Ming Long

The Role of Macrolide Antibiotics in Increasing Cardiovascular Risk

BACKGROUND Large cohort studies provide conflicting evidence regarding the potential for oral macrolide antibiotics to increase the risk of serious cardiac events. OBJECTIVES This study performed a meta-analysis to examine the link between macrolides and risk of sudden cardiac death (SCD) or ventricular tachyarrhythmias (VTA), cardiovascular death, and death from any cause. METHODS We performed a search of published reports by using MEDLINE (January 1, 1966, to April 30, 2015) and EMBASE (January 1, 1980, to April 30, 2015) with no restrictions. Studies that reported relative risk (RR) estimates with 95% confidence intervals (CIs) for the associations of interest were included. RESULTS Thirty-three studies involving 20,779,963 participants were identified. Patients taking macrolides, compared with those who took no macrolides, experienced an increased risk of developing SCD or VTA (RR: 2.42; 95% CI: 1.61 to 3.63), SCD (RR: 2.52; 95% CI: 1.91 to 3.31), and cardiovascular death (RR: 1.31; 95% CI: 1.06 to 1.62). No association was found between macrolides use and all-cause death or any cardiovascular events. The RRs associated with SCD or VTA were 3.40 for azithromycin, 2.16 for clarithromycin, and 3.61 for erythromycin, respectively. RRs for cardiovascular death were 1.54 for azithromycin and 1.48 for clarithromycin. No association was noted between roxithromycin and adverse cardiac outcomes. Treatment with macrolides is associated with an absolute risk increase of 118.1 additional SCDs or VTA, and 38.2 additional cardiovascular deaths per 1 million treatment courses. CONCLUSIONS Administration of macrolide antibiotics is associated with increased risk for SCD or VTA and cardiovascular death but not increased all-cause mortality.

Effectiveness and Safety of Warfarin in Dialysis Patients With Atrial Fibrillation: A Meta-Analysis of Observational Studies

AbstractIn routine practice, warfarin is widely used in dialysis patients with atrial fibrillation (AF) for stroke prevention though the ratio of risks to benefits remains unclear. Recent cohort studies investigating the association between warfarin use and the risks of stroke and bleeding in dialysis patients with AF present conflicting results.The objective of this study was to assess the effectiveness and safety of warfarin use in patients with AF undergoing dialysis.Three databases PubMed, EMBASE, and OVID were searched from their inception to August 2015.Observational studies which assessed the ischemic stroke or bleeding risk of warfarin use in dialysis patients with AF were included. Two reviewers independently extracted data and assessed methodological quality based on the Newcastle–Ottawa Scale score. Combined hazard ratios (HRs) and 95% confidence intervals (CIs) were calculated using the random-effects model and heterogeneity was assessed based on the Cochrane Q-statistic test and the I2 statistic. Metaregression analyses were performed to explore the source of heterogeneity.A total of 11 eligible studies with 25,407 patients were included in the analysis. Warfarin use, in comparison with no-warfarin use, was not associated with a lower risk for ischemic stroke (HR 0.95, 95% CI 0.66–1.35). Sensitivity analyses found results to be robust. Metaregression analysis showed that demographic feature, clinical characteristics, or study-level variable had no impact of warfarin use on stroke risk. In addition, warfarin use was associated with a 27% higher risk for bleeding (95% CI 1.04–1.54). Overall, warfarin use did not have a significant association with reduced mortality (95% CI 0.96–1.11).It appears that warfarin use is not beneficial in reducing stroke risk, but with a high risk for bleeding in dialysis patients with AF. Randomized trials are needed to determine the risk-benefit ratio of warfarin in dialysis patients with AF.

