Ventricular asynchrony predicts a better outcome in patients with chronic heart failure receiving cardiac resynchronization therapy.

OBJECTIVES: The aim of this study was to evaluate whether the clinical benefit of cardiac resynchronization therapy (CRT) can be prospectively predicted by means of the baseline evaluation of left ventricular asynchrony. BACKGROUND: The reverse remodeling associated with CRT is more evident in patients with severe heart failure (HF) and left bundle branch block (LBBB) who have left ventricular asynchrony. METHODS: Baseline left ventricular asynchrony was assessed in 60 patients with severe HF and LBBB by calculating the electrocardiographic duration of QRS and the echocardiographic septal-to-posterior wall motion delay (SPWMD). Left ventricular size and left ventricular ejection fraction (LVEF), mitral valve regurgitation, and functional capacity were also evaluated. The progression toward HF (defined as a worsening clinical condition leading to a sustained increase in conventional therapies, hospitalization, cardiac transplantation, and death) was assessed during follow-up, as were the changes in LVEF after six months. RESULTS: During the median follow-up of 14 months, 16 patients experienced HF progression. Univariate analysis showed that ischemic cardiomyopathy, changes in the QRS duration after implantation, and SPWMD significantly correlated with events. At multivariate analysis, a long SPWMD remained significantly associated with a reduced risk of HF progression (hazard ratio: 0.91; 95% confidence interval: 0.83 to 0.99; p <0.05). An improvement in LVEF was observed in 79% of the patients with a baseline SPWMD of > or =130 ms and in 9% of those with an SPWMD of <130 ms (p <0.0001). CONCLUSIONS: Baseline SPWMD is a strong predictor of long-term clinical improvement after CRT in patients with severe HF and LBBB.

Independent and incremental prognostic value of endogenous ouabain in idiopathic dilated cardiomyopathy.

Increased circulating levels of endogenous ouabain (EO) have been observed in some heart failure patients, but their long term clinical significance is unknown. This study investigated the prognostic value of EO for worsening heart failure among 140 optimally treated patients (age 50+/-14 years; 104 male; NYHA class 1.9+/-0.7) with idiopathic dilated cardiomyopathy. Plasma EO was determined by RIA and by liquid chromatography mass spectrometry, values were linearly correlated (r = 0.89) in regression analysis. During follow-up (13+/-5 months), heart failure progression was defined as worsening clinical condition leading to one or more of the following: sustained increase in conventional therapies, hospitalization, cardiac transplant, or death. NYHA functional class, age, LVEF, peak VO2 and plasma levels of EO were predictive for heart failure progression. Heart failure worsened 1.5 fold (HR: 1.005; 95% CI: 1.001-1.007; p<0.01) for each 100 pmol/L increase in plasma EO. Moreover, those patients with higher plasma EO values had an odds ratio of 5.417 (95% CI: 2.044-14.355; p<0.001) for heart failure progression. Following multivariate analysis, LVEF, NYHA class and plasma EO remained significantly linked with clinical events. This study provides the first evidence that circulating EO is a novel, independent and incremental marker that predicts the progression of heart failure.

Shortened head-up tilting test guided by systolic pressure reductions in neurocardiogenic syncope.

BACKGROUND: Asymptomatic reductions in arterial pressure have been reported to occur before the onset of tilt-induced syncope. We investigated the predictive value of these reductions for a positive tilt result. METHODS AND RESULTS: In a first study, 238 consecutive healthy subjects with unexplained syncope underwent a passive tilt table test. Finger systolic arterial pressure (SAP) recordings made it possible to calculate how many of the beat-to-beat SAP values during the first 15 minutes of tilt were lower than the lowest value recorded at baseline. Neurocardiogenic syncope was diagnosed in 73 subjects; 28 fainted after 15 minutes of tilt and experienced more pressure reductions than did the subjects with a negative test (328+/-400 versus 119+/-284; P<0.01). More than 14 SAP reductions during the first 15 minutes of tilt allowed us to predict a positive test with 93% sensitivity, 58% specificity, and positive and negative predictive values of 28% and 98%, respectively. In a second prospective study (80 consecutive subjects), the online analysis of this criterion by visually inspecting a Finapres monitor showed 80% sensitivity, 85% specificity, and positive and negative predictive values of 57% and 94%. CONCLUSIONS: In healthy subjects with unexplained syncope, the evaluation of SAP reductions during the first 15 minutes of tilt is a marker of systolic pressure instability preceding syncope and constitutes a simple and good predictor of tilt outcome that could be used to guide test duration.

