Joyner, Michael J.

Background— The gene encoding ACE exhibits an insertion/deletion polymorphism resulting in 3 genotypes (DD, ID, and II), which affects serum and tissue ACE activity as well as other vasoactive substances. Pulmonary function is frequently abnormal in patients with congestive heart failure (CHF), the mechanism of which has not been completely characterized. ACE inhibition has been shown to improve diffusion across the alveolar-capillary membrane and to improve exercise capacity and gas exchange in CHF. The aim of the current study was to determine if ACE genotype is associated with altered pulmonary function and exercise intolerance in patients with treated CHF. Methods and Results— Fifty-seven patients (stratified according to ACE genotype as17 DD, 28 ID, 12 II) with ischemic and dilated cardiomyopathy, left ventricular ejection fraction (LVEF) <35%, and <10 pack-years of smoking history were studied. All patients were receiving standard therapy for left ventricular systolic dysfunction. Pulmonary function, LVEF, serum ACE, plasma angiotensin II, atrial natriuretic peptide, and brain natriuretic peptide were measured at baseline. Peak V̇ o 2 and gas exchange measurements were assessed with graded exercise. Resting LVEF was similar among the genotype groups (25% to 28%), and no differences were observed in diastolic function or pulmonary artery pressures ( P >0.05). Mean peak V̇ o 2 and forced vital capacity (% Pred) were significantly reduced ( P <0.05), whereas mean serum ACE activity and plasma angiotensin II concentration were highest in DD homozygotes. Subjects homozygous for the D-allele also demonstrated higher mean ventilatory equivalents for carbon dioxide (V̇ e /V̇ co 2 ) during exercise ( P <0.05). Conclusions— ACE DD genotype is associated with decreased exercise tolerance in CHF, possibly mediated by altered pulmonary function. Pharmacological strategies effecting more complete inhibition of serum and tissue ACE and/or potentiation of bradykinin may improve exercise capacity in patients with CHF and ACE DD genotype.

Background— Muscle sympathetic vasoconstrictor nerve activity increases with age in healthy humans but does not result in an augmented forearm vasoconstrictor tone. We tested the hypothesis that this is due to a reduction in postjunctional α-adrenergic responsiveness to endogenous norepinephrine (NE) release and determined whether this was specific to α 1 - or α 2 -adrenergic receptors. Methods and Results— Forearm blood flow (FBF, by strain-gauge plethysmography) responses to local intra-arterial infusions of tyramine (which evokes endogenous NE release), phenylephrine (selective α 1 -agonist), and clonidine (α 2 -agonist) were determined in 10 young (aged 26±1 [mean±SEM] years) and 10 older (aged 65±1 years) healthy normotensive men after local β-adrenergic blockade with propranolol. Basal forearm vascular tone was not different in young men and older men. The percentage reduction in FBF in response to the highest dose of tyramine was blunted in older men compared with young men (−37±3% versus −49±3%, respectively; P <0.01) despite a greater increase in deep venous NE concentration in older men (910±103 versus 565±69 pg/mL, respectively; P <0.001). Maximal reductions in FBF to phenylephrine were also blunted in older men (−47±2% versus −58±3% in young men, P <0.05). In contrast, the reductions in FBF (−36±7% versus −40±3% for older versus young men, respectively) and also in venous NE concentration (−79±24 versus −84±13 pg/mL for older versus young men, respectively) to clonidine were similar in the 2 groups. Finally, forearm sympathetic α-adrenergic vasoconstrictor tone (assessed via nonselective α-blockade with phentolamine) was significantly lower in older men. Conclusions— Our results indicate that human aging is associated with a reduction in forearm postjunctional α-adrenergic responsiveness to endogenous NE release and that this might be specific to α 1 -adrenergic receptors. Furthermore, the contribution of sympathetic α-adrenergic vasoconstriction to basal forearm vascular tone is reduced with age in healthy men.