PDE5 inhibitor sildenafil in the treatment of heart failure: A meta-analysis of randomized controlled trials

BACKGROUND Clinical trials have evaluated the use of phosphodiesterase (PDE) 5 inhibitors sildenafil as a potential adjunct in the treatment of heart failure (HF) with mixed results. Thus, we undertook a meta-analysis to evaluate the clinical viability of sildenafil in HF. METHODS Relevant studies were searched and identified in the MEDLINE and EMBASE databases. Randomized clinical trials (RCT) comparing sildenafil to placebo, in heart failure patients, reporting at least one outcome of interest were included. Data were extracted regarding the characteristics and clinical outcomes. RESULTS We identified 9 RCTs enrolling 612 HF patients. There were no significant differences in adverse events between sildenafil group and placebo group (RR=1.10, 95% CI=0.74 to 1.65, P=0.41), whereas sildenafil therapy was associated with a marked improvement in hemodynamic parameter peak VO2 (MD=3.25, 95% CI=2.07 to 4.42, P<0.00001) in HF with reduced ejection fraction (HFrEF) patients but not in HF with preserved ejection fraction (HFpEF) patients. Also, sildenafil therapy improved VO2 at anaerobic threshold (AT) (MD=3.47, 95% CI=1.68 to 5.27, P=0.0002), VE/VCO2 slope (MD=-7.06, 95% CI=-8.93 to -5.19, P<0.00001) and LV ejection fraction (MD=5.43, 95% CI=3.66 to 7.20, P<0.00001) compared to placebo in HF patients, which had no impact on blood pressure and heart rate. For quality of life (emotional function, fatigue and breathlessness), there was no significant difference between the two groups. CONCLUSIONS Sildenafil improved hemodynamic parameters particularly in HFrEF patients when compared to placebo, with no increase in adverse events. Sildenafil treatment was well tolerated and had no impact on quality of life.

Thermodilution-Derived Coronary Microvascular Resistance and Flow Reserve in Patients With Cardiac Syndrome X

Background—Although increased coronary microvascular resistance (CMR), resulting in coronary microvascular dysfunction, is speculated to be responsible for myocardial ischemia in patients with cardiac syndrome X (CSX), it has never been directly demonstrated, and the correlation between CMR and severity of myocardial ischemia has not been elucidated in this setting. This study aimed to ascertain the increased CMR directly and to explore the relationship between CMR and severity of ischemia in patients with CSX. Methods and Results—We studied 18 patients with CSX and 18 age- and sex-matched control subjects. Thermodilution-derived coronary flow reserve and index of microvascular resistance were measured using a pressure–temperature sensor-tipped coronary wire. Exercise treadmill test was performed by the Bruce protocol for calculating Duke treadmill score. Coronary flow reserve was significantly lower (2.37±0.81 versus 3.68±0.72; P<0.001) and index of microvascular resistance was higher (33.1±7.9 versus 18.8±5.6 U; P<0.001) in patients with CSX compared with those in control subjects. The Duke treadmill score was correlated positively to coronary flow reserve (r=0.539; P=0.021) and negatively to index of microvascular resistance (r=−0.742; P<0.001) in patients with CSX. Conclusions—Using an intracoronary thermodilution method, we for the first time directly demonstrated an increased microvascular resistance in patients with CSX. Furthermore, severity of ischemia was found to be intimately associated with CMR in this setting.

Change in high-sensitive C-reactive protein during abdominal aortic aneurysm formation.

Objectives We try to clear the relationship between high-sensitive C-reactive protein (hsCRP) release and abdominal aortic aneurysm formation. Methods and results A rabbit abdominal aortic aneurysm model was created by elastase perfusion. At days 10, 20, and 30 after elastase perfusion, mean serum hsCRP levels detected by ELISA increased over 200% over their basal level (n = 11, P < 0.05). Serum hsCRP levels were significantly higher in the aneurysm groups than in the sham controls by day 5 (n = 11, P < 0.05) and were positively correlated with percentage vessel diameter changes in the aneurysm group by day 10 (r = 0.8012, n = 33, P < 0.05). In the aneurysm group, increased serum CRP was derived from the liver in early stages, yet from dilated vessels in the later stages, as shown by immunostaining, western blot, and reverse transcriptase-PCR. Similar increased hsCRP levels were also observed in dissected rabbit aortic ring explants from the aneurysm model. Pretreatment with the stretch-activated channel blockers gadolinium or streptomycin, as well as nuclear factor-κB inhibitor SN50, blocked hsCRP production in the dilated aortic rings. Stretch-activated channel blockers also inhibited the activation of nuclear factor-κB. Conclusion During abdominal aortic aneurysm formation, increased serum hsCRP levels derive from aneurysmal arteries with degenerating elastic lamina. This process is mediated by mechanical stretch-activated channel-dependent nuclear factor-κB translocation to the nucleus.

