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Background: Atrial fibrillation (AF) is an important risk factor for stroke and is common among elderly patients undergoing transcatheter aortic valve implantation. The aim of this study was to assess the impact of AF on clinical outcomes among patients undergoing transcatheter aortic valve implantation., Methods and Results: Between August 2007 and October 2011, a total of 389 high-risk patients undergoing transcatheter aortic valve implantation were included into a prospective registry. AF was recorded in 131 patients (33.7%) with a mean CHA(2)DS(2)-VASC score of 4.5±1.2 and was paroxysmal in 26 (25.0%), persistent in 8 (7.7%), and permanent in 70 patients (67.3%). Patients with and without AF had similar baseline characteristics except for fewer revascularization procedures (coronary artery bypass grafting: 12% versus 22%; P=0.03) among AF patients. At 1 year, all-cause mortality was higher among patients with AF (30.9%) compared with those without AF (13.9%; hazard ratio [HR], 2.36; 95% confidence interval [CI], 1.43-3.90; P=0.0008). This was observed irrespective of the type of AF (permanent, HR, 2.47; 95% CI, 1.40-4.38; persistent, HR, 3.60; 95% CI, 1.10-11.78; paroxysmal, HR, 2.88; 95% CI, 1.37-6.05). Mortality gradually increased with higher CHA(2)DS(2)-VASC scores (score 1-3: HR, 2.20; 95% CI, 0.92-5.27; score 6-8: HR, 4.12; 95% CI, 2.07-8.20). The risks of stroke (3.9% versus 5.1%; HR, 0.76; 95% CI, 0.23-1.96; P=0.47) and life-threatening bleeding (19.8% versus 14.7%; HR, 1.37; 95% CI, 0.86-2.19; P=0.19) were similar among patients with and without AF., Conclusions: AF is common among high-risk patients with severe aortic stenosis undergoing transcatheter aortic valve implantation and is associated with a >2-fold increased risk of all-cause and cardiovascular mortality, irrespective of the type of AF. The gradient of risk directly correlates with the CHA(2)DS(2)-VASC score.

Heart valves have long been considered exclusively passive structures that open and close in response to changes in transvalvular pressure during the cardiac cycle. Although this is partly true, recent evidence suggests that valves are far more sophisticated structures. Microscopic examination of heart valves reveals a complex network of endothelial cells, interstitial cells, an extracellular matrix and a rich network of intrinsic nerves. The distribution of these nerve networks varies between the four valves, but is remarkably conserved between species. The present review will focus mainly on aortic valve innervation for several reasons: it is most commonly involved in disease processes, it lies in a unique hemodynamic environment and is exposed to extreme mechanical forces. These nerves are likely to play a significant role in the modulation of aortic valve structure and function and its adaptation to different hemodynamic and humoral conditions. The objectives of this review are first to describe the anatomy of aortic valve innervation, then detail the functional significance of innervation to the valve and finally make the case for the clinical relevance of understanding the neural control of aortic valves and its potential pharmacologic implications.

Neural structures have been shown to be present in valve cusp tissue. We aimed to characterise the influence of neuronal stimulation on the component structures of the aortic root and cusps. Specimens of sinus, sinotubular junction (STJ), annulus and cusp tissue were dissected from porcine aortic roots and either stimulated with electrical field stimulation (EFS) in isolated tissue baths or fixed for immunohistochemical characterisation of neuronal structures. Sinus, STJ and annular tissue all gave tetrodotoxin-sensitive, frequency-dependent contractions in response to EFS. Contractions in annular tissue were only evident in tissue from the left- and non-coronary cusps, but not from the right-coronary cusp. Cusp tissue gave no contractile response to EFS, however in the presence of 1 mumol tetrodotoxin a strong contractile response was evident. This contractile response was unmasked when cusp tissue was stimulated in the presence of a nitric oxide synthase or guanylate cyclase inhibitors. Immunohistochemical analysis identified a network of neurofilament positive fibers in tissue from all aortic root structures that were associated with the presence of tyrosine hydroxylase and choline acetyl transferase. The nerve fibers in cusp tissue were in close proximity to the endothelial surface and demonstrated positive staining for neuronal nitric oxide synthase. Nerves in the aortic valve exert a nitric oxide-mediated neurogenic dilator tone in cusp tissue and are capable of producing contractile responses in different components of the aortic root. These responses could influence valve function in health and disease.

