Serum markers of collagen turnover predict future shocks in implantable cardioverter-defibrillator recipients with dilated cardiomyopathy on optimal treatment.

OBJECTIVES: We investigated prospectively whether serum markers of collagen turnover could be used as predictors for the occurrence of malignant ventricular arrhythmias in patients with nonischemic dilated cardiomyopathy (NIDC) who had received an implantable cardioverter-defibrillator (ICD) for primary prevention. BACKGROUND: Extracellular matrix alterations in NIDC might provide electrical heterogeneity, thus potentially contributing to the occurrence of ventricular arrhythmia and subsequent sudden cardiac death (SCD). METHODS: Serum C-terminal propeptide of collagen type-I, C-terminal telopeptide of collagen type-I, matrix metalloproteinase (MMP)-1, and tissue inhibitor of MMP-1 were measured as markers of collagen synthesis and degradation in 70 patients with mild to moderate symptomatic heart failure due to NIDC with left ventricular ejection fraction <35%, who received an ICD for primary prevention of SCD. Patients were evaluated for any appropriate ICD delivered therapy, whether shock or antitachycardia pacing, during a 1-year follow-up period. RESULTS: Appropriate device therapies were delivered in 14 of the 70 patients during the follow-up period, with antitachycardia pacing in 2, antitachycardia pacing with shocks in 4, and shocks in 8. Pre-implantation serum concentrations of C-terminal telopeptide of collagen type-I levels were significantly higher in patients who had appropriate ICD-delivered therapy than in those who did not have any therapy (0.46 +/- 0.19 ng/ml vs. 0.19 +/- 0.07 ng/ml, p < 0.001, respectively). The same was true for baseline MMP-1 and tissue inhibitor of MMP-1 (27.7 +/- 1.6 ng/ml vs. 24.1 +/- 2.5 ng/ml, p < 0.001, and 89 +/- 14 ng/ml vs. 58 +/- 18 ng/ml, p = 0.008, respectively). CONCLUSIONS: If the maximum benefit is to be achieved from ICD therapy in NIDC patients for the primary prevention of SCD, a more precise risk stratification is required. As extracellular matrix alterations affect the arrhythmogenic substrate in NIDC, we observed that serum markers of collagen turnover could predict arrhythmic events in ICD recipients.

Effect of sinus rhythm restoration after electrical cardioversion on apelin and brain natriuretic Peptide prohormone levels in patients with persistent atrial fibrillation.

Because humoral alterations have been implicated in the generation and perpetuation of atrial fibrillation (AF), we aimed to elucidate possible abnormalities in atrial endocrine function in the setting of lone AF. Levels of plasma apelin and amino terminal fragment of the brain natriuretic peptide prohormone (NT-pro-BNP) were measured in 40 patients with persistent AF, before and 1 month after electrical cardioversion, and in 15 controls in sinus rhythm (SR). All patients were successfully cardioverted to SR, although in 9 of them AF recurred. Baseline apelin levels were lower and NT-pro-BNP levels higher in patients with AF compared to controls (380 +/- 186 vs 700 +/- 151 pg/ml, p <0.001, and 615 +/- 611 vs 50 +/- 28 pg/ml, p <0.001, respectively). Maintenance of SR resulted in an increase of apelin and a decrease of NT-pro-BNP levels during the postcardioversion follow-up period compared to baseline (497 +/- 170 vs 368 +/- 178 pg/ml, p <0.001, and 206 +/- 106 vs 398 +/- 269 pg/ml, p <0.001 respectively). Patients who developed AF recurrence by the end of the follow-up period had similar values of apelin and NT-pro-BNP on final and initial evaluations (444 +/- 142 vs 422 +/- 217 pg/ml, p = 0.62, and 1,328 +/- 714 vs 1,362 +/- 862 pg/ml, p = 0.74, respectively). Stepwise logistic regression analysis showed that left atrial diameter (b =-0.49, p = 0.05), and baseline NT-pro-BNP (b = 0.006, p = 0.022), but not apelin, were independent predictors for AF recurrence. In conclusion, this study suggests that endocrine heart function, as judged from apelin and NT-pro-BNP levels, is reversibly modified in the setting of lone AF. This could influence systemic hemodynamics and pharmacologic measures designed to treat this arrhythmia.

