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Background: The presence of significant preoperative aortic insufficiency (AI) or the need for cusp repair has been suggested as a risk factor for poorer outcomes after aortic valve (AV)-sparing surgery. We analyzed the influence of these factors on the mid-term outcomes of AV surgery., Methods and Results: Between 1996 and 2008, 164 consecutive patients underwent elective AV-sparing surgery. Severe preoperative AI (grade > or =3+) was present in 93 patients (57%), and 54 (33%) had a bicuspid valve. Root repair was performed with either the reimplantation (74%) or the remodeling (26%) technique, and cusp repair was performed in 90 patients (55%). Mean clinical follow-up was 57 months. Hospital mortality was 0.6%. Cusp repair was required in 52% of the patients with preoperative AI < or =2+ and in 57% of those with AI > or =3+ (P=0.6). Cusp repair was required more frequently in bicuspid versus tricuspid valves (91% versus 38%, P<0.001). Overall survival at 8 years was 88+/-8%. Freedom from AV reoperation at 8 years was similar with preoperative AI < or =2+ versus preoperative AI > or =3+ (89+/-11% versus 90+/-7%, P=0.7) and with versus without cusp repair (84+/-17% versus 92+/-8%, P=0.5). Freedom from recurrent AI (grade > or =3+) at 5 years was also similar between groups (90+/-10% versus 89+/-8%, P=0.9, and 90+/-8% versus 89+/-9%, P=0.8, respectively). By multivariate analyses, predictors of recurrent AI > or =2+ were preoperative left ventricle end-diastolic diameter and AI >1+ on discharge echocardiography., Conclusions: With a systematic approach to cusp assessment and repair, AV-sparing surgery for root pathology has an acceptable mid-term outcome, irrespective of preoperative AI or need for cusp repair.

Background: The therapeutic effects of nonspecific beta-blockers are limited by vasoconstriction, thus justifying the interest in molecules with ancillary vasodilating properties. Nebivolol is a selective beta1-adrenoreceptor antagonist that releases nitric oxide (NO) through incompletely characterized mechanisms. We identified endothelial beta3-adrenoreceptors in human coronary microarteries that mediate endothelium- and NO-dependent relaxation and hypothesized that nebivolol activates these beta3-adrenoreceptors., Methods and Results: Nebivolol dose-dependently relaxed rodent coronary resistance microarteries studied by videomicroscopy (10 micromol/L, -86+/-6% of prostaglandin F2alpha contraction); this was sensitive to NO synthase (NOS) inhibition, unaffected by the beta(1-2)-blocker nadolol, and prevented by the beta(1-2-3)-blocker bupranolol (P<0.05; n=3 to 8). Importantly, nebivolol failed to relax microarteries from beta3-adrenoreceptor-deficient mice. Nebivolol (10 micromol/L) also relaxed human coronary microvessels (-71+/-5% of KCl contraction); this was dependent on a functional endothelium and NO synthase but insensitive to beta(1-2)-blockade (all P<0.05). In a mouse aortic ring assay of neoangiogenesis, nebivolol induced neocapillary tube formation in rings from wild-type but not beta3-adrenoreceptor- or endothelial NOS-deficient mice. In cultured endothelial cells, 10 micromol/L nebivolol increased NO release by 200% as measured by electron paramagnetic spin trapping, which was also reversed by NOS inhibition. In parallel, endothelial NOS was dephosphorylated on threonine(495), and fura-2 calcium fluorescence increased by 91.8+/-23.7%; this effect was unaffected by beta(1-2)-blockade but abrogated by beta(1-2-3)-blockade (all P<0.05)., Conclusions: Nebivolol dilates human and rodent coronary resistance microarteries through an agonist effect on endothelial beta3-adrenoreceptors to release NO and promote neoangiogenesis. These properties may prove particularly beneficial for the treatment of ischemic and cardiac failure diseases through preservation of coronary reserve.

Background: Coronary vessel tone is modulated in part by beta-adrenergic relaxation. However, the implication of specific beta-adrenoceptor subtypes and their downstream vasorelaxing mechanism(s) in human coronary resistance arteries is poorly defined. beta3-Adrenoceptors were recently shown to vasodilate animal vessels and are expressed in human hearts., Methods and Results: We examined the expression and functional role of beta3-adrenoceptors in human coronary microarteries and their coupling to vasodilating nitric oxide (NO) and/or hyperpolarization mechanisms. The expression of beta3-adrenoceptor mRNA and protein was demonstrated in extracts of human coronary microarteries. Immunohistochemical analysis revealed their exclusive localization in the endothelium, with no staining of vascular smooth muscle. In contractility experiments in which videomicroscopy was used, the nonspecific beta-agonist isoproterenol and the beta3-preferential agonist BRL37344 evoked an approximately 50% relaxation of endothelin-1-preconstricted human coronary microarteries. Relaxations were blocked by the beta1/beta2/beta3-adrenoceptor antagonist bupranolol but were insensitive to the beta1/beta2-adrenoceptor antagonist nadolol, confirming a beta3-adrenoceptor-mediated pathway. Relaxation in response to BRL37344 was absent in human coronary microarteries devoid of functional endothelium. When human coronary microarteries were precontracted with KCl (thereby preventing vessel hyperpolarization), the relaxation to BRL37344 was reduced to 15.5% and totally abrogated by the NO synthase inhibitor L-omega-nitroarginine, confirming the participation of a NO synthase-mediated relaxation. The NO synthase-independent relaxation was completely inhibited by the Ca2+-activated K+ channel inhibitors apamin and charybdotoxin, consistent with an additional endothelium-derived hyperpolarizing factor-like response. Accordingly, membrane potential recordings demonstrated vessel hyperpolarization in response to beta3-adrenoceptor stimulation., Conclusions: Beta3-adrenoceptors are expressed in the endothelium of human coronary resistance arteries and mediate adrenergic vasodilatation through both NO and vessel hyperpolarization.