Enhanced reflex response to baroreceptor deactivation in subjects with tilt-induced syncope.

OBJECTIVES: We sought to evaluate whether changes in resting baroreflex control of heart rate are a distinctive feature of healthy subjects with a history of syncope prone to a positive tilt-test response. BACKGROUND: The mechanisms involved in the pathogenesis of vasovagal syncope (VVS) are still poorly understood; in particular, the contribution of arterial baroreflex control of heart rate is matter of discussion. METHODS: A passive tilt-table test was performed in 312 consecutive, otherwise healthy subjects (age 36 +/- 15 years) with unexplained syncope and 100 control subjects. At baseline, spontaneous baroreflex sensitivity (BRS; ms/mm Hg) and the baroreflex effectiveness index (BEI) were assessed using the sequence method. RESULTS: The study population showed normal baroreflex function. Tilt-induced VVS in 94 subjects who were younger than both the tilt-negative and control subjects (30 +/- 14, 38 +/- 15, and 37 +/- 14 years, respectively; p = 0.00005) showed greater BRS (17.4 +/- 9.8, 13.2 +/- 7.9, and 12.8 +/- 8.2 ms/mm Hg, respectively; p = 0.0001), but had a similar BEI (0.59 +/- 0.18, 0.56 +/- 0.19, and 0.58 +/- 0.2, respectively; p = NS). On Cox multivariate analysis, the occurrence of VVS during tilt was inversely related to age (hazard ratio 0.97; p = 0.0004) and directly related to the BRS slope of sequences, implying a baroreceptor deactivation (hazard ratio 1.05; p = 0.02), but not of sequences characterized by arterial baroreceptor stimulation. CONCLUSIONS: Subjects with tilt-induced VVS showed greater resting BRS but had a normal BEI. The enhanced reflex tachycardic response to arterial baroreceptor deactivation at rest may represent a characteristic feature of subjects prone to tilt-induced VVS.

Cardiac resynchronization therapy tailored by echocardiographic evaluation of ventricular asynchrony.

OBJECTIVES: The value of interventricular and intraventricular echocardiographic asynchrony parameters in predicting reverse remodeling after cardiac resynchronization therapy (CRT) was investigated. BACKGROUND: Cardiac resynchronization therapy has been suggested as a promising strategy in patients with severe heart failure and left bundle branch block (LBBB), but the entity of benefit is variable and no criteria are yet available to predict which patients will gain. METHODS: Interventricular and intraventricular mechanical asynchrony was evaluated in 20 patients (8 men and 12 women, 63 +/- 10 years) with advanced heart failure caused by ischemic (n = 4) or nonischemic dilated cardiomyopathy (n = 16) and LBBB (QRS duration of at least 140 ms) using echocardiographic Doppler measurements. Left ventricular end-diastolic volume index (LVEDVI) and left ventricular end-systolic volume index (LVESVI) were calculated before and one month after CRT. Patients with a LVESVI reduction of at least 15% were considered as responders. RESULTS: Cardiac resynchronization therapy significantly improved ventricular volumes (LVEDVI from 150 +/- 53 ml/m(2) to 119 +/- 37 ml/m(2), p < 0.001; LVESVI from 116 +/- 43 ml/m(2) to 85 +/- 29 ml/m(2), p < 0.0001). At baseline, the responders had a significantly longer septal-to-posterior wall motion delay (SPWMD), a left intraventricular asynchrony parameter; only QRS duration and SPWMD significantly correlated with a reduction in LVESVI (r = -0.54, p < 0.05 and r = -0.70, p < 0.001, respectively), but the accuracy of SPWMD in predicting reverse remodeling was greater than that of the QRS duration (85% vs. 65%). CONCLUSIONS: In patients with advanced heart failure and LBBB, baseline SPWMD is a strong predictor of the occurrence of reverse remodeling after CRT, thus suggesting its usefulness in identifying patients likely to benefit from biventricular pacing.

