Arrhythmia monitoring and outcome after myocardial infarction (BIO|GUARD-MI): a randomized trial.

Objectives: Cardiac arrhythmias predict poor outcome after myocardial infarction (MI). We studied if arrhythmia monitoring with an insertable cardiac monitor (ICM) can improve treatment and outcome. Design: BIO|GUARD-MI was a randomized, international open-label study with blinded outcome assessment. Setting: Tertiary care facilities monitored the arrhythmias, while the follow-up remained with primary care physicians. Participants: Patients after ST-elevation (STEMI) or non-ST-elevation MI with an ejection fraction >35% and a CHA2DS2-VASc score ≥4 (men) or ≥5 (women). Interventions: Patients were randomly assigned to receive or not receive an ICM in addition to standard post-MI treatment. Device-detected arrhythmias triggered immediate guideline recommended therapy changes via remote monitoring. Main outcome measures: MACE, defined as a composite of cardiovascular death or acute unscheduled hospitalization for cardiovascular causes. Results: 790 patients (mean age 71 years, 72% male, 51% non-STEMI) of planned 1,400 pts were enrolled and followed for a median of 31.6 months. At 2 years, 39.4% of the device group and 6.7% of the control group had their therapy adapted for an arrhythmia [hazard ratio (HR) = 5.9, P < 0.0001]. Most frequent arrhythmias were atrial fibrillation, pauses and bradycardia. The use of an ICM did not improve outcome in the entire cohort (HR = 0.84, 95%-CI: 0.65-1.10; P = 0.21). In secondary analysis, a statistically significant interaction of the type of infarction suggests a benefit in the pre-specified non-STEMI subgroup. Risk factor analysis indicates that this may be connected to the higher incidence of MACE in patients with non-STEMI. Conclusions: The burden of asymptomatic but actionable arrhythmias is large in post-infarction patients. However, arrhythmia monitoring with an ICM did not improve outcome in the entire cohort. Post-hoc analysis suggests that it may be beneficial in non-STEMI patients or other high-risk subgroups. Clinical Trial Registration: [https://www.clinicaltrials.gov/ct2/show/NCT02341534], NCT02341534.

Automatic daily remote monitoring in heart failure patients implanted with a cardiac resynchronisation therapy-defibrillator: a single-centre observational pilot study.

Introduction: The impact of remote monitoring (RM) on clinical outcomes in heart failure (HF) patients with cardiac resynchronisation therapy-defibrillator (CRT-D) implantation is controversial. This study sought to evaluate the performance of an RM follow-up protocol using modified criteria of the PARTNERS HF trial in comparison with a conventional follow-up scheme. Material and methods: We compared cardiovascular (CV) mortality (primary endpoint) and hospitalisation events for decompensated HF, and the number of ambulatory in-office visits (secondary endpoint) in CRT-D implanted patients with automatic RM utilising daily transmissions (RM group, n = 45) and conventional follow-up (CFU group, n = 43) in a single-centre observational study. Results: After a median follow-up of 25 months, a significant advantage was seen in the RM group in terms of CV mortality (1 vs. 6 death event, p = 0.04), although RM follow-up was not an independent predictor for CV mortality (HR = 0.882; 95% CI: 0.25-3.09; p = 0.845). Patient CV mortality was independently influenced by hospitalisation events for decompensated HF (HR = 3.24; 95% CI: 8-84; p = 0.022) during follow-up. We observed significantly fewer hospitalisation events for decompensated HF (8 vs. 29 events, p = 0.046) in the RM group. Furthermore, a decreased number of total (161 vs. 263, p < 0.01) and unnecessary ambulatory in-office visits (6 vs. 19, p = 0.012) were seen in the RM group as compared to the CFU group. Conclusions: Follow-up of CRT-D patients using automatic RM with daily transmissions based on modified PARTNERS HF criteria enabled more effective ambulatory interventions leading indirectly to improved CV survival. Moreover, RM directly decreased the number of HF hospitalizations and ambulatory follow-up burden compared to CRT-D patients with conventional follow-up.

Impact of remote monitoring in heart failure patients with cardiac implantable electronic devices during COVID-19 pandemic: a single center experience.

