Effects of polymorphisms in chemokine ligands and receptors on susceptibility to coronary artery disease.

INTRODUCTION: Atherosclerosis, the underlying disorder of coronary artery disease (CAD), is an inflammatory process involving multiple molecular pathways. Chemokine-mediated mechanisms are potent regulators of atherosclerosis. Genetic variations that alter such signaling pathways could affect susceptibility to CAD. We investigated the effect of 5 common variations of chemokine and chemokine receptor genes (SDF1-3'A, CCR5-delta32, CCR2-64I, CX3CR1-V249I and CX3CR1-T280M) on predisposition to CAD. MATERIALS AND METHODS: The hypothesis was tested by screening the prevalence of the above polymorphisms in 210 angiographically diagnosed CAD patients (152 with history of acute coronary syndromes, 58 with stable disease) in comparison to 165 selected controls with negative coronary angiography. Genotyping was performed by PCR/RFLP analysis. RESULTS: There were no significant differences among cases and controls concerning allelic and genotypic frequencies of SDF1-3'A, CCR5-delta32, CCR2-64I and CX3CR1-V249I variations. A borderline higher allelic frequency of the M280 variant was observed in controls compared to CAD group (adjusted OR=0.65, 95% CI: 0.35-0.99, p=0.05). Subjects carrying at least one copy of the M280 allele were significantly more common in the control group, suggesting an atheroprotective effect of this variant (adjusted OR=0.58, 95% CI: 0.35-0.97, p=0.04). CONCLUSIONS: The study confers additional data in the field of genetic predisposition to CAD: it confirms the atheroprotective effect of the M280 variant in a completely different population and supports the role of the fractalkine-CX3CR1 pathway in atherosclerosis.

Phasic coronary blood flow velocity pattern and flow reserve in the atrium: regulation of left atrial myocardial perfusion.

OBJECTIVES: The purpose of this study was to assess rest and stress atrial coronary blood flow (CBF) velocity and flow reserve. BACKGROUND: Because of the limitations of the methods used until now for assessing myocardial perfusion (MP) in the small mass of atrial tissue, data are lacking for human atrial MP. METHODS: Seventeen patients with suitable coronary anatomy underwent CBF velocity measurements with the use of a Doppler guide wire in the proximal left circumflex coronary artery (LCx) and left atrial circumflex branch (LACB), at baseline and after adenosine administration. All measurements were performed at resting heart rate and at 100 and 120 beats/min. RESULTS: Coronary blood flow velocity in the LACB showed a predominant systolic pattern in contrast to the diastolic pattern of the LCx. There was a disproportionate increase in baseline time-averaged peak coronary flow velocity (cm/s) between the LACB and LCx during the two levels of pacing-induced stress (16.8 +/- 5.5 vs. 16.2 +/- 5.1 at rest; 22.9 +/- 7.9 vs. 18.4 +/- 5.2 at 100 beats/min; and 27.1 +/- 8.0 vs. 20.4 +/- 5.1 at 120 beats/min; significant interaction, p < 0.001), but there were no significant differences in coronary flow reserve (CFR). CONCLUSIONS: Coronary blood flow in the left atrium is out of phase with that in the ventricular myocardium, showing a predominant systolic pattern. Although atrial and ventricular CFR show no significant differences at rest and with two levels of stress, the disproportionate increase in atrial blood flow velocity during stress indicates a peculiarity of atrial perfusion regulation.

Left ventricular mechanics during right ventricular apical or left ventricular-based pacing in patients with chronic atrial fibrillation after atrioventricular junction ablation.

