Ivabradine and Bisoprolol on Doppler-derived Coronary Flow Velocity Reserve in Patients with Stable Coronary Artery Disease: Beyond the Heart Rate.

INTRODUCTION: Coronary flow velocity reserve (CFVR) is an important prognostic marker in patients with stable coronary artery disease (CAD). Beta-blockers and ivabradine have been shown to improve CFVR in patients with stable CAD, but their effects were never compared. The aim of the current study was to compare the effects of bisoprolol and ivabradine on CFVR in patients with stable CAD. METHODS: Patients in sinus rhythm with stable CAD were enrolled in this prospective, randomized, double-blind trial. Patients had to be in a stable condition for at least 15 days before enrollment, on their usual therapy. Patients who were receiving beta-blockers or ivabradine entered a 2-week washout period from these drugs before randomization. Transthoracic Doppler-derived CFVR was assessed in left anterior descending coronary artery, and was calculated as the ratio of hyperemic to baseline diastolic coronary flow velocity (CFV). Hyperemic CFV was obtained using dipyridamole administration using standard protocols. After CFVR assessment, patients were randomized to ivabradine or bisoprolol and entered an up-titration phase, and CFVR was assessed again 1 month after the end of the up-titration phase. RESULTS: Fifty-nine patients (38 male, 21 female; mean age 69 ± 9 years) were enrolled. Transthoracic Doppler-derived assessment of CFV and CFVR was successfully performed in all patients. Baseline characteristics were similar between the bisoprolol and ivabradine groups. No patient dropped out during the study. At baseline, rest and hyperemic peak CFV as well as CFVR was not significantly different in the ivabradine and bisoprolol groups. After the therapy, resting peak CFV significantly decreased in both the ivabradine and bisoprolol groups, but there was no significant difference between the groups (ivabradine group 20.7 ± 4.6 vs. 22.8 ± 5.2, P < 0.001; bisoprolol group 20.1 ± 4.1 vs. 22.1 ± 4.3, P < 0.001). However, hyperemic peak CFV significantly increased in both groups, but to a greater extent in patients treated with ivabradine (ivabradine: 70.7 ± 9.4 vs. 58.8 ± 9.2, P < 0.001; bisoprolol: 65 ± 8.3 vs. 58.7 ± 8.2, P < 0.001). Accordingly, CFVR significantly increased in both groups (ivabradine 3.52 ± 0.64 vs. 2.67 ± 0.55, P < 0.001; bisoprolol 3.35 ± 0.70 vs. 2.72 ± 0.55, P < 0.001), but it was significantly higher in ivabradine group, despite a similar decrease in heart rate (63 ± 7 vs. 61 ± 6; P not significant). CONCLUSION: Ivabradine improves hyperemic peak CFV and CFVR to a greater extent than bisoprolol in patients with stable CAD, despite a similar decrease in heart rate. These data demonstrate that the benefits from ivabradine therapy go beyond the heart rate. This could be due to a different mechanism such as diastolic perfusion time, isovolumic ventricular relaxation, end-diastolic pressure, and collaterals. FUNDING: Servier.

Effects of ranolazine on noninvasive coronary flow reserve in patients with myocardial ischemia but without obstructive coronary artery disease.

INTRODUCTION: Ranolazine reduces the Na-dependent calcium overload via inhibition of the late sodium current, improving diastolic tone and oxygen handling during myocardial ischemia. In patients with angina, evidence of myocardial ischemia, but no obstructive coronary artery disease (CAD), abnormal coronary autoregulation plays a key role. Transthoracic Doppler-derived coronary flow reserve (CFR) is an index of coronary arterial reactivity and decreases in both microvascular dysfunction and coronary artery stenosis. The aim of this study was to assess the effect of ranolazine on CFR in this group of patient. METHODS: Fifty-eight (39M, 19F) patients with angina and evidence of myocardial ischemia, but no obstructive CAD, were enrolled in a double-blind, placebo-controlled trial. Participants were assigned to ranolazine (29) or placebo (29) for 8 weeks (up to 500 mg twice a day). CFR was determined as the ratio of hyperemic, induced by intravenous dypiridamole administration, to baseline diastolic coronary flow velocity. CFR was assessed before and after 8-week therapy. RESULTS: CFR was successfully performed in all patients. There were no significant differences in baseline characteristics and CFR between ranolazine and placebo group. After 8 weeks CFR significantly increased in ranolazine group (2.54 ± 0.44 vs. 1.91 ± 0.31; P = 0.005) but not in placebo group (1.99 ± 0.32 vs. 1.94 ± 0.29; P = ns). No patient dropped out during 8 weeks therapy. Side effects were similar in both groups. CONCLUSIONS: Ranolazine is able to improve CFR in these patients. This is probably due to improvement in abnormal coronary autoregulation, both reducing baseline diastolic coronary flow velocity and increasing hyperemic diastolic coronary flow velocity.