BACKGROUND: Coronavirus disease 2019 (COVID-19) had spread into a pandemic affecting healthcare providers worldwide. Heart failure patients with implanted cardiac devices require close follow-up in-spite of pandemic related healthcare restrictions. METHODS: Patients were retrospectively registered and clinical outcomes were compared of 61 remote monitored (RMG) versus 71 conventionally (in-office only) followed (CFG) cardiac device implanted, heart failure patients. Follow-up length was 12 months, during the COVID-19 pandemic related intermittent insitutional restrictions. We used a specified heart failure detection algorithm in RMG. This investigation compared worsening heart failure-, arrhythmia- and device related adverse events as primary outcome and heart failure hospitalization rates as secondary outcome in the two patient groups. RESULTS: No significant difference was observed in the primary composite end-point during the first 12 months of COVID-19 pandemic (p = 0.672). In RMG, patients who had worsening heart failure event had relative modest deterioration in heart failure functional class (p = 0.026), relative lower elevation of N terminal-pro BNP levels (p < 0.01) at in-office evaluation and were less hospitalized for worsening heart failure in the first 6 months of pandemic (p = 0.012) compared to CFG patients. CONCLUSIONS: Specified remote monitoring alert-based detection algorithm and workflow in device implanted heart failure patients may potentially indicate early worsening in heart failure status. Preemptive adequate intervention may prevent further progression of deteriorating heart failure and thus prevent heart failure hospitalizations.

Assessment of serum phenylalanine and tyrosine isomers in patients with ST-segment elevation vs non-ST-segment elevation myocardial infarction.

BACKGROUND: Under conditions of oxidative stress, hydroxyl radicals can oxidize phenylalanine (Phe) into various tyrosine (Tyr) isomers (meta-, ortho-, and para-tyrosine; m-, o-, and p-Tyr), depending on the location of the hydroxyl group on the oxidized benzyl ring. This study aimed to compare patients with ST-segment elevation myocardial infarction (STEMI) and non-STEMI (NSTEMI) and the serum levels of Phe and Tyr isomers at the aortic root and distal to the culprit lesion in both groups. METHODS: Forty-four patients participated in the study: 23 with STEMI and 21 with NSTEMI. Arterial blood samples were taken from the aortic root through a guiding catheter and from the culprit vessel segment distal from the primary lesion with an aspiration catheter, during the percutaneous coronary intervention. Serum levels of Phe, p-Tyr, m-Tyr, and o-Tyr were determined using reverse-phase high-performance liquid chromatography. RESULTS: Serum levels of Phe were significantly higher distal to the culprit lesion compared to the aortic root in patients with STEMI. Serum p-Tyr/Phe and m-Tyr/Phe concentration ratios were both lower distal to the culprit lesion than at the aortic root in patients with STEMI. There were no statistically significant differences with respect to changes in serum Phe and Tyr isomers distal to the culprit lesion compared to the aortic root in patients with NSTEMI. CONCLUSION: Our data suggest that changes in serum levels of different Tyr isomers can mediate the effects of oxidative stress during myocardial infarction.

Cardiac resynchronization therapy with intraoperative epicardial mapping via minithoracotomy: 10 years' experience.

BACKGROUND: Cardiac resynchronization therapy (CRT) is considered an efficient method to improve the left ventricular (LV) dysfunction with left bundle branch block. However, coronary venous anatomy is not appropriate in about 10% of the cases; thus other alternatives, such as epicardial lead implantation via minithoracotomy are needed. METHODS: During the period 2007-2017, a total of 57 patients were operated at our institute via left anterior minithoracotomy after an unsuccessful transvenous CRT. The best position of the LV epicardial electrode was determined by intraoperative epicardial mapping, that is locating the latest activation spot relative to the right ventricular (RV) electrode. The authors analyzed the survival by Kaplan-Meier estimator with Tarone-Ware equality test and multiple Cox regression analysis, the changes of the LV ejection fraction (LVEF) and dimensions, the development of the impedance and threshold of the LV epicardial electrode, the possible associations between the survival and intraoperative sensed RV-LV activation delay. RESULTS: The intraoperative RV-LV activation delay was 92.250 ± 26.538 milliseconds. There were no intraoperative complications except ventricular fibrillation in three patients. Within 30 days there were neither wound healing complications nor pocket hematoma. There was no significant difference in survival with regard to gender or etiology, but significantly better survival was found in the cohort with intraoperative sensed RV-LV activation delay >86 milliseconds. The LVEF and dimensions improved following the operation and continued to be improved in the survivors. CONCLUSION: CRT via minithoracotomy with epicardial mapping is a safe, efficient, simple, and reproducible second-line alternative to the transvenous method.