OBJECTIVES: The aim of the study was to evaluate whether left ventricular (LV) mechanics are better under LV-based pacing than under right ventricular (RV) apical pacing in patients with permanent atrial fibrillation (AF) after atrioventricular junction (AVJ) ablation. BACKGROUND: "Ablate and pace" is an acceptable therapy for drug-refractory AF. However, the RV apical stimulation commonly used seems to interfere with the beneficial hemodynamic effect of regularization of heart rhythm. METHODS: The study included 12 patients (5 men, mean age 62 +/- 8.3 years), 6 with impaired and 6 with normal LV systolic function. All of them had a biventricular pacemaker system implanted and underwent atrioventricular node ablation for drug-refractory chronic AF. Using a conductance catheter, we analyzed LV pressure-volume loops during routine coronary angiography in order to evaluate short-term changes in LV mechanics during RV apical and LV-based (LV free wall or biventricular) pacing. RESULTS: Compared with RV pacing, LV-based pacing significantly improved the indexes of LV systolic function (i.e., end-systolic pressure and volume, cardiac index, stroke work, preload recruitable stroke work, maximal rate of rise of LV pressure [dP/dt(max)], LV ejection fraction, and end-systolic elastance). The LV diastolic filling indexes, end-diastolic pressure and volume, were better during LV-based pacing, whereas LV diastolic function indexes, -dP/dt(max), passive diastolic chamber stiffness, and time constant of LV isovolumic relaxation showed no clear change. CONCLUSIONS: In the short term, LV-based pacing is superior to RV apical pacing in terms of contractile function and LV filling after AVJ ablation for drug-refractory AF.

Left ventricular mechanics and myocardial blood flow following restoration of normal activation sequence in paced patients with long-term right ventricular apical stimulation.

STUDY OBJECTIVES: Asynchronous ventricular activation, as induced by ventricular pacing, is known to affect left ventricular (LV) systolic and diastolic function and myocardial blood flow. However, it is not clear whether the long-term disturbances it causes are reversible after the restoration of the normal ventricular activation sequence. DESIGN: In this study, we used the conductance catheter method and a Doppler guidewire to assess the changes in LV mechanics, and correspondingly in myocardial blood flow, after the restoration of the normal ventricular activation sequence in patients with long-term right ventricular apical pacing. PATIENTS: Sixteen patients (mean [+/- SD] age, 61 +/- 11 years; 9 men) with right ventricular apical stimulation and complete ventricular pacing capture for a very long period were studied. In eight patients, we analyzed pressure-volume loops before and immediately after the restoration of the normal ventricular activation sequence, and in the remaining eight patients the myocardial blood flow and flow reserve were analyzed. MEASUREMENTS AND RESULTS: End-systolic elastance (Ees) [5.503 +/- 0.6 vs 4.287 +/- 0.28 mm Hg/mL, respectively; p = 0.003] and its ratio to effective arterial elastance (1.63 +/- 0.51 vs 2.00 +/- 0.64, respectively; p = 0.009), which are indexes of systolic function and ventriculoarterial coupling, respectively, improved significantly after restoration of the normal ventricular activation sequence. Indexes of diastolic function and the predicted myocardial oxygen consumption (MO(2)) showed no clear change. Coronary flow in the dominant coronary artery increased significantly (46.55 +/- 14.12 vs 71.55 +/- 27.53 mL/min, respectively; p = 0.002), while the coronary flow reserve in the same artery decreased (3.5 +/- 1.0 vs 2.6 +/- 0.5, respectively; p = 0.008). CONCLUSIONS: The restoration of a normal activation sequence after long-term ventricular asynchrony enhances acutely contractile function without affecting MO(2). These changes in LV function do not appear to have causal relationships with myocardial blood flow changes.

Pharmacological cardioversion of recent onset atrial fibrillation with intravenous amiodarone in patients receiving long-term amiodarone therapy: is it reasonable?

In clinical practice the use of intravenous amiodarone has been proposed for the conversion of recurrent atrial fibrillation in patients already under chronic treatment with the same drug. Given that intravenous amiodarone exhibits different electrophysiological properties than when the drug is taken orally over a long period, this approach seems reasonable, but its effectiveness and safety have not been investigated systematically before. Of 45 patients under chronic treatment with amiodarone for the maintenance of sinus rhythm who had atrial fibrillation of recent onset, 23 were given intravenous loading of the same drug for 24 hours and 22 received placebo. Nine patients underwent an electrophysiological study several months after the successful restoration of sinus rhythm, before and after another intravenous loading dose of amiodarone, in order to examine the possible electrophysiological changes. In the amiodarone group 20 patients were successfully converted to sinus rhythm, compared to 13 of the placebo group (p < 0.05). No serious side effects of the intravenous administration were observed. Prolongation of refractoriness was seen in all 9 patients who underwent electrophysiological study after intravenous loading, without any effect on repolarization, atrioventricular conduction or sinus node function. In conclusion an intravenous loading dose of amiodarone exerts an additional electrophysiological effect in patients already under chronic treatment with the same drug. Such a combined therapy could be used with a high efficacy and safety for the conversion of recent onset atrial fibrillation in patients who are receiving long-term amiodarone therapy.

