Abstract: OBJECTIVE: To evaluate the role of brain natriuretic peptide (BNP) in predicting the progression of heart failure (HF) after cardiac resynchronization therapy (CRT). BACKGROUND: It has been shown that BNP predicts the prognosis and can guide the treatment of HF. METHODS: We studied 50 consecutive patients (61+/-10 years, 23 male) with HF (8 with ischaemic cardiomyopathy), NYHA class III, left bundle branch block, left ventricular ejection fraction (LVEF) </=35% (mean 24+/-6%) who underwent CRT. All patients were taking conventional HF therapy and were clinically stable. Plasma BNP levels were evaluated by two-site dual-monoclonal immunochemiluminescent assay before, and 1 month after CRT. The predictive value of BNP was assessed using univariate and multivariate regression analyses. RESULTS: During follow-up (mean 19+/-12 months), HF progression was observed in 14 patients (11 were hospitalised and 3 died after worsening of HF). Multivariate analysis showed that BNP levels before (HR: 2.07; CI: 1.19-3.62; p=0.01) and 1 month after CRT (HR: 2.23; CI: 1.26-3.94; p=0.006) were significantly related to events. At 1 month, a BNP level >91.5 pg/ml had 89% sensitivity, 59% specificity, and negative and positive predictive values of 96% and 33%, respectively, for HF progression after 12 months. CONCLUSIONS: HF patients with high BNP values after 1 month of CRT have worse prognosis during follow-up. Therefore, in these patients other therapeutic options should be considered.
Abstract: 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.
Abstract: BACKGROUND: Brugada syndrome is associated with a high risk of sudden cardiac death and is caused by mutations in the cardiac voltage-gated sodium channel gene. Previously, the R282H-SCN5A mutation in the sodium channel gene was identified in patients with Brugada syndrome. In a family carrying the R282H-SCN5A mutation, an asymptomatic individual had a common H558R-SCN5A polymorphism and the mutation on separate chromosomes. Therefore, we hypothesized that the polymorphism could rescue the mutation. METHODS AND RESULTS: In heterologous cells, expression of the mutation alone did not produce sodium current. However, coexpressing the mutation with the polymorphism produced significantly greater current than coexpressing the mutant with the wild-type gene, demonstrating that the polymorphism rescues the mutation. Using immunocytochemistry, we demonstrated that the R282H-SCN5A construct can traffic to the cell membrane only in the presence of the H558R-SCN5A polymorphism. Using fluorescence resonance energy transfer and protein fragments centered on H558R-SCN5A, we demonstrated that cardiac sodium channels preferentially interact when the polymorphism is expressed on one protein but not the other. CONCLUSIONS: This study suggests a mechanism whereby the Brugada syndrome has incomplete penetrance. More importantly, this study suggests that genetic polymorphisms may be a potential target for future therapies aimed at rescuing specific dysfunctional protein channels.
Abstract: BACKGROUND: The offspring of hypertensive families are characterized by higher arterial blood pressure values and a depressed autonomic control of heart rate. The present study aimed to verify whether these differences are associated with a different genotype distribution of functionally relevant polymorphisms of the alpha- and beta-adrenergic receptor (AR) genes. METHODS: We selected 109 age- and sex-matched young normotensive subjects with (FH+, n = 56) and without (FH-, n = 53) a family history of hypertension who underwent evaluation of arterial pressure; 24-h electrocardiogram monitoring to assess time-domain parameters of autonomic heart rate control [i.e. mean RR interval (NN), SD of RR intervals (SDNN) and mean square root of the differences of consecutive RR intervals (rMSSD)]; spectral baroreflex sensitivity measurement; and echo-Doppler to assess diastolic function and left ventricular mass. They were also characterized for the following polymorphisms by means of polymerase chain reaction-restriction fragment polymorphism analysis: Arg492Cys in the alpha1a-AR; Del301-303 in the alpha2b-AR; Ser49Gly and Arg389Gly in the beta1-AR; and the 5' leader cistron Arg19Cys, Arg16Gly and Gln27Glu in the beta2-AR. RESULTS: FH+ individuals showed a higher systolic pressure, a lower SDNN and a greater isovolumic relaxation time compared to normotensive offspring. No differences were found between the two groups when genotype distribution of the studied polymorphisms was considered. Subjects carrying alpha1a-AR Cys492 allelic variant showed lower values of NN, SDNN and rMSSD, independent of age, gender and body mass index. CONCLUSIONS: The functionally relevant polymorphisms of alpha2b-, beta1- and beta2-AR genes are not associated with a family history of essential hypertension. The Arg492Cys polymorphism of the alpha1a-AR gene, although not associated with a family history of hypertension, was strongly related to autonomic control of heart rate.
Abstract: 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.
Abstract: 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.
Abstract: 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.
Abstract: 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.
Abstract: 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.