Transmission and loss of ECG snapshots: Remote monitoring in implantable cardiac monitors.

INTRODUCTION: Remote monitoring including transmission of electrocardiogram (ECG) strips has been implemented in implantable cardiac monitors (ICM). We appraise whether the physician can rely on remote monitoring to be informed of all possibly significant arrhythmias. METHODS: We analyzed remote monitoring transmissions of patients in the ongoing BIO|GUARD-MI study, in which Biotronik devices are used. Once per day, the devices automatically transmit messages with up to six ECG snapshots to the Home Monitoring Service Center. If more than one type of arrhythmia is recorded during a day, at least one ECG of each arrhythmia type is transmitted. RESULTS: 212 study patients were registered at the service center. The mean age of the patients was 70 ±â€¯8 years, and 74% were male. Patients were followed for an average of 13 months. The median time from device implantation until the first message receipt in the service center was 2 days. The median patient-individual transmission success was 98.0% (IQR 93.6-99.8) and remained stable in the second and third year. The most frequent arrhythmias were atrial fibrillation, bradycardia and high ventricular rate. 17.3% of the messages with ECG snapshots contained more than one arrhythmia type. DISCUSSION: Our analysis confirms that the physician can rely on Home Monitoring to be informed of all possibly significant arrhythmias during long-term follow-up. We have found hints that the transmission of only one episode per day may lead to the loss of clinically relevant information if patients with ICMs are followed by remote monitoring only.

Examination of Pituitary Adenylate Cyclase-Activating Polypeptide (PACAP) as a Potential Biomarker in Heart Failure Patients.

Pituitary adenylate cyclase-activating polypeptide (PACAP) is a pleiotropic and multifunctional neuropeptide having neurotrophic, neuroprotective, and general cytoprotective actions in a variety of tissues based on its anti-apoptotic, anti-inflammatory, and antioxidant effects. Several studies have demonstrated its cardioprotective effects in vitro and in various animal models. However, few data are available on the presence of PACAP in human cardiac tissues and its role in the pathomechanism and progression of different cardiac disorders, particularly heart failure. Earlier, our research group has shown PAC1 receptor immunoreactivity in human heart tissue samples and we have found significantly elevated PACAP27- and PACAP38-like immunoreactivity in ischemic cardiac samples compared to valvular abnormalities with radioimmunoassay. In the last few years, numerous studies examined the presence and the changes of PACAP levels in different human tissue samples and biological fluids to show alterations in different physiological and pathological conditions. Therefore, the aim of the present study was to measure the alterations of blood PACAP levels in chronic heart failure caused by primary dilated cardiomyopathy or ischemic cardiomyopathy and to examine the possible relationship between serum levels of PACAP, N-terminal prohormone of brain natriuretic peptide (NT-proBNP), and systolic left ventricular function, the most reliable biomarkers of heart failure. In the group of mild heart failure patients, a significant strong negative correlation was detected. Furthermore, in moderate heart failure, we found a significant moderate negative correlation between PACAP and NT-proBNP levels only in ischemic subgroup. Positive correlation was found between serum PACAP level and ejection fraction only in patients with heart failure due to ischemic cardiomyopathy but not in patients with primary dilated cardiomyopathy. In summary, remarkable differences were observed between the ischemic and non-ischemic heart failure suggesting that PACAP might play an important role in the pathomechanism and progression of ischemic heart failure and it might be a potential biomarker of cardiac diseases in the future.

Clinical outcomes in patients treated for coronary in-stent restenosis with drug-eluting balloons: Impact of high platelet reactivity.