Thermodilutional Confirmation of Coronary Microvascular Dysfunction in Patients With Recurrent Angina After Successful Percutaneous Coronary Intervention

BACKGROUND Recurrent angina (RA) after percutaneous coronary intervention (PCI) remains a challenging problem that confronts cardiologists in routine clinical practice. In patients without epicardial coronary causes, RA is commonly speculated as resulting from coronary microvascular dysfunction. The aim of this study was to investigate the coronary microvascular function in patients with RA late after successful PCI and without epicardial stenosis at the time of repeat angiography. METHODS We studied 39 consecutive patients with RA in whom PCI was successfully performed 6 to 12 months previously because of angina and single-vessel disease and without restenosis and disease progression at the time of repeat angiography. Twelve subjects without RA were recruited as the control group. Thermodilution-derived coronary flow reserve (CFR) and index of microvascular resistance (IMR) were measured using a pressure-temperature sensor-tipped coronary wire. The exercise treadmill test was performed according to the Bruce protocol. RESULTS Patients with RA showed significantly higher IMR and lower CFR than control subjects, in the target arteries and in the reference vessels (P < 0.05). The hyperemic IMR was more remarkably increased in the target arteries than in the reference vessels (29.3 ± 11.7 vs 24.4 ± 9.7; P = 0.008). The hyperemic IMR was increased and the CFR was impaired more significantly in patients with a positive exercise treadmill test (P < 0.05). CONCLUSIONS Using an intracoronary thermodilution method, to our knowledge, we have for the first time confirmed that, in patients who underwent successful coronary stenting and without epicardial stenosis at repeat angiography late after PCI, coronary microvascular dysfunction was responsible for the RA.

Relationship Between Mean Platelet Volume and Coronary Blood Flow in Patients with Atrial Fibrillation

INTRODUCTION Atrial fibrillation (AF) is associated with impaired coronary flow by means of Thrombolysis in Myocardial Infarction (TIMI) frame count (TFC). Mean platelet volume (MPV) is elevated in patients with AF. In the present study we aimed to investigate the relationship between MPV and TFC in patients with AF in the absence of obstructive coronary artery disease (CAD). METHODS This observational study enrolled 185 AF patients and 189 control subjects, all with angiographically documented normal coronary arteries. MPV was measured at baseline and mean TFC was assessed after diagnostic coronary angiography. RESULTS The MPV was 9.95±1.32 in the AF group and 9.02±1.16 in the control group (p<0.001). In AF patients, MPV was significantly correlated with mean TFC (r=0.419, p<0.001), AF duration (r=0.407, p<0.001), AF classification (r=0.378, p<0.001), systemic hypertension (r=0.165, p=0.024), diabetes mellitus (r=0.233, p=0.001), left ventricular ejection fraction (r=-0.347, p<0.001), and baseline use of diuretics (r=0.177, p=0.016). In linear regression analysis, mean TFC, left ventricular ejection fraction and diabetes mellitus were found to be independently associated with MPV (p<0.001, p=0.028 and p=0.045 respectively). CONCLUSION Mean platelet volume seems to be independently associated with coronary blood flow in patients with atrial fibrillation in the absence of obstructive coronary artery disease.

Thrombin and its receptor enhance ST-segment elevation in acute myocardial infarction by activating the KATP channel.

