Source: DGNews  |  Posted 4 years ago

By Chris Berrie

HAMBURG, GERMANY -- June 13, 2007 -- The Glu27 polymorphism of the beta-2-adrenergic receptor gene is associated with greater improvement in left ventricular function (LVF) and haemodynamic variables after long-term carvedilol treatment among patients with chronic heart failure (CHF), according to a study presented here on June 11th at the Heart Failure Association of the European Society of Cardiology Heart Failure (ESC-HF) congress.

Although the beta-blocker carvedilol can provide highly significant improvements in LVF and outcomes in patients with CHF, individual patient responses are, however, heterogeneous, according to investigator Natalia Pezzali, MD, physician in cardiology, section of cardiovascular diseases, department of experimental and applied medicine, University Hospital, Brescia, Italy.

Carvedilol is an adrenergic receptor blocker that acts on both the beta-1 and beta-2 adrenergic receptors and the genes that regulate beta-2-adrenergic receptor expression are polymorphic. Therefore, Dr. Pezzali and colleagues conducted a study to investigate whether there is any relationship between the two common beta-2 adrenergic receptor gene polymorphisms and the long-term beneficial effects of carvedilol in patients with CHF.

These two gene polymorphisms involve the substitution of Arg for Gly at position 16 and that of Gln for Glu at position 27, Dr. Pezzali detailed. "These two polymorphisms are important because they may affect the regulation of the beta-2-adrenergic receptors," she added.

To investigate this, the researchers used multigated radionuclide angiography (MUGA) and right heart catheterisation to study 183 patients with CHF before and more than 12 months after chronic carvedilol therapy at a mean dose of 34 mg/day.

Of these patients, 31 were homozygotes for the Arg16 polymorphism, 83 were heterozygotes, and 69 were homozygotes for Gly16Gly. Similarly, 27 were homozygotes for the Glu27 polymorphism (Glu27Glu), 66 were heterozygotes (Gln27Glu), and 90 were homozygotes for the wild-type Gly27 polymorphism (Gln27Gln).

While the Arg16Gly polymorphism showed no relation to the response to carvedilol in these patients, the Glu27Glu population, which is associated with reduced agonist-promoted beta-2-adrenergic receptor downregulation []in vitro[], showed a greater response to carvedilol.

Baseline clinical characteristics between the Glu27Glu group (n = 27) as compared to the combined Gln27Glu plus Gln27Gln group (n = 156) showed no significant differences for left ventricular ejection fraction (LVEF), heart rate, systolic volume index (SVI), and pulmonary-wedge pressure (PWP). The cardiac index was, however, significantly greater for the Glu27Glu group ([]P[] <.05).

When the same patient groups were compared for the changes from baseline with regard to LVF and other haemodynamic variables following chronic carvedilol treatment, significant benefits were seen for the Glu27Glu group over the other combined group for changes in LVEF ([]P[] =.011), PWP ([]P[] =.027), and SVI ([]P[] =.044). Changes seen in the left ventricular end-diastolic pressure index were, however, not significant.

Of note, although the comparison of Glu27Glu and the wild-type gene polymorphism (Gln27Gln; i.e. removal of the Gln27Glu heterozygotes from the comparison) showed little differences in changes to LVEF and PWP, the significance of these data were further improved ([]P[] =.004; []P[] =.007; respectively).

In the final multivariate analysis, the Glu27Glu polymorphism was seen to be related to LVEF changes ([]P[] =.015), along with baseline systolic blood pressure ([]P[] <.001) and dose of carvedilol ([]P[] =.002).

This analysis thus demonstrates that the Glu27 polymorphism in the beta-2-adrenergic receptor, which produces a reduced agonist-promoted beta-2-adrenergic receptor down-regulation []in vivo[], also leads to an enhancement in the benefits of chronic carvedilol treatment in patients with CHF.

"This it an idea that needs to be developed, in order to target the heart failure therapy to the individual patient," added Dr. Pezzali.

[[]Presentation title: Beta-2-Adrenergic Receptor Polymorphisms Influence the Effects of Carvedilol in the Patients With Chronic Heart Failure. Abstract P465[]]