Predicting future shocks in implantable cardioverter defibrillator recipients: the role of biomarkers.

Simple clinical and laboratory indexes have been identified as predictors of arrhythmic events in implantable cardioverter defibrillator patients. Biomarkers, which are playing a growing role in the prognosis and treatment of patients with heart failure, could provide an auxiliary tool in this context, given that their measurement is now easy and widely available.

Extracellular matrix alterations in patients with paroxysmal and persistent atrial fibrillation: biochemical assessment of collagen type-I turnover.

OBJECTIVES: We investigated whether the serum markers of collagen turnover differed in various forms of atrial fibrillation (AF) and in sinus rhythm (SR) in humans. BACKGROUND: Structural alterations and fibrosis have been implicated in the generation and perpetuation of AF. METHODS: Serum C-terminal propeptide of collagen type-I (CICP), C-terminal telopeptide of collagen type-I (CITP), matrix metalloproteinase-1, and tissue inhibitor of matrix metalloproteinases-1 were measured as markers of collagen synthesis and degradation in 70 patients with AF and 20 healthy control subjects in SR. RESULTS: C-terminal propeptide of collagen type-I and CITP were significantly higher in AF patients than in control subjects (91 +/- 27 ng/ml vs. 67 +/- 11 ng/ml, p < 0.001 and 0.38 +/- 0.20 ng/ml vs. 0.25 +/- 0.08 ng/ml, p < 0.001, respectively). Persistent AF patients had higher levels of CICP (105 +/- 28 ng/ml vs. 80 +/- 21 ng/ml, p < 0.001), but not CITP, compared with those with paroxysmal AF. Patients with persistent AF had lower levels of matrix metalloproteinase-1 but increased levels of tissue inhibitor of matrix metalloproteinases-1 compared with patients with paroxysmal AF (11.90 +/- 4.79 ng/ml vs. 14.98 +/- 6.28 ng/ml, p = 0.03 and 155 +/- 45 ng/ml vs. 130 +/- 38 ng/ml, p < 0.001, respectively). Tissue inhibitor of matrix metalloproteinases-1 levels were significantly lower in control subjects compared with those in both paroxysmal and persistent AF patients (102 +/- 15 ng/ml vs. 130 +/- 38 ng/ml vs. 155 +/- 45 ng/ml, respectively, p < 0.001). CONCLUSIONS: Serum markers of collagen type-I turnover differed significantly between patients with AF and SR. Furthermore, these markers also differed significantly between paroxysmal and persistent AF patients, suggesting that the intensity of the extracellular synthesis and degradation of collagen type-I may be related to the burden or type of AF.

Electrophysiological effects of carvedilol administration in patients with dilated cardiomyopathy.

PURPOSE: Several studies suggest the clinical efficacy of carvedilol in reducing atrial and ventricular arrhythmias in patients with left ventricular dysfunction (LVD) due to congestive heart failure (CHF) or following myocardial infarction. However, the mechanisms supporting its antiarrhythmic efficacy have been derived from experimental studies. In this prospective, placebo-controlled trial we examined the electrophysiological effects of a high oral dose of carvedilol in patients with CHF and LVD due to non-ischemic dilated cardiomyopathy. METHODS: Thirty-one patients with stable CHF underwent electrophysiological study and were randomly assigned to treatment with carvedilol or placebo. After 2 months of treatment the study was repeated. RESULTS: Carvedilol prolonged almost all conduction times. In the same group atrial and ventricular effective refractory periods were significantly prolonged, while the parameters of repolarization remained virtually unchanged. The prolongation of refractoriness was most pronounced in the atrium. The change in ventricular refractoriness was correlated with ejection fraction (r = 0.94, p < 0.01) suggesting that patients with more preserved left ventricular function responded to treatment with greater prolongation. CONCLUSION: Even after a short period of administration carvedilol has marked and diffused electrophysiological effects that would be beneficial for patients with CHF and may contribute to the positive outcome of clinical trials.

Endothelial cell function during atrial fibrillation and after restoration of sinus rhythm.

