M. V. Pitzalis

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.

Usefulness of Conventional Transthoracic Echocardiography in Selecting Heart Failure Patients Likely to Benefit from Cardiac Resynchronisation Therapy

Beneficial effects of cardiac resynchronisation therapy (CRT), including reverse remodelling, improvement in ejection fraction, and decrease in mitral regurgitation as well as clinical improvements in exercise tolerance, quality of life, and hospitalisation rate, have been well documented [1–4], supporting the routine use of CRT as a worthwhile therapeutic option for patients with severe heart failure and left intraventricular conduction delay (QRS duration > 120 ms) who remain symptomatic despite receiving ‘optimal’ medical treatment. However, not all patients have subjective and/or objective responses to CRT [5, 6]. Given the complexity of the procedure and the associated costs, there is a need for parameters other than QRS duration that could prospectively identify the patients who would benefit most [7]. The beneficial effects of CRT are due to the fact that it corrects dyssynchrony resulting from interand intraventricular conduction delay, thus counteracting its negative haemodynamic effects. Left ventricular conduction delay induces a particular pathophysiological condition in which abrupt anterior septal motion, occurring at the time of decreasing right ventricular volume with pulmonary ejection [8], is associated with delayed contraction of the postero-lateral left ventricular wall. This condition increases wall stress during systole and oxygen demand. Moreover, the asynchrony between the septum and the lateral wall impairs the coaptation of mitral leaflets, thus favouring mitral regurgitation. Finally, tricuspid valve opening and right ventricular filling occur much earlier than mitral valve opening and left ventricular filling, thus contributing to early diastolic displacement of the septum into the left ventricle, a reduced septal contribution to ejection fraction,

443 Beta1‐adrenergic receptor polymorphisms predict heart failure progression in idiopathic dilated cardiomyopathy

Background: Mitochondria is known to represent the main intracellular source of ROS. However, the role that the mitochondrial KATP (mKATP) channel could play in the oxidative stress during myocardial hypoxiareoxygenation remains unclear. Methods: Spontaneously beating hearts were dissected from 4-day-old chick embryos, mounted in vitro and submitted successively to 45 min normoxia (21% O2), 30 min anoxia (0% O2) and 60 min reoxygenation at 37°C. The time-course of ROS production in the ventricle was determined by measuring changes in fluorescence resulting from oxidation of the intracellular probe DCFH (10 μM) and expressed as arbitrary units per second (a.u./s). In order to determine the contribution of the mitochondria-derived ROS and its dependence on O2 concentration during reoxygenation, hearts were reoxygenated with 21% or 98% O2 in the absence (control) or in the presence of the complex III inhibitor myxothiazol (10μM). The involvement of the mKATP channel in ROS production has been assessed by using an opener (diazoxide, 50μM) or a blocker (5-hydroxydecanoate, 500 μM) of this channel. Results: In control hearts, ROS production was 0.18±0.04 (n=6) a.u./s under steady normoxia (mean±SD), was suppressed by anoxia and peaked after 9±3 min of reoxygenation, reaching 1.02±0.37 (n=6) and 1.63±0.34 (n=3) a.u./s with 21 and 98% O2, respectively (mean±SD). In myxothiazol-treated hearts, the peak of ROS at reoxygenation was reduced to 0.29±0.18 (n=3) and 0.41±0.08 (n=3) a.u./s with 21 and 98% O2, respectively. With respect to control, 5-hydroxydecanoate (n=5) and diazoxide (n=5) had no effect on DCFH signal measured under normoxia. By contrast, the peak of ROS production during the phase of reoxygenation was doubled by diazoxide (p<0.03) whereas 5-hydroxydecanoate had no effect. Furthermore, although the mKATP channel opener was markedly prooxidant during reoxygenation, it did not significantly alter the chrono-, dromoand inotropic disturbances observed during oxygen deprivation and readmission. Conclusion: It appears that the mKATP channel of the developing myocardium remains in closed state throughout anoxia-reoxygenation, limiting the mitochondrial oxidative burst.