabilitation. Shortly after hospital admission due to AMI, females had significantly higher TMAO blood concentrations than males. These initially high TMAO levels remained almost unchanged in the female AMI patients until the start of cardiac rehabilitation and only reached the lower TMAO concentrations observed in the male patients after rehabilitation [female patients: TMAO (acute myocardial infarction) = 5.93 µmol/L (SE = 1.835); TMAO (start of rehabilitation) = 5.68 µmol/L (SE = 1.217); TMAO (end of rehabilitation) = 3.89 µmol/L (SE = 0.554); male patients: TMAO (acute myocardial infarction) = 3.02 µmol/L (SE = 0.255), TMAO (start of rehabilitation) = 3.91 µmol/L (SE = 0.346), TMAO (end of rehabilitation) = 4.04 µmol/L (SE = 0.363)]. After AMI, women might be at higher cardiovascular risk due to persistently higher levels of TMAO. High TMAO levels in women might decrease after cardiac rehabilitation due to cardiac rehabilitation-associated lifestyle modifications. These lifestyle modifications after AMI might also prevent increases in TMAO concentrations in men.

Effects of linagliptin on endothelial function and postprandial lipids in coronary artery disease patients with early diabetes: a randomized, placebo-controlled, double-blind trial.

BACKGROUND: Early glucose lowering intervention in subjects with type 2 diabetes mellitus was demonstrated to be beneficial in terms of micro- and macrovascular risk reduction. However, most of currently ongoing cardiovascular outcome trials are performed in subjects with manifest atherosclerosis and long-standing diabetes. Therefore, the aim of this study is to investigate the effects of the dipeptidylpeptidase-4 inhibitor linagliptin in subjects with coronary artery disease (CAD) but early type 2 diabetes mellitus (T2DM) on a set of cardiovascular surrogate measurements. METHODS: In this randomized, placebo-controlled, double-blind, single-center study, we included subjects with early diabetes (postchallenge diabetes (2 h glucose > 200 mg/dl) or T2DM treated with diet only or on a stable dose of metformin monotherapy and an HbA1c < 75 mmol/mol) and established CAD. Participants were randomized to receive either linagliptin (5 mg) once daily orally or placebo for 12 weeks. The primary outcome was the change in flow mediated dilatation (FMD). The secondary objective was to investigate the effect of linagliptin treatment on arginine bioavailability ratios [Global arginine bioavailability ratio (GABR) and arginine to ornithine ratio (AOR)]. Arginine, ornithine and citrulline were measured in serum samples with a conventional usual amino acid analysis technique, involving separation of amino acids by ion exchange chromatography followed by postcolumn continuous reaction with ninhydrin. GABR was calculated by L-arginine divided by the sum of (L-ornithine plus L-citrulline). The AOR was calculated by dividing L-arginine by L-ornithine levels. Group comparisons were calculated by using a two-sample t-test with Satterthwaite adjustment for unequal variances. RESULTS: We investigated 43 patients (21% female) with a mean age of 63.3 ± 8.2 years. FMD at baseline was 3.5 ± 3.1% in the linagliptin group vs. 4.0 ± 2.9% in the placebo group. The change in mean FMD in the linagliptin group was not significantly different compared to the change in the placebo group (0.43 ± 4.84% vs. - 0.45 ± 3.01%; p = 0.486). No significant improvements were seen in the arginine bioavailability ratios (GABR; p = 0.608 and AOR; p = 0.549). CONCLUSION: Linagliptin treatment in subjects with CAD and early T2DM did not improve endothelial function or the arginine bioavailability ratios. Trial registration ClinicalTrials.gov, NCT02350478 ( https://clinicaltrials.gov/ct2/show/NCT02350478 ).

The effects of linagliptin on endothelial function and global arginine bioavailability ratio in coronary artery disease patients with early diabetes: study protocol for a randomized controlled trial.