QT-interval prolongation in right precordial leads: an additional electrocardiographic hallmark of Brugada syndrome.

OBJECTIVES: The aim of this study was to evaluate whether the occurrence of the Brugada Syndrome typical electrocardiogram (ECG) pattern (i.e., right bundle branch block, coved-type ST-segment elevation, and T-wave inversion in the right precordial leads) is characterized by a concomitant lengthening of QT intervals in the right precordial leads. BACKGROUND: It has been suggested that the typical ECG pattern of Brugada syndrome is due to a decreased net inward current during phase 1 of the action potential, which also leads to its prolongation in the right epicardium. METHODS: Thirty-two subjects (19 males) age 37 +/- 15 years with a suspicious baseline ECG, or who were relatives of Brugada syndrome patients, underwent 12-lead ECG before and after the administration of flecainide. RESULTS: The flecainide test was negative in 14 and positive in 18 subjects. After flecainide administration, the positive ECGs were characterized by a greater QT interval corrected for heart rate (QTc) prolongation in the right precordial leads than that in the negative ECGs (78.2 +/- 35.5 ms vs. 22.0 +/- 28.4 ms in V(1) and 107.1 +/- 43.8 ms vs. 26.7 +/- 30.1 ms in V(2); p < 0.01), whereas there was no difference in the QTc prolongation in the left precordial leads (55.2 +/- 25.3 ms vs. 35.1 +/- 28.1 ms in V(5) and 53.1 +/- 32.8 ms vs. 27.3 +/- 22.4 ms in V(6); p = NS). CONCLUSIONS: In accordance with the electrophysiological background, the typical ECG pattern of Brugada syndrome is also characterized by a considerable prolongation of the QT interval in right precordial leads.

High circulating levels of endogenous ouabain in the offspring of hypertensive and normotensive individuals.

OBJECTIVE: Impaired diastolic function and left ventricular hypertrophy can occur early in the natural history of essential hypertension. High circulating levels of endogenous ouabain (EO) have been described in essential hypertension and have also been associated with left ventricular hypertrophy. The aim of this study was to investigate whether these cardiac modifications are related to plasma EO levels in the offspring of hypertensive families. METHODS: The study involved 41 subjects with (FAM+) and 45 subjects without (FAM-) a family history of hypertension. Arterial blood pressure, left ventricular geometry and function, and plasma EO levels were measured in each subject. RESULTS: Plasma EO levels were higher in the FAM+ subjects (221.5 +/- 10.95 versus 179.6 +/- 9.58 pmol/l, P = 0.004), and directly correlated with both systolic (r = 0.417, P < 0.0001) and diastolic blood pressure (r = 0.333, P = 0.002). Plasma EO was inversely related to an index of cardiac diastolic function determined as the ratio between the early and late peak flow velocity (r = -0.286, P = 0.012) and isovolumetric relaxation time (IVRT) (r = 0.32, P = 0.003). The IVRT was also significantly higher in FAM+, correlated with the IVRT (r = 0.32, P = 0.003). The IVRT was also significantly higher in FAM+, whereas the other echocardiographic parameters were similar to FAM-. CONCLUSIONS: Among the offspring of families with a positive history of hypertension, circulating EO levels and blood pressure are increased. Plasma EO levels are related to alterations of some indexes of diastolic heart function in these individuals.