Beat-to-beat variation in blood flow dynamics during atrial fibrillation (AF) has been associated with evidence of endothelial dysfunction. The aim of the present work is to confirm endothelial dysfunction in patients with AF and test the hypothesis that endothelial dysfunction is reversible upon restoration of normal sinus rhythm. Endothelium-dependent (flow-mediated dilation [FMD]) and endothelium-independent (nitroglycerin-mediated dilation [NMD]) vasodilator function of the brachial artery were measured using high-resolution ultrasound in 46 patients with persistent AF who were scheduled for internal electrical cardioversion and in 25 control subjects. In patients who remained in sinus rhythm after cardioversion, these measurements were repeated after 24 hours (n = 32) and 1 month (n = 19). Compared with control subjects, patients (n = 32) showed lower FMD during AF (8.1 +/- 3.6% vs 12.2 +/- 3.2%, respectively, p <0.001) and similar NMD (17.0 +/- 3.5% vs 15.9 +/- 3.1%, respectively, p = 0.21). In 19 patients who remained in sinus rhythm, FMD increased at both 24 hours (8.0 +/- 3.9% vs 10.6 +/- 4.6%, p = 0.015) and 1 month (8.0 +/- 3.9% vs 13.6 +/- 5.3%, p <0.001). In contrast, NMD was not significantly altered at 24 hours or 1 month after sinus rhythm restoration (17.1 +/- 3.9% vs 17.2 +/- 4.0% vs 16.9 +/- 4.1%). In conclusion, AF is associated with impairment in endothelial function that improves after sinus rhythm restoration.

Evidence of mechanoelectric feedback in the atria of patients with atrioventricular nodal reentrant tachycardia.

OBJECTIVE: Patients with atrioventricular nodal reentrant tachycardia (AVNRT) could serve as a clinical model to study the effects of mechanical stretch in the electrical properties of atrial myocardium. MATERIALS AND METHODS: We studied 14 patients with AVNRT. Peak, mean and minimal atrial pressures, atrial refractoriness (ERP) in the right atrial appendage and high right atrial lateral wall and monophasic action potential duration at 90% of repolarisation (MAPd90) in the right atrial appendage were assessed during atrial pacing at 500 and 400 ms and after 2 min of pacing at the tachycardia cycle length. Measurements were repeated from the same positions after ventricular pacing at the same cycle lengths and after 2 min of tachycardia. Susceptibility to atrial fibrillation (AF) was assessed by noting whether AF was induced during ERP evaluation. RESULTS: Atrial pressure showed a statistically significant increase during ventricular pacing compared to baseline. This increase remained substantially unchanged when the tachycardia was induced. A significant reduction in atrial ERP and MAPd90 was also observed during ventricular pacing at all cycle lengths compared to atrial pacing. Two minutes of spontaneous tachycardia were enough to change the atrial ERP and MAPd90 to values significantly lower than those during atrial pacing at the cycle length of tachycardia. During the ERP evaluation AF was induced more often during the tachycardia (28%) than during ventricular (14%) and atrial pacing (0%). CONCLUSION: In AVNRT patients, ventricular pacing and reentrant tachycardia significantly increase right atrial pressures and subsequently shorten ERP and MAPd90, leading to an enhanced propensity for AF.

Amino-terminal pro-brain natriuretic peptide predicts ventricular arrhythmogenesis in patients with ischemic cardiomyopathy and implantable cardioverter-defibrillators.