BACKGROUND: Patients with type 2 diabetes (T2DM) are at increased risk for macrovascular events as well as for microvascular complications. There is evidence that in patients with coronary artery disease (CAD), about 35 % suffer from manifest T2DM. Early glucose-lowering intervention in subjects with T2DM has been demonstrated to be beneficial in terms of cardiovascular risk reduction. But thus far, no data are available regarding investigating the impact of linagliptin treatment in patients with early diabetes on cardiovascular endpoints or surrogate parameters. Therefore, the aim of this study is to investigate the effects of linagliptin in CAD patients with early T2DM on various cardiovascular surrogate measurements including mechanical and biochemical endothelial function assessments. METHODS/DESIGN: Forty-two subjects with early diabetes and CAD are included in this investigator-driven, randomized, placebo-controlled, double-blind, phase IV, single-center study. Participants will be randomized to receive either linagliptin (5 mg) administered once daily per os or placebo for 12 weeks. Before and after the intervention, evaluation of endothelial function (flow-mediated dilatation and biochemical biomarkers) and a Meal Tolerance Test are performed. DISCUSSION: Cardiovascular surrogate parameters, such as endothelial function, are able to provide insights into the potential mechanisms of the cardiovascular effects of antihyperglycemic agents. Currently ongoing trials do not specifically focus on early diabetes as a target of intervention and we therefore believe that our study will contribute to a better understanding of the cardiovascular effects of dipeptidylpeptidase-4 (DPP-4) inhibitors in early diabetes. TRIAL REGISTRATION: NCT02350478 . Registered 26 January 2015. Protocol date/version 24 October 2014/version 2.4 EudraCT number: 2013-000330-35.

Reduction of coronary risk factors immediately and 1 year after inpatient rehabilitation in a highly motivated patient cohort.

Adherence to medical advice, driven by high patient motivation, could lead to a significant reduction in risk factors during cardiac rehabilitation.During a 1-year period, 9082 patients were admitted to six cardiac rehabilitation centres. A total of 1195 highly motivated subjects were selected based on their reliable completion of a survey regarding cardiac risk factors.Study subjects had lower risk factors at baseline compared with a contemporary Austrian database. At discharge from the rehabilitation programme subjects showed further reductions in median weight, low-density lipoprotein cholesterol, blood pressure and resting pulse rate (due to increased levels of daily exercise). Smoking also decreased. Most of these changes were still significant after 1 year.The risk factors in these highly motivated patients were low to begin with and were further reduced by an inpatient rehabilitation programme. The content and method of delivery of this programme seem to be effective. Efforts should focus on increasing motivation.

Premature preoperative discontinuation of antiplatelet drug therapy in cardiovascular risk patients: a preliminary study on the role of P2Y12 receptor monitoring.

BACKGROUND AND OBJECTIVE: In high-bleeding risk procedures, discontinuation of antiplatelet drug therapy with clopidogrel may be requested by surgeons, usually 7-10 days before the surgical procedure. New platelet function tests, such as the vasodilator-stimulated phosphoprotein phosphorylation assay, may help to assess the perioperative status of the clopidogrel-specific P2Y12 receptor. METHODS: Using vasodilator-stimulated phosphoprotein phosphorylation assay, the platelet reactivity index (PRI) was measured in 80 individuals, including 20 healthy volunteers, 20 cardiologic patients under full antiplatelet drug therapy with clopidogrel and aspirin, 20 surgical patients without any antiplatelet drugs and 20 patients under clopidogrel, discontinued 7 days before the surgical procedure. RESULTS: The mean PRI (95% confidence interval) in healthy volunteers was 86 (82-89%) and that in the surgical control group was 77% (72-81%). In cardiologic patients under full antiplatelet therapy, mean PRI was 51% (42-60%). In the clopidogrel discontinuation group, PRI increased from 51% (40-62%) on day 0 to 65% (57-74%) on day 3 and to 76% (69-84%) on day 5. On the morning of surgery, mean PRI was 85% (80-91%). The PRI values on the 5th day were equivalent to those of the surgical control group (mean difference -0.4%, 95% confidence interval -8.6% to 7.8%, P = 0.9). Fifty-five percent of the patients in the discontinuation group had a PRI of more than 50% on day 0. CONCLUSION: The study using vasodilator-stimulated phosphoprotein phosphorylation assay, one of the new platelet function assays for the assessment of inhibition of platelet P2Y12 receptor, demonstrates that the PRI on day 5 after discontinuation of clopidogrel is equivalent to a surgical control group and it questions the rigid practice of delaying surgery for 7-10 days, particularly in patients without a clopidogrel effect.

Continuous haemodynamic monitoring during exercise in patients with pulmonary hypertension.