Effect of family history of type 2 diabetes on the intima-media thickness of the common carotid artery in normal-weight, overweight, and obese glucose-tolerant young adults.

OBJECTIVE: To evaluate the effect of a first-degree family history of type 2 diabetes on the intima-media thickness of the common carotid artery (IMT-CCA), a surrogate marker of coronary atherosclerosis, in glucose-tolerant young adults. RESEARCH DESIGN AND METHODS: IMT-CCA was measured by high-resolution B-mode ultrasound imaging in 401 individuals aged 18-45 years with normal glucose tolerance (NGT). A total of 213 subjects had no family history of type 2 diabetes until the third generation (FH(-)), and 188 subjects had a family history of type 2 diabetes (FH(+)), defined as having one or both parents with type 2 diabetes. Other measurements included: central fat accumulation, evaluated by waist circumference; insulin resistance, estimated by homeostasis model assessment for insulin resistance (HOMA(IR)); systolic and diastolic blood pressure; fasting and postload concentrations of glucose; fasting insulin levels; and lipid profile. RESULTS: IMT-CCA and both 1- and 2-h postchallenge glucose concentrations were significantly higher in FH(+) than in FH(-) subjects. IMT-CCA was positively correlated with age, BMI, waist circumference, triglycerides, systolic and diastolic blood pressure levels, basal glucose concentrations, 1- and 2-h postchallenge glucose concentrations, and HOMA(IR). IMT-CCA was inversely associated with HDL cholesterol. After multivariate analysis, IMT-CCA maintained a significant association with family history of type 2 diabetes, BMI, waist circumference, HDL cholesterol, diastolic blood pressure, and fasting glucose. CONCLUSIONS: This study indicates that a genetic predisposition to type 2 diabetes, probably in association with slightly elevated glucose levels, may accelerate the development of atherosclerosis and increase the risk for coronary heart disease in glucose-tolerant individuals.

Association of beta-adrenergic receptor polymorphisms and progression to heart failure in patients with idiopathic dilated cardiomyopathy.

PURPOSE: Increased sympathetic nervous system activation via the beta-adrenergic pathway influences the evolution of idiopathic dilated cardiomyopathy. We assessed the effects of beta-adrenergic receptor variants on heart failure in idiopathic dilated cardiomyopathy. METHODS: We prospectively analyzed 171 consecutive patients (mean [+/- SD] age, 49 +/- 14 years; 129 men) with idiopathic dilated cardiomyopathy who were receiving conventional treatment. All were characterized by polymerase chain reaction-restriction fragment length polymorphism analysis for Ser49Gly and Arg389Gly in the beta1-adrenergic receptor; the 5' leader cistron (LC) Arg19Cys, Arg16Gly, Gln27Glu, and Thr164Ile in the beta2-adrenergic receptor; and Arg64Trp in the beta3-adrenergic receptor. The endpoint was heart failure, defined as a worsening of clinical condition leading to hospitalization for heart failure, cardiac transplantation, or death from heart failure. RESULTS: During a median follow-up of 33 months, 24 patients had heart failure. In a Cox univariate analysis, the beta1Gly49 and beta2 5'LC-Cys19, Arg16, and Gln27 alleles were associated with a lower risk of heart failure. In a multivariate analysis that considered age, functional class, left ventricular ejection fraction, and beta-blocker use, three beta2-adrenergic receptor alleles were associated with lower risk: 5'LC-Cys19 (hazard ratio [HR]: 0.15; 95% confidence interval [CI]: 0.05 to 0.42), Arg16 (HR: 0.12; 95% CI: 0.04 to 0.35), and Gln27 (HR: 0.15; 95% CI: 0.05 to 0.42). CONCLUSION: The Gly49 allele in the beta1-adrenergic receptor and the 5' LC-Cys19, Arg16, and Gln27 alleles in the beta2-adrenergic receptor were associated with a lower risk of heart failure in idiopathic dilated cardiomyopathy, suggesting that the beta1- and beta2-adrenergic receptor genes are modifier genes.