BACKGROUND: The impact of high platelet reactivity (HPR) on clinical outcomes after elective percutaneous coronary interventions (PCI) with drug-eluting balloons (DEB) due to in-stent restenosis (ISR) is unknown. OBJECTIVE: We sought to evaluate the prognostic importance of HPR together with conventional risk factors in patients treated with DEB. METHODS: Patients treated with DEB due to ISR were enrolled in a single-centre, prospective registry between October 2009 and March 2015. Only patients with recent myocardial infarction (MI) received prasugrel, others were treated with clopidogrel. HPR was defined as an ADP-test >46U with the Multiplate assay and no adjustments were done based on results. The primary endpoint of the study was a composite of cardiovascular mortality, MI, any revascularization or stroke during one-year follow-up. RESULTS: 194 stable angina patients were recruited of whom 90% were treated with clopidogrel. Clinical characteristics and procedural data were available for all patients; while platelet function testing was performed in 152 subjects of whom 32 (21%) had HPR. Patients with HPR had a higher risk for the primary endpoint (HR: 2.45; CI: 1.01-5.92; p = 0.03). The difference was primarily driven by a higher risk for revascularization and MI. According to the multivariate analysis, HPR remained a significant, independent predictor of the primary endpoint (HR: 2.88; CI: 1.02-8.14; p = 0.04), while total DEB length and statin treatment were other independent correlates of the primary outcome. CONCLUSION: HPR was found to be an independent predictor of repeat revascularization and MI among elective patients with ISR undergoing PCI with DEB.

Effectiveness and safety of anti-ischemic trimetazidine in patients with stable angina pectoris and Type 2 diabetes.

Aim & methods: This 6-month prospective, observational, noninterventional, open-label clinical study assessed the effectiveness/safety of trimetazidine in 737 patients with stable angina pectoris and Type 2 diabetes mellitus (OGYI/51534-1/2014). RESULTS: Trimetazidine-based therapy was effective in stable coronary artery disease, with significant improvements from baseline (p < 0.05) in: number of angina attacks/week (2.9 ± 2.4 vs 1.1 ± 1.6), angina severity (Canadian Cardiovascular Society Classification 1.9 ± 0.8 vs 1.2 ± 0.8), exercise capacity (metabolic equivalents 6.1 ± 1.7 vs 6.5 ± 1.7), and exercise-induced myocardial ischemia (min 5.5 ± 2.5 vs 6.5 ± 2.6). DISCUSSION: Trimetazidine treatment significantly (p < 0.05) improved glucose metabolism, lowered HbA1c (7.1 ± 1.1% vs 6.6 ± 1.0%), glucose levels (7.7 ± 2.1 mmol/l vs 6.9 ± 1.6 mmol/l) and decreased arterial stiffness (pulse wave velocity 11.2 ± 2.1 m/s vs 10.4 ± 2.2 m/s). In most patients, the tolerability of trimetazidine was rated as excellent to good, with a low incidence of adverse events.

[Carvedilol in the everyday interventional cardiology practice]. / Carvedilol alkalmazása a mindennapi kardiológiai és intervenciós kardiológiai gyakorlatban.

The treatment of severe coronary stenoses with stent implantation is very effective nevertheless, the underlying problem of atherosclerosis remains unsolved with the implantation of a stent. Therefore, besides lifestyle changes, the adequate medication therapy is of pivotal importance. In the majority of patients scheduled for or acutely undergoing catheterisation, beta-blockers form the basis of medication therapy. Members of the group, however, show significant differences in terms of pharmacodynamics. The third-generation beta-blocker and vasodilator carvedilol possesses complex adrenerg-blocking and Ca-channel blocking effects as well. In the background of the favourable effects, a further positive property is its anti-free-radical effect which most beta-blockers do not have. Therefore, as has been proven by several studies, it provides considerable benefits in hypertension, after myocardial infarction, in diabetes and also in the treatment of patients with cardiac failure. These positive effects have been markedly observed in interventional cardiology practice, as the majority of patients undergoing cardiac catheterisation have hypertension, diabetes or hyperlipidaemia. Its anti-free-radical effect is especially beneficial together with its smooth muscle proliferation-inhibitor effect which may favourably affect in-stent restenosis (ISR) as well. To summarise, due to its vasculoprotective effect, carvedilol is an ideal drug of choice following stent implantation in routine everyday practice. Orv Hetil. 2017; 158(37): 1453-1457.

[Analysis of telemetry, on-line and non-telemetry data for characterization of the physical activity of patients with heart failure]. / Telemetriás és online nontelemetriás adatok elemzése szívelégtelen betegek fizikai aktivitásának jellemzésére.