ST-segment elevation is the major clinical criterion for committing patients with chest pain to have emergent coronary revascularizations; however, the mechanism responsible for ST-segment elevation is unknown. In a guinea pig model of ST-segment elevation acute myocardial infarction (AMI), local application of hirudin, a thrombin antagonist, significantly decreased AMI-induced ST-segment elevation in a dose-dependent manner. Hirudin-induced (5 antithrombin units [ATU]) decrease in ST elevation was reversed by 250 nmol/L thrombin receptor activator peptide (TRAP). TRAP (250 nmol/L [100 µL]) significantly induced ST-segment elevation in hearts without AMI. The TRAP effect was blocked by 4 mg/kg glibenclamide and 4 mg/kg HMR1098 and partially blocked by 3 mg/kg 5HD. Pinacidil (0.45 mg/kg) simulated the effect of TRAP (250 nmol/L [100 µL]) on hearts without AMI. Moreover, single-channel recordings showed that TRAP induced ATP-sensitive K+ channel (KATP channel) activity, and this effect was blocked by HMR1098 but not 5HD. Finally, TRAP significantly shortened the monophasic action potential (MAP) at 90% repolarization (MAP90) and epicardial MAP (EpiMAP) duration. These effects of TRAP were completely reversed by HMR1098 and partially reversed by 5HD. Thrombin and its receptor activation enhanced ST-segment elevation in an AMI model by activating the sarcolemmal KATP channel.

Thrombin receptor and ventricular arrhythmias after acute myocardial infarction.

The mechanism mediating the development of ventricular arrhythmia (VA) after acute myocardial Infarction (AMI) Is still uncertain. Thrombin receptor (TR) activation has been proven to be arrhythmogenic in many other situations, and we hypothesize that it may participate in the genesis of post-AMI VA. Using a left coronary artery ligation rat model of AMI, we found that a local injection of hirudin into the left ventricle (LV) significantly reduced the ratio of VA durations to infarction sizing, whereas injection of thrombin receptor-activating peptide (TRAP) increased the ratios of VA duration to infarction sizing. The effects of TR activation on whole-cell currents were investigated in isolated myocytes. TRAP increased a glibenclamide-sensitive outward current. Pretreatment of rats with glibenclamide (4 mg/kg intraperitoneally) eliminated the effects of a local injection of TRAP on the ratios of VA durations to infarction sizing. TR mRNA and protein expression in the ischemic left ventricle had reached its peak by 20 min postligation in the rat AMI model (P < 0.05). TR-immunoreactive myocytes were observed in infarcted LV but were seldom seen in the right ventricle or in the normal heart. By 60 min, TR transcript levels had returned to control levels. We conclude that increased TR activation and expression in the infarcted LV after AMI may contribute to VA through a mechanism involving glibenclamide-sensitive potassium channels.

Association of Inflammation and Endothelial Dysfunction with Coronary Microvascular Resistance in Patients with Cardiac Syndrome X

Background Although a proportion of CSX patients have impaired brachial artery flow-mediated dilatation (FMD) in response to hyperemia, suggesting that endothelial dysfunction in these patients may be systemic and not just confined to the coronary circulation; the underlying mechanisms triggering endothelial dysfunction in these patients are still incompletely understood. Objectives To assess the association of the index of Microcirculatory Resistance (IMR) with endothelial dysfunction and inflammation in patients with CSX. Methods We studied 20 CSX patients and 20 age and gender-matched control subjects. Thermodilution-derived coronary flow reserve (CFR) and IMR were measured using a pressure-temperature sensor-tipped guidewire. Brachial artery FMD was measured using high-resolution, two-dimensional ultrasound images obtained with a Doppler ultrasound device (HDI-ATL 5000, USA) with a 5 MHz to 12 MHz linear-array transducer. Results Compared with in control subjects, CFR was significantly lower (2.42 ± 0.78 vs. 3.59 ± 0.79, p < 0.001); IMR was higher (32.2 ± 8.0 vs. 19.5 ± 5.5, p < 0.001); the concentration of hs-CRP and FMD was higher (4.75 ± 1.62 vs. 2.75 ± 1.50; 5.24 ± 2.41 vs. 8.57 ± 2.46, p < 0.001) in CSX patients. The Duke treadmill score (DTS) was correlated positively to CFR and FMD (0.489 and 0.661, p < 0.001), it was negative to IMR and hsCRP (-0.761 and -0.087, p < 0.001) in CSX patients. Conclusions The main finding in this study is that the DTS measured in patients with CSX was associated to hsCRP and FMD. Moreover, the independent effects of exercise tolerance can significantly impair FMD and hsCRP in CSX patients; especially it is particularly important to whom where FMD was associated negatively with IMR.