BACKGROUND: Right heart haemodynamic parameters can be recorded continuously with the help of an implanted haemodynamic monitor. Aim of the study was to assess the haemodynamic response with and without inhalation of iloprost during cardiopulmonary exercise testing (CPET) in patients with pulmonary hypertension. MATERIALS AND METHODS: Five female patients with documented pulmonary hypertension (mean +/- S.D. age 47 +/- 16 years, 4 arterial, 1 venous) previously implanted with a haemodynamic monitor underwent an incremental exercise test on 2 separate days. The tests were performed before and immediately after inhalation of a single dose of iloprost (17 microg). Parameters recorded by the device were right ventricular (RV)-afterload (RV systolic pressure, RVSP), RV-preload (RV diastolic pressure, RVDP), estimated pulmonary artery diastolic pressure (ePAD), heart rate (HR) and maximum positive rate of RV pressure development (RVdP/dt) (reflecting the dynamic and inotropic state of the RV). RESULTS: After inhalation of iloprost, RV systolic pressure was always reduced at rest. It was followed by an increase with higher workloads without any difference at VO(2peak). The time course of RV systolic pressure was not linear with a flattening at higher workload during the test. This behaviour was found irrespective of iloprost treatment. The remaining determinants of RV performance showed no relevant differences and a linear behaviour during the exercise test. CONCLUSIONS: Inhalation of aerosolised iloprost resulted in a reduction in right ventricular pressure at rest but not at maximal workload. The implantable haemodynamic monitor (IHM) may be useful for the evaluation of RV haemodynamics during exercise and in assessing treatment efficacy.

Superior left atrial approach to the mitral valve: incidence of postoperative arrhythmia.

BACKGROUND AND AIM OF THE STUDY: The superior left atrial approach to mitral surgery involves exposure of the mitral valve through a longitudinal, craniocaudally orientated incision in the roof of the left atrium. The study aim was to evaluate the incidence of postoperative arrhythmias following this procedure. METHODS: Fifty-nine patients underwent either mitral valve repair (n = 20), mitral valve replacement (n = 26) or an associated procedure (n = 13), including aortic valve replacement, coronary artery bypass grafting and atrial septal defect closure. Eight patients had undergone previous surgery on the mitral valve. Patients were classified according to their preoperative rhythm: sinus rhythm (SR), paroxysmal or chronic atrial fibrillation (AF), or permanent pacing. Changes in cardiac rhythm were evaluated postoperatively, after four weeks, and at late follow up (mean 23.8 months). RESULTS: Preoperatively, 24 patients had shown SR, 10 had paroxysmal AF, 24 had chronic AF, and one patient had permanent pacing. At the time of discharge, SR was recorded in 18 patients who had SR preoperatively, in seven who had paroxysmal AF preoperatively, and in one patient who had chronic AF preoperatively. At follow up, SR was seen in 19 patients with preoperative SR, in seven with paroxysmal AF preoperatively, and in two with chronic AF preoperatively. Four patients received permanent pacemakers postoperatively due to total heart block or bradycardia. CONCLUSION: The superior left atrial approach to mitral valve surgery appears to be safe as it maintains the sinus rhythm in a high proportion of patients postoperatively. In addition, it is not normally prone to technical complications.

Use of abciximab prior to primary angioplasty in STEMI results in early recanalization of the infarct-related artery and improved myocardial tissue reperfusion - results of the Austrian multi-centre randomized ReoPro-BRIDGING Study.

AIMS: The aim of the ReoPro-BRIDGING Austrian multi-centre study was to investigate the effects of abciximab (ReoPro) on early reperfusion in ST-elevation myocardial infarction prior to or during primary percutaneous coronary angioplasty (pPCI). METHODS AND RESULTS: Fifty-five patients with STEMI were randomized either to start abciximab (0.25 mg/kg bolus followed by 10 microg/min infusion) during the organization phase for pPCI (Group 1, n=28) or immediately before pPCI (Group 2, n=27). The time between first bolus of abciximab and first balloon inflation of pPCI was 83+/-18 vs 21+/-13 min in Group 1 vs 2. The pre-pPCI ST-segment resolution (55+/-21.4% vs 42.4+/-18.2%, p=0.005), TIMI flow grade 3 (29% vs 7%, p=0.042), corrected TIMI frame count (58.4+/-32.7 vs 78.9+/-28.4 frame, p=0.018) %diameter stenosis (76.3 /63.5-100/ vs 100 /73.5-100/; median /interquartile range/, p=0.023), were significantly higher in Group 1 vs Group 2. Quantitative myocardial dye intensity measurement revealed a significantly higher grade of myocardial tissue perfusion (1 /0-9.25/ vs 0 /0-3.0/ grey pixel unit, p=0.048) in Group 1 before pPCI. Rapid release of cardiac enzymes was observed in Group 1 as compared with Group 2: rate of rise of CK was 210+/-209 vs 97+/-95 U/l/h (p=0.015). QRS score indicated a smaller infarct size in Group 1 (4.8+/-3.8 vs 7.6+/-3.5, p=0.011) on day 7. CONCLUSION: The use of abciximab in the organization phase for pPCI results in signs of early recanalization of the infarct-related artery and a subsequent improved myocardial tissue reperfusion.

