Roberta Romito

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.

SCN5A Polymorphism Restores Trafficking of a Brugada Syndrome Mutation on a Separate Gene

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.

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.

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.

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.

Influence of gender and family history of hypertension on autonomic control of heart rate, diastolic function and brain natriuretic peptide

Objective To verify in a unitary view whether autonomic control of heart rate and cardiac structure and function are modified early in offspring of hypertensive families. Methods and results We selected 87 age- and sex-matched young normotensive subjects with (n = 45) and without (n = 42) a family history of hypertension who underwent evaluations of arterial pressure, time-domain parameters of autonomic heart rate control (24-h ECG monitoring), spectral baroreflex sensitivity, left ventricular geometry and function (echo-Doppler) and plasma brain natriuretic peptide levels (BNP). The group with a family history of hypertension significantly differed from their counterparts for systolic pressure (119 ± 11 versus 114 ± 9 mmHg, P< 0.05), heart rate (RR interval, 766 ± 64 versus 810 ± 93 ms, P< 0.05), heart rate variability [the standard deviation of normal RR intervals (SDNN), 147 ± 29 versus 171 ± 33 ms, P< 0.05], diastolic function (isovolumetric relaxation time, 65 ± 9 versus 60 ± 8 ms, P< 0.05) and BNP (23 ± 13 versus 37 ± 10 pg/ml, P< 0.05). Baroreflex sensitivity values did not differ between the two groups. When gender was considered, all the above-mentioned measures, as well as baroreflex sensitivity, were significantly different between males with and without a family history of hypertension but not between females, except for BNP, which was lower in males and females with a history of hypertension (males, 24 ± 11 versus 38 ± 8 pg/ml, P< 0.01; females 21 ± 14 versus 36 ± 13 pg/ml, P< 0.05). Conclusions Male, but not female, hypertensive offspring have modified diastolic function and autonomic control of heart rate; BNP is the only parameter able to characterize hypertensive offspring independently from the influence of gender. This provides the hypothesis that the impaired production of this hormone could play a primary role in the pre-hypertensive state.

Prognostic value of brain natriuretic peptide in the management of patients receiving cardiac resynchronization therapy

To evaluate the role of brain natriuretic peptide (BNP) in predicting the progression of heart failure (HF) after cardiac resynchronization therapy (CRT).

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 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.

Beta1- and beta2-adrenergic receptor polymorphisms affect susceptibility to idiopathic dilated cardiomyopathy.

Objective β1- and β2-adrenergic receptors (ARs) play a pivotal role in myocardial function. We investigated whether functionally relevant polymorphisms within the genes encoding for these receptors indicate susceptibility to idiopathic dilated cardiomyopathy (DCM). Methods This case–control association study involved 189 patients with DCM and 378 gender- and age-matched control subjects. All of the subjects were characterised by polymerase chain reaction–restriction fragment length polymorphism analysis in terms of Ser49Gly and Arg389Gly polymorphisms in the β1-AR, and the 5′ leader cistron Arg19Cys, Arg16Gly, Gln27Glu, and Thr164Ile polymorphisms in the β2-AR. Genotype, allele and haplotype frequencies were analysed. Results Univariate analysis showed that the distribution of genotype and allele frequencies of the β1-Ser49Gly, β1-Arg389Gly and β2-Arg16Gly polymorphisms was significantly different between the patients and controls, and the β1-Gly49/β1-Arg389 haplotype was significantly more represented in the patients. Multivariate analysis showed that only the β1-Gly49 variant (odds ratio 1.91; 95% confidence interval 1.24–2.95; P = 0.003) and β2-Gly16Gly genotype (odds ratio 1.58; 95% confidence interval 1.10–2.26; P = 0.013) carriers were at significantly higher risk of developing DCM. Conclusions In our population from southern Italy, the Gly49 allele of the β1-AR and the Gly16Gly genotype of the β2-AR were significantly and independently associated with the DCM phenotype, thus suggesting their role in favouring susceptibility to the disease.

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.