Effect of intraventricular dyssynchrony on diastolic function and exercise tolerance in patients with heart failure.

AIMS: Intraventricular dyssynchrony may contribute to the severity of heart failure [congestive heart failure (CHF)]. We assessed the correlates of intraventricular dyssynchrony and evaluated dyssynchrony as an independent predictive variable of exercise intolerance in CHF patients. METHODS AND RESULTS: Eighty-one CHF patients (66 +/- 9 years) underwent cardiopulmonary exercise test. Left ventricular (LV) diastolic function was evaluated by transmitral patterns and tissue Doppler. Intraventricular dyssynchrony was calculated according to time intervals between the onset of QRS and the onset of systolic velocities of basal septum and lateral wall. We divided the patients based on the mean value (40 ms) of dyssynchrony. Patients with intraventricular dyssynchrony (>40 ms) showed higher New York Heart Association class (2.7 +/- 0.6 vs. 2.2 +/- 0.4, P < 0.001), higher brain natriuretic peptide (BNP) (415 +/- 478 vs. 194 +/- 205, P = 0.014), more frequent restrictive transmitral pattern (33 vs. 7%, P = 0.013), higher E/E(a) (13 +/- 7 vs. 10 +/- 6, P = 0.016), lower mitral annulus peak systolic velocity (4.5 +/- 1.1 vs. 5.5 +/- 1.5 cm/s, P = 0.01), and peak oxygen consumption (13.8 +/- 3.5 vs. 18.1 +/- 3.9, P < 0.001), than patients without dyssynchrony (< or =40 ms). Predictors of exercise tolerance were intraventricular dyssynchrony (P = 0.035), log BNP (P = 0.003), and E/E(a) (P = 0.004). CONCLUSION: Intraventricular dyssynchrony correlates with higher LV filling pressure and lower ejection fraction and it is an independent predictor of poor aerobic capacity; it may be helpful for functional evaluation of CHF patients.

Effect on quality of life of different accelerated diagnostic protocols for management of patients presenting to the emergency department with acute chest pain.

This study assessed the effects on quality of life (QoL) of dobutamine-atropine stress echocardiography (DASE) and electrocardiogram exercise testing (EET) accelerated diagnostic protocols for early stratification of low-risk patients with acute chest pain (ACP). A total of 290 patients with ACP, a nondiagnostic electrocardiogram, and negative biomarkers were randomly assigned to an accelerated diagnostic protocol (DASE, n = 110, or EET, n = 89) or usual care (n = 91) and followed up for 2 months. QoL was assessed at discharge and 2-month follow-up using the Nottingham Health Profile questionnaire. Baseline and 2-month follow-up answers to the Nottingham Health Profile questionnaire were available for 207 patients (71%; 55 in the usual-care, 77 in the DASE, and 75 in the ETT arm). At predischarge, patients in the usual-care arm reported higher impairment in the physical mobility and pain dimensions compared with the DASE and EET arms (p = 0.019 and p = 0.023, respectively). At 2-month follow-up, QoL improved in all groups; however, patients in the usual-care arm had significantly worse scores than patients managed using accelerated diagnostic protocols in the physical mobility, pain, social isolation, emotional reactions, and energy level dimensions (p = 0.014, p = 0.002, p = 0.04, p = 0.01, and p = 0.003, respectively). In conclusion, low-risk patients with ACP had non-negligible impairment of QoL in the acute phase. Emergency department ADPs with early DASE and EET reduced QoL impairment at both baseline and 2-month follow-up.

Effect of weight loss on coronary circulation and adiponectin levels in obese women.