Influence of beta-blocker use on percentage of target heart rate exercise prescription.

BACKGROUND: Exercise is recommended for cardiac patients irrespective of beta-blockers. Percentages of maximal heart rate (%HRmax) and heart rate reserve (%HRR) are widely used to determine training intensities. The purpose of this study was to investigate the influence of chronic cardioselective beta blockade on the %HRmax and %HRR model. METHODS: Ten healthy male subjects randomly received oral placebo or beta-blocker bisoprolol (5 mg/day) for 2 weeks using a double-blind, crossover design. In the second week, the subjects performed a cardiopulmonary exercise test until exhaustion to determine the aerobic (AeT) and anaerobic (AnT) threshold. RESULTS: No significant differences were found for absolute and relative values of oxygen consumption, power output and ratings of perceived exertion at AeT, AnT and maximum workload. Mean HR was significantly (P<0.05) lower at rest (-15 +/- 5 bpm), AeT (-19 +/- 8 bpm), AnT (-22 +/- 10 bpm) and maximal workload (-19 +/- 11 bpm) with bisoprolol compared to placebo. Percentage of maximal heart rate (%HRmax) was significantly (P<0.05) reduced at rest (43 versus 39%), AeT (64 versus 60%) and AnT (86 versus 82%), a trend for a reduction was found for %HRR at AnT (75 versus 71%, P=0.07). CONCLUSIONS: Exercise prescription using %HRmax or %HRR methods are of limited accuracy for patients taking beta-blockers. Although %HRmax and %HRR are easy to determine and therefore attractive, we suggest that the most precise exercise prescription would depend on AeT and AnT. Percentages of maximal oxygen consumption or maximal workload or ratings of perceived exertion may be suggested as a substitute. Alternatively, upper limits for %HRmax and %HRR should be lower for patients taking beta-blockers.

Patterns of use of heparins in ACS. Correlates and hospital outcomes: the Global Registry of Acute Coronary Events (GRACE).

A systematic study that compares the patterns of use of unfractionated heparin (UFH) and low-molecular-weight heparin (LMWH) in patients with acute coronary syndromes (ACS) has, to date, not been carried out in the "real-world" setting. The aim of this report is to identify patterns of use of UFH and LMWH and to report their correlates and outcomes in a broad spectrum of ACS patients enrolled in the observational Global Registry of Acute Coronary Events (GRACE). The use of LMWH and UFH was analysed in 13,231 ACS patients according to patient history, concomitant treatment and invasive procedures in US and non-US sites. Frequency of use in hospitals with and without facilities for percutaneous coronary interventions (PCI) was investigated, and outcomes were analysed. Results show that younger patients (<60 years), those receiving antiplatelet therapies, thrombolytics, beta-blockers, angiotensin-converting enzyme inhibitors, patients admitted to hospitals with PCI facilities, and patients undergoing invasive procedures were more likely to receive UFH, or both UFH and LMWH than LMWH alone (80.1% enoxaparin, 19.9% other LMWH). LMWH was used less often in US than non-US sites. After adjusting for confounding variables, patients receiving LMWH had significantly lower rates of hospital mortality (P = 0.009) and major bleeding (P < 0.0001). Similar results were observed in patients with ST-segment elevation myocardial infarction and non-ST-segment elevation myocardial infarction or unstable angina. We can conclude that UFH tends to be used more frequently than LMWH, but hospital outcomes appeared to be better with LMWH after adjusting for covariables.