Comparison of the effect of valsartan and lisinopril on autonomic nervous system activity in chronic heart failure.

BACKGROUND: In chronic heart failure (CHF), the derangement of autonomic nervous system activity has a deep impact on the progression of the disease. It has been demonstrated that modulation of the renin-angiotensin aldosterone system (RAAS) increases autonomic control of heart rate and reduces adrenergic activity. We sought to evaluate, in CHF, the different effects of an ACE inhibitor (lisinopril) and of an AT1 receptor antagonist (valsartan) on heart rate variability, baroreflex sensitivity and norepinephrine plasma levels. METHODS: Ninety patients (61 +/- 10 years, 2.3 +/- 0.5, New York Heart Association class) with CHF and left ventricular ejection fraction <40% were randomly assigned in a double-blind fashion to receive lisinopril (uptitrated to 20 mg/d) or valsartan (uptitrated to 160 mg/d) therapy for 16 weeks. Heart rate variability (evaluated by measuring standard deviation of normal R-R intervals on 24-hour ECG recordings), spontaneous baroreflex sensitivity and aldosterone and norepinephrine plasma levels were assessed before and after drug therapy. RESULTS: There were no significant differences between valsartan and lisinopril in their effects on left ventricular function, arterial pressure, aldosterone plasma levels and autonomic control of heart rate. Both lisinopril and valsartan significantly reduced plasma norepinephrine levels, but the reduction induced by valsartan was significantly greater than that observed for lisinopril (27% vs 6%, P <.05). CONCLUSIONS: This study shows a comparable effect of ACE inhibition (lisinopril) and of AT1 receptor antagonism (valsartan) on cardiac vagal control of heart rate, whereas valsartan has shown a more effective modulation of sympathetic activity measured by plasma norepinephrine levels.

Allelic variants of natriuretic peptide receptor genes are associated with family history of hypertension and cardiovascular phenotype.

OBJECTIVE: Abnormalities in the natriuretic peptide system could play a key role in the genesis of hypertension. We evaluated the associations between a family history of hypertension, cardiovascular phenotype and allelic variants of Npr1 and Npr3, two candidate genes that codify for natriuretic peptide receptors. METHODS: We genotyped 45 young normotensive subjects (19 males, 26.8 +/- 3.7 years) with accurately assessed family history of hypertension (FH+) and 52 (26 males, 26.1 +/- 3.1 years) without (FH-) for the known variants of Npr1 and Npr3 genes, and for a novel length difference (3C/4C) polymorphism at position 15129 in the 3'-untranslated region of the Npr1 gene. Blood pressure, echocardiography and plasma brain natriuretic peptide were assessed. RESULTS: Both the novel Npr1 3C allele (59 versus 33%, P < 0.001) and the 3C/3C genotype (31 versus 8%; P < 0.001) were significantly more frequent in FH+ than in FH-. The inverse distribution of the 4C/4C genotype suggested that a casual association was very unlikely. Moreover, the 3C/3C homozygous had significantly higher systolic blood pressure (121.1 +/- 6.3 versus 115.6 +/- 7.8 mmHg in 4C/4C; P < 0.05) and a longer left ventricular isovolumic relaxation time (67 +/- 10 versus 61 +/- 9 ms; P < 0.05). The Npr3 C(-55) allele variant was also more frequent in FH+ (88 versus 76%, P < 0.05), but was not associated with the cardiovascular phenotype. CONCLUSIONS: The novel Npr1 gene 3C variant and the Npr3 gene C(-55) allele are associated with hypertensive family history. Moreover, the functional Npr1 3C variant, when homozygous, is also associated with higher systolic blood pressure and prolonged ventricular relaxation.