BACKGROUND: Obesity is independently associated with coronary endothelial dysfunction. Adiponectin, a protein whose circulating levels are decreased in obesity, has direct effects on vascular function. The aim of this study was to investigate in obese women the effect of sustained weight loss on coronary circulation and circulating adiponectin levels. METHODS: Coronary flow velocity reserve (CFVR), assessed by transthoracic Doppler echocardiography (TTDE), blood pressure, lipid, glucose and insulin, HOMA scores, CRP-protein (CRP), and adiponectin parameters were investigated in forty obese pre-menopausal women and 40 healthy matched normal weight women at baseline and after sustained weight loss. RESULTS: At baseline, the obese group had significantly higher fasting glucose (P<0.05), insulin concentrations (P<0.01), HOMA scores (P<0.001), C-reactive protein (CRP) levels (P<0.001) and lower plasma adiponectin levels (P<0.001) than the controls. CFVR was significantly lower in obese group than in the normal weight group (P<0.05). After 12 months of a multidisciplinary program of weight reduction, obese women lost at least 10% of their original weight. Fasting glucose (<0.001) and insulin concentrations (P<0.001), HOMA scores (P<0.001), CRP levels (P<0.01) were significant reduced, whereas adiponectin levels (P<0.001) and HDL cholesterol (P<0.05) showed a significant increment. CFVR value significantly improved in obese subjects (P<0.001). There was a significant correlation between changes in CFVR and changes in adiponectin levels (r=0.47, P<0.05). Multivariate analysis showed that adiponectin was the only independent predictor of change in CFVR (r=0.38, P<0.05). CONCLUSIONS: In obese women the weight loss improves coronary circulation and increases adiponectin levels. The improvement in coronary circulation is associated with adiponectin levels.

Comparison of early dobutamine stress echocardiography and exercise electrocardiographic testing for management of patients presenting to the emergency department with chest pain.

This study compared the cost-effectiveness of dobutamine-atropine stress echocardiography (DASE) and electrocardiographic exercise testing (EET) implemented in emergency department accelerated diagnostic protocols for the early stratification of low-risk patients presenting with acute chest pain (ACP). One hundred ninety-nine patients with ACP, nondiagnostic electrocardiographic results, and negative biomarker results were randomized to DASE (n = 110) or EET (n = 89) <6 hours after emergency department presentation. Patients with negative risk assessment results were immediately discharged and followed for 2 months. Ninety patients (82%) in the DASE arm and 78 (88%) in the EET arm were discharged after the diagnosis of nonischemic ACP. The mean lengths of stay in the hospital were 23 +/- 12 and 31 +/- 23 hours in the DASE and EET arms, respectively (p = 0.01). No 2-month follow-up events occurred in DASE patients, and the event rate was significantly higher in EET patients (0% vs 11%, p = 0.004). The DASE strategy showed lower costs compared with the EET strategy at 1-month ($1,026 +/- $250 vs $1,329 +/- $1,288, p = 0.03) and 2-month ($1,029 +/- 253 vs $1,684 +/- $2,149, p = 0.005) follow-up. In conclusion, early DASE in emergency department triage of low-risk patients with ACP is safe and reduces costs of care compared to EET.

Antiarrhythmic drug therapy after radiofrequency catheter ablation in patients with atrial fibrillation.

OBJECTIVES: The use of antiarrhythmic drugs after ablation is a controversial issue when evaluating the efficacy of atrial fibrillation (AF) ablation. This study compares in a prospective and randomized fashion the impact of an antiarrhythmic drug in preventing AF recurrence after AF ablation. METHODS: From February 2004 to May 2005, 107 consecutive patients (mean age 57 +/- 10 years, 69 men), with paroxysmal (60%) or persistent (40%) drug refractory AF, were randomly assigned to ablation alone (Group A, 53 patients) or combined with the best antiarrhythmic therapy, preferably amiodarone (Group B, 54 patients). All patients underwent cavo-tricuspid and left inferior pulmonary vein (PV)-mitral isthmus ablation plus circumferential PV ablation, using a guided electro-anatomical approach. Standard electrocardiograms (ECG), and ambulatory and transtelephonic ECG monitoring were used to assess AF recurrences. Recurrences during the first month after ablation were excluded from this analysis. RESULTS: At 12 months of follow-up, no significant difference was observed in the rates of AF recurrences between Group A (18/53 patients, 34%) and Group B (16/54 patients, 30%). The percentage of patients with >/= 1 asymptomatic AF episode was higher in Group B than in Group A (10/16 patients, 63%, vs 5/18 patients, 28%, P = 0.04). CONCLUSIONS: Continuing antiarrhythmic drug therapy in patients who undergo catheter ablation for AF did not lower the rate of AF recurrences. Antiarrhythmic drugs increased the proportion of patients with asymptomatic AF episodes.

Long-term results of hybrid therapy in patients with atrial fibrillation who develop atrial flutter during flecainide infusion.