INTRODUCTION: Several studies have demonstrated that the prevalence of heart disease can be accounted for between 0.4 and 2% in developed countries. AIM: The present study aimed to use the PA% of the telemetry data to estimate the 6-minute walk test result. METHOD: A total of seventeen patients with heart disease; 3 females and 14 males; age: 57.35 yrs ± 9.54; body mass 98.71 ± 9.89 kg; average BMI 36.69 ± 3.67 were recruited into the study. Using the two sets of values describing physical performance, linear regression was calculated providing a mathematical equation, thus, the Physical Activity % value is used to estimate the distance traveled over a 6-minute walk test. RESULTS: On further data analysis, we have come to the conclusion that the distance walked during the six-minute-long test may be measured by PA% from the data of CRT device. CONCLUSIONS: With our method, based on the values received from the physical activity sensor implanted into the resynchronisation devices, changes in patients' health status could be monitored telemetrically with the assistance from the implanted electronic device. Orv Hetil. 2017; 158(35): 1390-1395.

[Telemetry data based on comparative study of physical activity in patients with resynchronization device]. / Reszinkronizációs készülékkel élo betegek fizikai aktivitásának összehasonlító vizsgálata telemetriás adatok alapján.

INTRODUCTION: The effect of regular physical activity on health is widely recognized, but several studies have shown its key importance for heart patients. AIM: The present study aimed to define the PA % values, and to convert them into metabolic equivalent values (MET), which describes oxygen consumption during physical activity. METHOD: A total of seventeen patients with heart disease; 3 females and 14 males; age: 57.35 yrs ± 9.54; body mass 98.71 ± 9.89 kg; average BMI 36.69 ± 3.67 were recruited into the study. The measured values from Cardiac Resynchronisation Therapy devices and outer accelerometers (ActiGraph GT3X+) were studied over a 7-day time period. Using the two sets of values describing physical performance, linear regression was calculated providing a mathematical equation, thus, the Physical Activity values in percentage were converted into MET values. RESULTS: During the 6-minute walk test the patients achieved an average of 416.6 ± 48.2 m. During 6MWT the measured values averaged at 1.85 ± 0.18 MET's, and MET values averaged at 1.12 ± 0.06 per week. It clearly shows that this test is a challenge for the patients compared to their daily regular physical activity levels. CONCLUSION: With our method, based on the values received from the physical activity sensor implanted into the resynchronisation devices, changes in patients' health status could be monitored telemetrically with the assistance from the implanted electronic device. Orv Hetil. 2017; 158(17): 748-753.

Safety and effectiveness of combined antihypertensive and cholesterol-lowering therapy in high-/very high-risk patients.

AIM: Controlling cardiovascular (CV) risk factors is paramount in reducing atherosclerotic events. This 6-month prospective noninterventional trial assessed the safety and effectiveness of fixed-combination lisinopril-amlodipine plus rosuvastatin. PATIENTS & METHODS: Patients with mild/moderate hypertension and hypercholesterolemia, at high-/very high-CV risk, received lisinopril-amlodipine (10/5, 20/5 or 20/10 mg/day) plus rosuvastatin (10 or 20 mg/day). Primary end points: systolic/diastolic blood pressure, low-density lipoprotein cholesterol. RESULTS: At 6 months, 91% of 2241 evaluable patients achieved blood pressure target (<140/90 mmHg); low-density lipoprotein cholesterol targets, <3, <2.5 and 1.8 mmol/l, were achieved by 67, 49 and 40% of patients, respectively. Adverse events (4.4%) were mostly mild. CONCLUSION: Lisinopril-amlodipine plus rosuvastatin was well tolerated and effective in patients with mild/moderate hypertension and hypercholesterolemia at high/very high CV risk.

Apelin increases cardiac contractility via protein kinase Cε- and extracellular signal-regulated kinase-dependent mechanisms.