Early cardiac gene transcript levels in peripheral blood mononuclear cells reflect severity in stable coronary artery disease.

INTRODUCTION: The early cardiac marker genes myocardin, GATA4 and Nkx2.5, play a role in both embryonic cardiovascular development and adult cardiovascular disease. We evaluated transcript levels of myocardin, GATA4 and Nkx2.5 in peripheral blood mononuclear cells (PBMCs) in patients with stable coronary artery disease (CAD) and we examined the relationship between these levels and the severity of the disease, estimated by the number of stenotic vessels involved. METHODS: Ninety-eight patients with stable CAD (age 66 ± 9 years) who underwent coronary angiography participated in the study; 66 healthy individuals (age 58 ± 13 years) were also included for comparison. Gene transcript levels were determined by quantitative real-time reverse transcription polymerase chain reaction. RESULTS: Patients with 3-vessel CAD had elevated transcript levels of myocardin (median difference 2.7, p=0.001, 95% confidence interval, CI: 1-5.8), GATA4 (median difference 0.3, p=0.015, 95% CI: 0.1-1.9) and Nkx2.5 (median difference 16.1, p<0.001, 95% CI: 4.5-23) compared to healthy controls. Patients with 3-vessel CAD also showed elevated transcript levels of myocardin (median difference 2.3, p=0.001, 95% CI: 0.49-5.5) and Nkx2.5 (median difference 11.8, p<0.001, 95% CI: 1.5-21.5) compared to patients with 1-vessel CAD. CONCLUSIONS: Early cardiac marker gene transcript levels are significantly higher in the PBMCs of patients with severe stable CAD than in those of healthy controls, and show alterations in their expression profile according to the disease severity status. Our results indicate for the first time that changes in the early cardiac gene expression in the peripheral blood of stable CAD patients, possibly as a result of alterations in circulating cardiovascular progenitor cells that express these genes, may reflect the level of disease severity.

Oxidative stress changes after stent implantation: a randomized comparative study of sirolimus-eluting and bare metal stents.

BACKGROUND: Although oxidative stress plays an important role in the pathophysiology of restenosis, its role following the implantation of sirolimus-eluting stents (SES) is unknown. METHODS: We examined the relation between total peroxides (TP), a marker of oxidative stress, and in-stent late luminal loss over a 6-month follow-up in patients with stable coronary artery disease and compared the results from SES with those from bare metal stents (BMS). We enrolled 75 consecutive patients, who underwent successful PCI and were randomly allocated to SES (n=37) or BMS (n=38). Blood samples were taken 24 h before, at 24 h, 48 h and 1 month after angioplasty; levels of TP were determined on each occasion. Follow-up coronary angiography was performed 6-8 months later. RESULTS: TP levels in the BMS group were significantly higher at 24 h and 48 h compared to baseline (p=0.006 for both). At one month there was a significant decline from the 48 h levels (p=0.029) to levels slightly, but not significantly higher than baseline. In contrast, in SES TP levels showed no significant changes during the first 48 h, while they declined to levels somewhat lower than baseline at 30 days. A significant correlation was found between TP changes and in-stent late luminal loss at 6 months in both groups. CONCLUSION: Our study showed that patients with stable coronary artery disease who received SES have a different behavior of oxidative stress after stenting compared with BMS, and this could contribute to the difference in restenosis rate between these 2 types of stents.

Vascular endothelial growth factor protein levels and gene expression in peripheral monocytes after stenting: a randomized comparative study of sirolimus: eluting and bare metal stents.