The flecainide infusion test has been proposed to screen candidates for hybrid pharmacological and ablation therapy. We report the long-term follow-up of 154 consecutive patients with paroxysmal or persistent atrial fibrillation (AF) who developed atrial flutter (AFL) during flecainide infusion (IC AFL), treated with inferior vena cava-tricuspid annulus isthmus catheter ablation and oral flecainide (hybrid therapy). Over a mean of 54.1 +/- 13.1 months 82 patients (53%) remained free of AF and AFL. Flecainide was discontinued because of adverse effects in 6 patients (4%). A history of persistent AF, and the documentation of >/=1 spontaneous AFL episode before the flecainide test were independent predictors of successful hybrid therapy. In patients with paroxysmal AF without documented spontaneous AFL, the long-term efficacy of hybrid therapy was 38.5% (P = 0.03). The flecainide infusion test reliably detects candidates for hybrid therapy. The efficacy of this therapy is maintained over the long-term with a high patient compliance.

Prediction of mortality in patients with right bundle branch block referred for pharmacologic stress echocardiography.

Right bundle branch block (RBBB) is independently associated with all-cause mortality in patients referred for noninvasive evaluation of coronary artery disease. However, further stratification of risk in these patients has not been specifically addressed. The aim of this study was to risk stratify patients with RBBB who were referred for stress echocardiography. The study population was comprised of 343 patients (267 men; age 66 +/- 9 years) with RBBB who underwent pharmacologic stress echocardiography (231 dipyridamole, 112 dobutamine) for evaluation of suspected or known coronary artery disease. Overall mortality was the only end point. Stress echocardiography was positive for ischemia in 109 patients (32%). During follow-up (38 +/- 32 months), 36 deaths occurred. Seventy-three patients underwent revascularization and were censored. Ischemia at stress echocardiography (hazard ratio [HR] 2.9, 95% confidence interval [CI] 1.5 to 5.5, p=0.002), left anterior fascicular block (LAFB) (HR 2.8, 95% CI 1.4 to 5.6, p = 0.002), age >65 years (HR 2.1, 95% CI 1.0 to 4.3, p=0.047), and wall motion score index at rest (HR 2.5, 95% CI 1.0 to 6.5, p=0.057) were multivariate predictors of mortality. On the basis of stress echocardiographic result and presence and/or absence of LAFB, 3 levels of risk were identified: (1) low-risk, in cases of no ischemia and no LAFB (49% of the entire study population); (2) intermediate-risk, in cases of ischemia or LAFB only; and (3) high-risk, in cases of ischemia and LAFB. Clinical data, electrocardiography at rest, and stress echocardiographic results can provide effective stratification of risk in patients with RBBB.

Prognostic implications of intraventricular conduction defects in patients undergoing stress echocardiography for suspected coronary artery disease.

PURPOSE: To investigate the prognostic implications of conduction defects in subjects without proven coronary artery disease who had been referred for stress echocardiography. METHODS: The study sample consisted of 1230 patients (574 men and 656 women; mean [+/- SD] age, 63 +/- 10 years) who underwent stress echocardiography with dipyridamole (n = 780) or dobutamine (n = 450) to evaluate suspected coronary artery disease. A summary wall motion score (on a 1 to 4 scale) was calculated. Patients were followed for a mean of 41 +/- 27 months; mortality was the only endpoint. RESULTS: Four hundred and twenty patients (34%) had intraventricular conduction defects on a resting electrocardiogram (173 with complete left bundle branch block, 98 with isolated right bundle branch block, 43 with right bundle branch block with left anterior hemiblock, and 106 with left anterior hemiblock). Ischemia at stress echo (new or worsening of preexisting wall motion abnormality) was found in 250 patients (20%). There were 56 deaths during follow-up; 138 patients underwent revascularization and were censored. Multivariate predictors of mortality were resting wall motion score index (hazard ratio [HR] = 6.0 per unit increase; 95% confidence interval [CI]: 2.3 to 16; P <0.0001), ischemia at stress echo (HR = 3.9; 95% CI: 2.2 to 6.7; P <0.0001), age >65 years (HR = 3.2; 95% CI: 1.7 to 5.9; P <0.0001), hypertension (HR = 1.8; 95% CI: 1.1 to 3.2; P = 0.03), and right bundle branch block with left anterior hemiblock (HR = 3.7; 95% CI: 1.8 to 7.5; P <0.0001). The other three forms of intraventricular conduction defects (left bundle branch block, isolated complete right bundle branch block, and left anterior hemiblock) were not associated with mortality in multivariate analyses, or among the 980 patients who did not have ischemia. CONCLUSION: Right bundle branch block with left anterior hemiblock is an independent predictor of mortality in patients with suspected coronary artery disease undergoing stress echocardiography, whereas isolated right bundle branch block is associated with outcomes similar to those observed in patients with no conduction defects.