STUDY OBJECTIVES: Even in high-risk population groups, not all patients have the same risk of sudden cardiac death (SCD). Given the emerging data about the amino-terminal fragment of the brain natriuretic peptide prohormone (NT-proBNP) value in heart failure, we planned to evaluate the importance of NT-proBNP levels in predicting the occurrence of malignant arrhythmias in patients with ischemic cardiomyopathy and implantable cardioverter-defibrillators (ICDs). DESIGN: Prospective study. SETTING: Tertiary referral center. PATIENTS: Thirty five ambulatory patients with previous myocardial infarction, left ventricular ejection fraction < 35%, and ICDs for primary prevention of SCD according to Multicenter Automatic Defibrillator Implantation Trial I criteria. INTERVENTIONS: Venous blood samples for plasma NT-proBNP measurement were obtained after 30 min of supine rest from all patients at the beginning of the study. Patients were evaluated every 2 months, or sooner in cases of device discharges, during a 1-year follow-up period. Data concerning arrhythmias and device therapy were stored at the time of device interrogation on each follow-up visit. MEASUREMENTS AND RESULTS: During 1-year follow-up, 11 of 35 patients (31.4%) received 18 antiarrhythmic device therapies for ventricular tachyarrhythmia (VT). Patients who experienced such arrhythmias had NT-proBNP levels of 997.27 +/- 335.14 pmol/L (mean +/- SD), whereas those without VT had NT-proBNP levels of 654.87 +/- 237.87 pmol/L (p = 0.001). An NT-proBNP cutoff value of 880 pmol/L had a sensitivity of 73%, a specificity of 88%, a positive predictive value of 80%, and a negative predictive value of 88% for the prediction of occurrence-sustained VT events. CONCLUSION: To achieve the maximum benefit by ICD therapy, more precise risk stratification is required, even in high-risk, post-myocardial infarction patients. Plasma NT-proBNP levels comprise a promising method that could help in the better identification of a patient group with an even higher risk of sudden death.

Acute electrophysiologic effects of inhaled salbutamol in humans.

STUDY OBJECTIVES: Although inhaled beta2-agonists are in widespread use, several reports question their potential arrhythmogenic effects. The purpose of this study was to evaluate the cardiac electrophysiologic effects of a single, regular dose of an inhaled beta2-agonist in humans. DESIGN: Prospective study. SETTING: Tertiary referral center. PATIENTS: Six patients with bronchial asthma and 12 patients with mild COPD. INTERVENTIONS: All patients underwent an electrophysiologic study before and after the administration of salbutamol solution (5 mg in a single dose). MEASUREMENTS AND RESULTS: Sinus cycle length, sinus node recovery time (SNRT), interval from the earliest reproducible rapid deflection of the atrial electrogram in the His bundle recording to the onset of the His deflection (AH), interval from the His deflection to the onset of ventricular depolarization (HV), Wenckebach cycle length (WCL), atrial effective refractory period (AERP), and ventricular effective refractory period (VERP) were evaluated just before and 30 min after the scheduled intervention. Salbutamol, a selective beta2-agonist, administered by nebulizer had significant electrophysiologic effects on the atrium, nodes, and ventricle. The AH length decreased from 86.1 +/- 19.5 ms at baseline to 78.8 +/- 18.4 ms (p < 0.001), and the WCL decreased from 354.4 +/- 44.2 to 336.6 +/- 41.7 ms (p = 0.001). Salbutamol significantly decreased the AERP and VERP too while leaving the HV unchanged. Additionally, inhaled salbutamol increased heart rate (from 75.5 +/- 12.8 beats/min at baseline to 93.1 +/- 16 beats/min, p < 0.001) and shortened the SNRT (from 1,073.5 +/- 178.7 to 925.2 +/- 204.9 ms, p = 0.001). CONCLUSION: Inhaled salbutamol results in significant changes of cardiac electrophysiologic properties. Salbutamol enhances atrioventricular (AV) nodal conduction and decreases AV nodal, atrial, and ventricular refractoriness in addition to its positive chronotropic effects. These alterations could contribute to the generation of spontaneous arrhythmias.

Effects of successful cardioversion of persistent atrial fibrillation on right ventricular refractoriness and repolarization.