Comparative effect of lercanidipine, felodipine, and nifedipine GITS on blood pressure and heart rate in patients with mild to moderate arterial hypertension: the Lercanidipine in Adults (LEAD) Study.

This multicenter, double-blind, parallel-group study compared the effects of three dihydropyridine calcium channel blockers (lercanidipine, felodipine, and nifedipine gastrointestinal therapeutic system) on blood pressure and heart rate in 250 patients with mild to moderate hypertension (diastolic blood pressure > or =95 and 109 mm Hg). Patients were randomized to 4 weeks of treatment with once-daily doses of lercanidipine 10 mg, felodipine 10 mg, or nifedipine gastrointestinal therapeutic system 30 mg. After 4 weeks of treatment, the dose was doubled in nonresponding patients. At 8 weeks, no significant differences in blood pressure were observed among the three groups. Increases in heart rate in all three groups induced by stressful conditions before and after treatment were not exacerbated during active treatment. The incidence of adverse drug reactions was lower in the lercanidipine and nifedipine groups than in the felodipine group (p<0.05); in particular, the incidence of edema for lercanidipine was 5.5% vs. 13% for felodipine and 6.6% for nifedipine.

The role of dobutamine stress echocardiography in idiopathic dilated cardiomyopathy.

In patients with chronic heart failure, myocardial contractile responsiveness to dobutamine is diminished as a result of beta-receptor desensitization due to chronic adrenergic activation. Changes in beta-receptor effector mechanisms are more marked in idiopathic dilated cardiomyopathy (IDCM) than in ischemic dilated cardiomyopathy. As the magnitude of the dobutamine effect is proportional to the severity of left ventricular systolic dysfunction, the heterogeneous cardiotonic effects of dobutamine in IDCM may represent different evolutive stages of a progressive disease process. On the basis of this pathophysiologic background, some studies were undertaken to investigate the prognostic and functional implications of dobutamine stress echocardiography (DSE) in IDCM. Prognostic studies consistently suggest that myocardial response to dobutamine is related to the clinical outcome. However, the limited number of patients and events in the individual studies are important limitations. Moreover, the impact of beta-blockers on the potential ability of DSE to predict the prognosis needs to be assessed. A few studies also suggest that changes in left ventricular systolic function parameters following dobutamine infusion are related to exercise tolerance, as assessed by peak exercise oxygen consumption and functional recovery of the failing myocardium. The data suggest that DSE is a promising method, which may improve the risk stratification process in patients with IDCM and provide further insights into the pathophysiologic mechanisms underlying progressive systolic pump dysfunction and exercise intolerance. Further studies are however needed to define the role of DSE in IDCM.

[Natriuretic peptides and essential arterial hypertension]. / Peptidi natriuretici e ipertensione arteriosa essenziale.

Natriuretic peptide system plays a well-defined role in the regulation of blood pressure and fluid volume. Although the effects of natriuretic peptides (atrial natriuretic peptide, brain natriuretic peptide and C-type natriuretic peptide) are mediated by specific biologic receptors, their plasma level is influenced by clearance receptors. It has been demonstrated that in hypertensive subjects plasma levels of natriuretic peptides are impaired; furthermore peptide receptor polymorphisms have been shown to be significantly associated with hypertension and cardiac hypertrophy. Studying normotensive subjects at high genetic risk of developing hypertension on the basis of family history makes it possible to investigate the role of natriuretic peptide system in the genesis of hypertension. It has been shown that plasma atrial and ventricular natriuretic peptide levels are significantly reduced in normotensive subjects with a family history of hypertension. Our study is the first one showing association among positive family history of essential hypertension and natriuretic peptide receptor polymorphisms. We identified a novel insertion/deletion polymorphism at position 15,129 in the 3'-untranslated region (3'-UTR) of NPRA receptor mRNA. The NPRA gene deletion variant is associated with hypertensive family history and higher systolic blood pressure. The "deletion 15129" variant might participate in the functional impairment of natriuretic peptide system defining an increased genetic susceptibility to hypertension.

