Patients with heart failure who had the Glu27 polymorphism of the beta-2 adrenergic receptor gene had a greater improvement after long-term administration of beta-blockers (mostly carvedilol) versus patients who did not have this polymorphism. These patients also had higher stroke volume and lower systemic vascular resistance before carvedilol therapy.

The beta-2 adrenergic receptor is involved in modulation of heart rate and cardiac contractility. Two common Beta-2 adrenergic receptor gene polymorphisms are the substitution of arginine (Arg) with glycine (Gly) at position 16, and the substitution of glutamine (Gln) with glutamic acid (Glu) at position 27.

Patients homozygous for the polymorphism in position 27 (Glu27Glu) are generally also homozygous for Arg at position 16. This genotype has been associated with a number of clinical effects. This includes reduced bronchoconstriction, increased vasodilatatory response, lower systolic blood pressure in hypertensive patients, reduced risk of preeclampsia, increased exercise tolerance and reduced risk of cardiovascular events in the elderly.

Dr. Metra and co-investigators related these 2 polymorphisms to long-term response to beta-blocker therapy in 150 patients with heart failure. Of this group, 125 patients received carvedilol (mean of 34 mg/day) and 35 received metoprolol (mean of 96 mg/day). Investigators looked at hemodynamic response and left ventricular function in these patients before and after beta-blocker therapy (range of 9 to 18 months of therapy).

Investigators found no relationship between the position 16 polymorphism and response to beta-blockers. In contrast, in patients homozygous for the Glu27 polymorphism, there was reduced agonist-promoted beta-2 adrenergic receptor downregulation. These patients also had greater beta-2 adrenergic receptor function and sensitivity.

Investigators looked further at the position 27 polymorphism and response. They divided patients into those homozygous for Gln27 (79 patients), those heterozygous for Gln27/Glu27 (57 patients), and those homozygous for Glu27 (24 patients). Clinical characteristics were similar between the three groups.

Baseline Clinical Characteristics by Gln27Glu Polymorphism   Glu27Glu Gln27Glu Gln27Gln Number of patients 24 57 79 Age, years 54 57 57 Left ventricular ejection fraction, % 21.9 21.8 21.6 Patients on carvedilol (%) 21 (87.5) 46 (80.7) 58 (73.4)

The main aim of the study was to assess the relationship between polymorphisms and response to beta-blocker therapy, which was mainly carvedilol. At baseline, left ventricular ejection fraction data was similar in the 3 study groups. On beta-blocker therapy, all three groups improved significantly. However, the change in ejection fraction was greatest in the 23 subjects homozygous for the Glu27 polymorphism. Similar changes were seen for change in left ventricular end diastolic volume.

The patients homozygous for Glu27 had a greater change in ejection fraction, pulmonary wedge pressure and stroke volume index versus the rest of the patients.

Investigators found heart rate was similar at rest and peak exercise in all study subgroups. However, peripheral vascular resistance was significantly lower in patients homozygous for the Glu27 polymorphism. This was true both at rest and at peak exercise. It was also true for the measurements before and after beta blocker treatment.

Similarly, the stroke volume index was significantly greater in the Glu27 homozygotes both before and after beta-blocker treatment, and at peak exercise on beta-blocker treatment.

Pulmonary vascular resistance was significantly reduced before beta-blocker treatment, and there was a tendency toward reduction during peak exercise.

With regard to hemodynamic data, the Glu27 homozygotes had a greater increase from baseline in the stroke volume index at rest. They also had a greater decline in pulmonary wedge pressure at rest and during peak exercise.

Multivariate analysis showed that there were 4 variables significantly related to greater improvement in ejection fraction after beta-blocker treatment: non-ischemic cardiomyopathy, greater baseline systolic blood pressure, dose of beta-blocker, and being homozygous for the Glu27 polymorphism.

These findings suggest the Glu27 gene polymorphism is associated with less impairment in left ventricular function, both before beta-blocker therapy and after long-term administration of carvedilol. Next, investigators will analyze the relationship between these polymorphisms and response in carvedilol-treated patients only.