BACKGROUND: Apelin, the endogenous ligand for the G protein-coupled apelin receptor, is an important regulator of the cardiovascular homoeostasis. We previously demonstrated that apelin is one of the most potent endogenous stimulators of cardiac contractility; however, its underlying signaling mechanisms remain largely elusive. In this study we characterized the contribution of protein kinase C (PKC), extracellular signal-regulated kinase 1/2 (ERK1/2) and myosin light chain kinase (MLCK) to the positive inotropic effect of apelin. METHODS AND RESULTS: In isolated perfused rat hearts, apelin increased contractility in association with activation of prosurvival kinases PKC and ERK1/2. Apelin induced a transient increase in the translocation of PKCε, but not PKCα, from the cytosol to the particulate fraction, and a sustained increase in the phosphorylation of ERK1/2 in the left ventricle. Suppression of ERK1/2 activation diminished the apelin-induced increase in contractility. Although pharmacological inhibition of PKC attenuated the inotropic response to apelin, it had no effect on ERK1/2 phosphorylation. Moreover, the apelin-induced positive inotropic effect was significantly decreased by inhibition of MLCK, a kinase that increases myofilament Ca2+ sensitivity. CONCLUSIONS: Apelin increases cardiac contractility through parallel and independent activation of PKCε and ERK1/2 signaling in the adult rat heart. Additionally MLCK activation represents a downstream mechanism in apelin signaling. Our data suggest that, in addition to their role in cytoprotection, modest activation of PKCε and ERK1/2 signaling improve contractile function, therefore these pathways represent attractive possible targets in the treatment of heart failure.

Optimizing P2Y12 receptor inhibition in patients with acute coronary syndrome on the basis of platelet function testing: impact of prasugrel and high-dose clopidogrel.

OBJECTIVES: This study sought to evaluate the impact of treatment with prasugrel and high-dose clopidogrel on the basis of platelet function testing in patients with acute coronary syndrome (ACS) who are undergoing percutaneous coronary intervention (PCI). BACKGROUND: The clinical impact of treatment with prasugrel in patients with ACS who have high platelet reactivity (HPR) is unknown. METHODS: Patients with ACS who were pre-treated with clopidogrel and undergoing successful PCI were enrolled in a single-center, prospective registry. Platelet function was measured 12 to 36 h after PCI with the Multiplate device (Roche Diagnostics GmbH, Mannheim, Germany). Patients with HPR (>46 U) were switched to prasugrel or treated with high-dose clopidogrel, and those without HPR continued treatment with 75 mg of clopidogrel. RESULTS: A total of 741 consecutive patients were enrolled in the study between September 2011 and August 2012, and 219 of these patients (29.5%) had HPR. Although platelet reactivity decreased after treatment adjustments in those with HPR, prasugrel provided significantly more potent platelet inhibition compared with high-dose clopidogrel (p < 0.0001). Compared with patients without HPR, the risk of all-cause death, myocardial infarction, stent thrombosis, or stroke at 1 year was significantly higher in the high-dose clopidogrel group (hazard ratio [HR]: 2.27; 95% confidence interval [CI]: 1.45 to 3.55; p < 0.0001), and patients who were switched to prasugrel had similar outcomes (HR: 0.90; 95% CI: 0.44 to 1.81; p = 0.76). Bleeding Academic Research Consortium (BARC) type 3/5 bleeding was also more frequent in patients treated with high-dose clopidogrel (HR: 2.09; 95% CI: 1.05 to 4.17; p = 0.04) than in patients switched to prasugrel (HR: 0.45; 95% CI: 0.11 to 1.91; p = 0.28). In a multivariate model, HPR with high-dose clopidogrel, but not with prasugrel, was an independent predictor of the composite ischemic endpoint (HR: 1.90; 95% CI: 1.17 to 3.08; p = 0.01). CONCLUSIONS: Switching patients with ACS who have HPR to treatment with prasugrel reduces thrombotic and bleeding events to a level similar to that of those without HPR; however, there is a higher risk of both thrombotic and bleeding complications with high-dose clopidogrel.

BGP-15, a PARP-inhibitor, prevents imatinib-induced cardiotoxicity by activating Akt and suppressing JNK and p38 MAP kinases.