[Diagnosis of neurogenic syncope--current views]. / Diagnosi di sincope neurocardiogena. Recenti vedute.

Neurocardiogenic syncope is a very common clinical problem and represents the most frequent cause of syncope. Its diagnosis is difficult because there are several and heterogeneous causes of syncope, that can interact each other, and the accuracy of the available diagnostic instruments is sometimes not high enough. For these reasons, the classification of a syncope as neurocardiogenic is the result of an evaluation, whose main purpose is the exclusion of the other possible causes of syncope with worse prognosis. The head tilt-up test is recommended for the diagnosis of the most frequent type of neurocardiogenic syncope, the vasovagal syncope. The methodological improvement of tilt test could, in the future, improve its diagnostic accuracy and could optimise the time of execution.

Metabolic treatment with L-carnitine in acute anterior ST segment elevation myocardial infarction. A randomized controlled trial.

BACKGROUND: Administration of L-carnitine in patients with anterior acute myocardial infarction (AMI) prevents left ventricular remodeling. Current study was aimed to assess the effect of L-carnitine administration on mortality and heart failure in patients with anterior AMI. METHODS: CEDIM 2 trial was a randomized, double-blind, multicenter, placebo-controlled trial planned to enroll 4,000 patients with acute anterior AMI. The trial was interrupted after the enrolment of 2,330 patients because of the lower than expected enrolment rate. The primary end point was a composite of death and heart failure at 6 months; 5-day mortality was the secondary end point. RESULTS: During the 6-month follow-up, the primary end-point was not significantly different between the L-carnitine and placebo group (9.2 vs. 10.5%, p = 0.27). A reduction in mortality was seen in the L-carnitine arm on day 5 (secondary end-point) from randomization (HR = 0.61, 95% CI 0.37-0.98, p = 0.041). CONCLUSIONS: In CEDIM 2 trial L-carnitine therapy led to a reduction in early mortality (secondary end-point) without affecting the risk of death and heart failure at 6 months in patients with anterior AMI, leading to a non-significant finding with respect to the primary end-point.

Clinical effects of endothelin receptor antagonism with bosentan in patients with severe chronic heart failure: results of a pilot study.

BACKGROUND: Endothelin receptor antagonism produces favorable short-term hemodynamic effects in heart failure, but the clinical effects of longer term therapy have not been evaluated. METHODS AND RESULTS: Three hundred and seventy patients with symptoms of heart failure at rest or on minimal exertion and a left ventricular ejection fraction <35% were randomly assigned (double-blind) to placebo (n = 126) or the endothelin receptor antagonist bosentan, titrated slowly (n = 121) or rapidly (n = 123) to a target dose of 500 mg twice daily. Treatment with the study drug was to be maintained for 26 weeks, whereas background medications for heart failure were kept constant. Safety concerns led to early termination of the trial when only 174 patients had had an opportunity to complete 26 weeks of therapy. Bosentan exerted no apparent benefit when all randomized patients were analyzed (P = .709). However, in the first 174 patients who were recruited at least 26 weeks before study termination and who could therefore be followed for the planned duration of the trial, patients in the bosentan groups were more likely to be improved (26% versus 19%) and were less likely to be worse (28% versus 43%), P = .045. When compared with placebo-treated patients, bosentan-treated patients had a increased risk of heart failure during the first month of treatment but a decreased risk of heart failure during the fourth, fifth, and sixth months of therapy. The major noncardiac adverse effects of bosentan included an increase in hepatic transaminases (in 15.6% of patients) and a decrease in hemoglobin (of about 1 g/L). CONCLUSION: Although bosentan exerted no favorable effects in the overall study, our findings suggest that the clinical responses to endothelin antagonism with bosentan in patients with severe chronic heart failure may be dependent on the duration of treatment.

Dynamics of ventricular repolarization in patients with dilated cardiomyopathy versus healthy subjects.