AIM: Changes in ventricular refractoriness and repolarization after successful electrical cardioversion to sinus rhythm in persistent atrial fibrillation (AF) patients were studied. METHODS AND RESULTS: In 33 AF patients with controlled ventricular response, right ventricular ERP (VERP) at three basic cycle lengths (600, 500, 400 ms), as well as monophasic action potential duration (MAPd(90)) at a drive cycle length of 500 ms, were measured just before, 20 min and 24 h after cardioversion. VERP at 600 ms changed from 241+/-19 ms to 249+/-21 ms to 253+/-24 ms (P<0.001), VERP at 500 ms changed from 234+/-19 ms to 242+/-22 ms to 246+/-23 ms (P<0.001) and VERP at 400 ms changed from 224+/-20 ms to 232+/-23 ms to 236+/-24 ms (P<0.001). MAPd(90) changed from 247+/-16 ms preconversion to 252+/-17 ms 20 min postconversion to 253+/-19 ms after 24 h (P<0.05). Change in refractoriness at 500 ms was well correlated with change of mean RR interval before and 20 min after conversion (R=0.616, P<0.001). There was no correlation between RR variability and VERP before cardioversion. CONCLUSION: Restoration of sinus rhythm in persistent AF patients is followed by significant effects on ventricular refractoriness and repolarization related to cycle length change. No AF related ventricular electrophysiological alterations were found.

Comparative effects of carvedilol and amiodarone on conversion and recurrence rates of persistent atrial fibrillation.

Pretreatment with antiarrhythmic agents could improve cardioversion and recurrence rates in patients with persistent atrial fibrillation. In a prospective controlled trial, 145 patients were randomly assigned to treatment with carvedilol, amiodarone, or placebo for 4 weeks before electrical cardioversion. Although the 2 drugs had similar effects on cardioversion rates, amiodarone was superior in terms of sinus rhythm maintenance after conversion.

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.

Effects of amiodarone and diltiazem on persistent atrial fibrillation conversion and recurrence rates: a randomized controlled study.

PURPOSE: To assess the effects of amiodarone and diltiazem on atrial fibrillation (AF) induced atrial electrical remodeling and their clinical implications. METHODS: Persistent AF patients were randomly assigned to three treatment groups over a period from 6 weeks before to 6 weeks after internal cardioversion: group A (35 patients, oral diltiazem), group B (34 patients, oral amiodarone) and group C (37 patients, no antiarrhythmic drugs). Several electrophysiological parameters were assessed 5 min and 24 h after cardioversion. RESULTS: Compared with controls, group B patients had significantly higher conversion rates (83% vs. 100%, p = 0.041) and a higher probability to maintain sinus rhythm (p = 0.037). Patients of group B had longer fibrillatory cycle length intervals than patients of group A and C (180 +/- 18 ms vs. 161 +/- 17 ms vs. 164 +/- 19 ms, p = 0.001) and longer atrial effective refractory periods (211 +/- 22 ms vs. 198 +/- 16 ms vs. 194 +/- 17 ms, p = 0.003) as assessed 5 min after conversion. Post-conversion density of supraventricular ectopics was significantly lower in group B compared to groups A and C (p = 0.001). CONCLUSIONS: Oral amiodarone increases conversion rates, prolongs fibrillatory cycle length and atrial effective refractory period and preserves sinus rhythm after cardioversion in persistent AF patients by suppressing the atrial ectopics that trigger AF.

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.

Plasma Levels of Nitrites/Nitrates in Patients with Chronic Atrial Fibrillation are Increased after Electrical Restoration of Sinus Rhythm.

INTRODUCTION: Patients with persistent atrial fibrillation (AF) have hemodynamic changes, which impair endothelial cell function resulting in decreased nitric oxide (NO) production. The aim of this work was to assess endothelial function in AF patients before and at various time points after cardioversion. METHODS: Forty-two patients with AF and 21 normal and age-adjusted healthy controls were studied. Nitrites and nitrates (NO(x)) and von Willebrand factor (vWf) concentrations were measured on blood samples taken just before cardioversion and over a 30 day period after the procedure. RESULTS: Plasma levels of NO(x) in AF were significantly lower compared to healthy controls (p < 0.001), but after cardioversion gradually increased to approach to those of the healthy controls by the end of the first month of sustained sinus rhythm (p = 0.004). Interestingly plasma levels of NO(x) were negatively correlated to left atrial volume measured by ultrasonography (r = -0.34, p < 0.05). Plasma levels of vWf in AF patients were significantly higher compared to the healthy controls (p < 0.01) but with sustained sinus rhythm decreased (p = 0.02). CONCLUSION: The parallel normalization of the NO(x) titers and vWf levels suggests that vascular endothelial function improves after 30 days of normal sinus rhythm.