In this study, we investigate the cardiotoxic effects of the well-known cytostatic agent imatinib mesylate (Gleevec), and presented evidence for the cardioprotective effect of BGP-15 which is a novel insulin sensitizer. The cardiotoxic effect of imatinib mesylate was assessed in Langendorff rat heart perfusion system. The cardiac high-energy phosphate levels (creatine phosphate (PCr) and ATP) were monitored in situ by (31)P NMR spectroscopy. The protein oxidation, lipid peroxidation, and the activation of signaling pathways were determined from the freeze-clamped hearts. Prolonged treatment of the heart with imatinib mesylate (20 mg/kg) resulted in cardiotoxicity, which were characterized by the depletion of high-energy phosphates (PCr and ATP), and significantly increased protein oxidation and lipid peroxidation. Imatinib mesylate treatment-induced activation of MAP kinases (including ERK1/2, p38, and JNK) and the phosphorylation of Akt and GSK-3beta. BGP-15 (200 µM) prevented the imatinib mesylate-induced oxidative damages, attenuated the depletion of high-energy phosphates, altered the signaling effect of imatinib mesylate by preventing p38 MAP kinase and JNK activation, and induced the phosphorylation of Akt and GSK-3beta. The suppressive effect of BGP-15 on p38 and JNK activation could be significant because these kinases contribute to the cell death and inflammation in the isolated perfused heart.

The effect of clopidogrel besylate and clopidogrel hydrogensulfate on platelet aggregation in patients with coronary artery disease: a retrospective study.

BACKGROUND: Recently several alternative forms of the original clopidogrel hydrogensulfate (CHS) were spread worldwide. A large amount of such drugs turned out to be clopidogrel besylate (CB). Only three studies, involving healthy volunteers, investigated the antiplatelet effect of CB, whereas its attribute remained unexplored in the case of patients with cardiovascular diseases. This retrospective study aimed to evaluate the difference between the antiplatelet effects of two clopidogrel formulas, CHS and CB, on patients with coronary artery diseases. METHODS: Data of 150 patients with previous CHS treatment were investigated. According to the documentations, the CHS therapy was shifted to CB. 94 patients of the selected population received dual antiplatelet therapy, clopidogrel and aspirin. The antiplatelet effects of CHS and CB were compared by ADP induced platelet aggregation measurements using light transmission aggregometry. RESULTS: Irrespective of the therapeutic combinations the performed statistical investigations failed to show significant difference (p=0.30) between the effect of CB (AGGmax(CB): 27.6±13.7%) or CHS (AGGmax(CHS): 29.0±15.3%) on the ADP induced platelet aggregation. Insignificant deviations were found in both forms of clopidogrel salts, either in the lack (AGGmax(CB) : 32.5±14,2%; AGGmax(CHS): 34,0±16,1%; p=0,29) or in the presence of aspirin (AGGmax(CB): 24.7±12,5%; AGGmax(CHS): 26,0±14,1%; p=0,31). CONCLUSION: Our results indicated that both CB and CHS had an identical inhibitory effect on ADP induced platelet aggregation in patients with cardiovascular diseases. Moreover their efficiency showed no overall significant difference in the case of dual antiplatelet therapy with aspirin as well. However there might be an inter- and intraindividual variability between the two clopidogrel formulas.

Justification of 150 mg clopidogrel in patients with high on-clopidogrel platelet reactivity.

BACKGROUND: The GRAVITAS trial showed that 150 mg clopidogrel did not improve outcome in patients with high on-clopidogrel platelet reactivity (HPR) screened by the VerifyNow assay. We aimed to determine the impact of 150 mg clopidogrel in stable angina patients with HPR identified with conventional aggregometry (LTA). MATERIALS AND METHODS: Clopidogrel-naive stable angina patients before ad hoc percutaneous coronary intervention were recruited into a randomized, double-blind, placebo-controlled trial (NCT00638326). Twelve to 24 h after the 600-mg loading dose of clopidogrel, ADP(5µM)-stimulated maximal (AGGmax), late platelet aggregation (AGGlate) and vasodilator-stimulated phosphoprotein phosphorylation (VASP-PRI) were evaluated. Patients with HPR (AGGmax ≥ 34%) were randomly allocated to 75 or 150 mg clopidogrel after 4 weeks. After control platelet function measurements at day 28, 75 mg clopidogrel was administered to all patients until 1 year. RESULTS: The study was prematurely terminated at the stage of 200 enroled patients. Administration of 150 mg clopidogrel significantly reduced platelet aggregation (AGGmax: 45·0 ± 6·8 vs. 33·8 ± 15·1, P < 0·01; AGGlate: 27·1 ± 14·7 vs. 13·8 ± 18·0, P < 0·01) and VASP-PRI (57·5 ± 15·2 vs. 37·2 ± 17·1; P < 0·01), while platelet reactivity remained unchanged in patients with HPR receiving 75 mg clopidogrel. The higher maintenance dose of clopidogrel was associated with a significant reduction in cardiovascular (CV) death and myocardial infarction (MI) (0% vs. 11·4%, P = 0·04) and in CV death, MI or target vessel revascularization (24·6% vs. 3·1%; P = 0·01) during 1 year. CONCLUSIONS: One-month administration of 150 mg maintenance dose of clopidogrel reduces platelet reactivity and might decrease the risk of thrombo-ischaemic complications in stable angina patients with HPR identified by LTA.