To determine the innervation of human semilunar valves, we examined the pulmonary and aortic valves of the normal autopsied hearts of 3 men (53 to 71 years old). Whole valve tissues with the aorta or pulmonary trunk were stained for acetylcholinesterase by a histochemical method. Acetylcholinesterase-positive nerve fibers with a diameter of 2 to 20 mm were located on the ventricular side of the semilunar valves. Innervation of the semilunar valves was extremely sparse compared with that of the atrioventricular valves and that of the aortic or pulmonary arterial wall. The nerves originated from the subendocardium of the ventricles and the adventitia of the arterial walls. The nerves were more distributed in the basal site than in the marginal site of the semilunar valve. The nerve fibers formed a network in basal two-thirds of the leaflet. Thick nerves ramified in the thin nerve plexus. The thick nerves had a varicose-like structure. Thin nerves had a dot- and brush-like ending. The nerves in human semilunar valves may play a role in valve motion.

We evaluated the distribution of the nerves in valve tissue of humans to clarify the relationship between mitral valve prolapse and autonomic nerve dysfunction. We studied 15 autopsy specimens of normal mitral valve, 10 prolapsed mitral valves, five each of normal tricuspid, aortic, and pulmonary valves, and three prolapsed mitral valves obtained at cardiac surgery. Immunohistochemical studies utilized the avidinbiotin peroxidase complex (ABC) method and several nerve-related antigens: 1) S-100 protein, glial fibrillary acidic protein (GFAP), and neurofilament protein (NFP) as markers of glial and Schwann cells of the nervous system; 2) choline acetyltransferase (ChAT) to identify cholinergic nerve endings; 3) neuropeptide Y (NPY), a neuropeptide that is distributed in accordance with sympathetic nerves; and 4) calcitonin gene-related peptide (CGRP), a neuropeptide that is distributed in accordance with afferent nerves. Distribution of adrenergic nerve fibers was also examined by fluorescence method. Morphology of nerve endings of the normal mitral valve was studied by electron microscopy. In normal valves, distributions of S-100 protein, GFAP, and NFP immunoreactivities were clearly visible along the subendocardial site on the coaptation aspect of the base-to-body portion of each valve, regardless of the kind of valve. In contrast, there was only a scanty distribution of these reactivities on the physiologic coaptation area of the tip. In prolapsed mitral valves, there was no distribution of S-100-positive protein or other nerve-related antigens in areas of the valve with myxomatous degeneration. Distribution of CGRP, ChAT, and NPY immunoreactivities, and adrenergic fluorescence, were the same as those of the nerve-related antigens in both normal and prolapsed mitral valves. Electron microscopic study of the atrial aspect of normal mitral valves revealed numerous small axons with aggregations of small clear vesicles, indicating cholinergic features. The results suggest that the subendocardial site on the atrial aspect at the middle portion of the mitral valve is rich in nerve endings, including the afferent nerves, and that mechanical stimuli from this area caused by abnormal coaptation in mitral valve prolapse may produce an improper circuit in autonomic nerve function between the central and mitral valve nervous systems.

In order to provide additional information on the morphology and the functional performance of semilunar valves, the presence of nerve fibers was investigated in the aortic and pulmonary leaflets by AChE techniques, formaldehyde-induced fluorescence methods, en block silver nitrate and gold chloride impregnation and electron microscopy. The results show that AChE positive and adrenergic nerve fibers are constantly present in every leaflet of all the animals examined. The pattern of innervation is similar in aortic and pulmonary valves and no differences exist between coronary and non coronary aortic leaflets. Nerve networks extend over the inferior two-thirds of the leaflets: they are composed of myelinated and non-myelinated axons and are mainly located in the ventricular side of the leaflets. Structures resembling free sensory endings can be shown both by light and electron microscopy. The presence in the leaflets of blood vessels and of an intrinsic smooth muscle system suggests that these two components are the most probable targets of the nerve fibers.