AIMS: Although previous studies have indicated that vascular endothelial growth factor (VEGF) plays an important role in the vascular-healing process after stent implantation, its effect on in-stent restenosis is unclear. We assessed VEGF serum protein levels and gene expression in peripheral monocytes in relation to in-stent restenosis after implantation of sirolimus-eluting (SES) and bare metal stents (BMS) in a non-blinded, randomized study. METHODS AND RESULTS: Forty-two patients (28 men, age 62 +/- 11 years) with stable angina, who underwent elective single-vessel percutaneous coronary intervention, were randomized to SES (n = 21) or BMS (n = 21) implantation. VEGF protein levels in the BMS group showed an increasing trend (P = 0.083), whereas in the SES group they decreased significantly (P = 0.002). BMS induced up-regulation of VEGF mRNA levels, whereas for SES down-regulation was observed. There was no correlation between serum levels and late luminal loss. A significant correlation was found between VEGF gene expression and late luminal loss in both groups (BMS: r = 0.98, P < 0.001; SES: r = 0.65, P = 0.002). CONCLUSION: SES, in comparison with BMS, results in lower VEGF protein levels and gene expression in peripheral monocytes. The latter shows a positive relationship with in-stent late-luminal loss, suggesting an essential role in the reduced in-stent restenosis seen in SES.

Combined use of aspiration catheter and distal embolisation protection device to facilitate angioplasty of a totally occluded saphenous vein graft.

Angioplasty of totally occluded saphenous vein grafts is a very challenging procedure and the likelihood of distal embolisation and no-reflow is much higher than in any conventional angioplasty. The use of thrombus aspiration and distal protection devices, although not well studied in a large number of patients, has been shown to be quite effective in preventing such complications. In this case we report our satisfactory experience from the combined use of a novel aspiration catheter and a distal protection device for the treatment of a totally occluded saphenous vein graft.

Effect of inhaled salbutamol on coronary circulation in humans.

In 12 patients we assessed the effect of inhaled salbutamol on the coronary circulation. According to our results, large doses of salbutamol increase coronary flow, but not in proportion to the needs of the myocardium (as documented by the increase in coronary oxygen extraction), and decrease coronary flow reserve. These effects may have deleterious consequences in patients with coronary artery disease, causing or worsening myocardial ischemia.

Efficacy and safety of oral amiodarone in controlling heart rate in patients with persistent atrial fibrillation who have undergone digitalisation.

INTRODUCTION: Oral amiodarone has been suggested by some authors for rate control in patients with persistent atrial fibrillation. In this study we evaluated the efficacy and safety of oral amiodarone versus placebo for rate control during exercise and daily activities in patients with chronic atrial fibrillation who had undergone digitalisation. METHODS: The study group consisted of 53 patients (35 men, mean age 65 +/- 9 years) with persistent atrial fibrillation (mean duration 17 +/- 7 months). All patients had therapeutic levels of digitalis and were under anticoagulation treatment with acenocoumarol. Twenty-eight of them were treated with amiodarone (200 mg per day orally) and 25 received placebo. All patients were assessed with 24-hour ECG monitoring, a maximal symptom-limited cardiopulmonary exercise test and evaluation of adverse events. RESULTS: The mean exercise duration was similar in both groups. Amiodarone produced a lower heart rate than placebo at all exercise levels (p<0.0001 for all). VO2 was similar in both groups whereas O2 pulse was higher in the amiodarone group at all exercise levels. During daily life, heart rate showed a significant circadian pattern in both groups, with higher values during the day than at night (time effect for both p<0.001). The mean value of heart rate under amiodarone was lower than for placebo (75 +/- 10 vs. 86 +/- 12/min, p<0.001) but this difference was due to a significant difference during the day (p<0.001) that was not present during the night (p =0.48). CONCLUSIONS: Oral amiodarone is very effective when combined with digoxin for control of heart rate in patients with chronic atrial fibrillation and it should be considered as an alternative treatment when more traditional drugs, such as Ca(+2) inhibitors or b-blockers have proven ineffective or are contraindicated.