Comparison of aortic and carotid arterial stiffness parameters in patients with verified coronary artery disease.

BACKGROUND: Arterial stiffness parameters are commonly used to determine the development of atherosclerotic disease. The independent predictive value of aortic stiffness has been demonstrated for coronary events. HYPOTHESIS: The aim of our study was to compare regional and local arterial functional parameters measured by 2 different noninvasive methods in patients with verified coronary artery disease (CAD). We also compared and contrasted these stiffness parameters to the coronary SYNTAX score in patients who had undergone coronary angiography. METHODS: In this study, 125 CAD patients were involved, and similar noninvasive measurements were performed on 125 healthy subjects. The regional velocity of the aortic pulse wave (PWVao) was measured by a novel oscillometric device, and the common carotid artery was studied by a Doppler echo-tracking system to determine the local carotid pulse wave velocity (PWVcar). The augmentation index (AIx), which varies proportionately with the resistance of the small arteries, was recorded simultaneously. RESULTS: In the CAD group, the PWVao and aortic augmentation index (Alxao) values increased significantly (10.1 ± 2.3 m/sec and 34.2% ± 14.6%) compared to the control group (9.6 ± 1.5 m/sec and 30.9% ± 12%; P < 0.05). We observed similar significant increases in the local stiffness parameters (PWVcar and carotid augmentation index [Alxcar]) in patients with verified CAD. Further, we found a strong correlation for PWV and AIx values that were measured with the Arteriograph and those obtained using the echo-tracking method (r = 0.57, P < 0.001 for PWV; and r = 0.65, P < 0.001 for AIx values). CONCLUSIONS: Our results indicate that local and regional arterial stiffness parameters provide similar information on impaired arterial stiffening in patients with verified CAD.

Role of reactive oxygen species in the regulation of cardiac contractility.

Increased production of reactive oxygen species (ROS) has been linked to the pathogenesis of contractile dysfunction in heart failure. However, it is unclear whether ROS can regulate physiological cellular processes in the myocardium. Here, we characterized the role of endogenous ROS production in the acute regulation of cardiac contractility in the intact rat heart. In isolated perfused rat hearts, endothelin-1 (ET-1, 1nmol/L) stimulated ROS formation in the left ventricle, which was prevented by the antioxidant N-acetylcysteine and the NAD(P)H oxidase inhibitor apocynin. N-acetylcysteine, the superoxide dismutase mimetic MnTMPyP, and apocynin significantly attenuated ET-1-mediated inotropic effect, which was accompanied by inhibition of extracellular signal regulated kinase 1/2 (ERK1/2) phosphorylation. Moreover, the mitochondrial K(ATP) channel blocker 5-HD, and the mitochondrial large conductance calcium activated potassium channel blocker paxilline, but not the sarcolemmal K(ATP) channel blocker HMR 1098 attenuated the inotropic response to ET-1. However, ET-1-induced ROS generation was not abolished by inhibiting mitochondrial K(ATP) channel opening. In contrast to ET-1 stimulation, the positive inotropic effect of ß(1)-adrenergic receptor agonist dobutamine (250nmol/L) was significantly augmented by N-acetylcysteine and apocynin. Moreover, dobutamine-induced phospholamban phosphorylation was markedly enhanced by apocynin. In conclusion, NAD(P)H oxidase-derived ROS play a physiological role in the acute regulation of cardiac contractility in the intact rat heart. Our results reveal that ET-1-induced increase in cardiac contractility is partially dependent on enhanced ROS generation, which in turn, activates the ERK1/2 pathway. On the other hand, ß-adrenergic receptor-induced positive inotropic effect and phospholamban phosphorylation is enhanced by NAD(P)H oxidase inhibition.