BACKGROUND: Patients with impaired left ventricular function have a high risk of developing ventricular arrhythmias and sudden death. Among different markers of risk, the prolongation and regional heterogeneity of repolarization are of increasing interest. However, there are limited data regarding feasibility of analyzing repolarization parameters and their dynamics in 24-hour Holter ECG recordings. METHODS: Dynamic behavior of repolarization parameters was studied with a new automatic algorithm in digital 24-hour Holter recordings of 60 healthy subjects and 55 patients with idiopathic dilated cardiomyopathy (IDC). Repolarization parameters included the mean value of QT and QTc durations, QT dispersion, and peaks of QT duration and QT dispersion above prespecified thresholds. RESULTS: In comparison to healthy subjects, patients with IDC had lower heart rate variability, longer mean QT and QTc durations, higher content of QTc peaks >500 ms, longer QT dispersion and its standard deviation, and a higher content of peaks >100 ms of QT dispersion (P < 0.01 for all comparisons). These repolarization parameters were significantly higher in IDC patients after adjustment for age, sex, and heart rate variability. The parameters of repolarization dynamics correlated with SDNN in healthy subjects but not in dilated cardiomyopathy patients. CONCLUSIONS: The automatic assessment of repolarization parameters in 24-hour digital ECG recordings is feasible and differentiates dilated cardiomyopathy patients from healthy subjects. Patients with dilated cardiomyopathy have increased QT duration, QT dispersion, and increased variability of QT dispersion reflecting variations in T-wave morphology, the factors which might predispose them to the development of arrhythmic events.

Far-field R wave oversensing in dual chamber pacemakers designed for atrial arrhythmia management: effect of pacing site and lead tip to ring distance.

INAMA, G., et al.: Far-Field R Wave Oversensing in Dual Chamber Pacemakers Designed for Atrial Arrhythmia Management: Effect of Pacing Site and Lead Tip to Ring Distance. The aim of the study was to determine the incidence and practical implications of far-field R wave oversensing (FFRWO) and its association with pacing site and lead tip to ring spacing (TTRS) in implantable devices designed to diagnose and treat atrial tachyarrhythmias and programmed with a fixed and short postventricular blanking period. The study included 395 patients who were implanted with a DDDRP pacemaker and prospectively followed. At implant and follow-up visits FFRWO was assessed by analyzing lead electrical measures and atrial tachyarrhythmic episodes collected in the device diagnostics. During a median follow-up of 12 months 11 (2.8%) of 395 patients showed a clinically significant FFRWO that induced inappropriate detection or pacemaker malfunctioning. The atrial pacing site of these 11 patients was right atrium appendage (RAA) for 3 patients, representing 1.1% of 254 RAA patients, coronary sinus ostium (CSO) for 7 patients, representing 7.4% of 94 CSO patients (P < 0.005 vs RAA), and lateral wall (LW) for 1 (2.9%) of 34 LW patients. The minimal value of the FFRWO to P wave ratio, measured at implant, associated with a clinically significant FFRWO was 0.6; therefore, a value of 0.5 was used as a cutoff to identify patients at risk of undesirable device behavior induced by FFRWO: there were 11 (9.6%) of 114 of RAA patients with short (< or = 10 mm) TTRS, 22 (18.8%) of 117 of RAA patients with long (> or = 17 mm) TTRS (P < 0.05 vs short TTRS), 21 (30.6%) of 64 of CSO patients short TTRS (P < 0.001 vs RAA patients with short TTRS) and 3 (30%) of 10 of CSO patients with long TTRS. The analysis showed that, despite the short postventricular blanking time, FFRWO inducing undesired functioning in AT500 pacemakers is infrequent (2.8% of patients). Compared to RAA, the CSO lead position was more frequently associated with FFRWO.TTRS < 10 mm was associated with lower risk of clinically significant FFRWO in RAA. (PACE 2004; 27:1221-1230).