Transcatheter Edge-to-Edge Mitral Valve Repair in a Patient With Anderson-Fabry Disease.

Severe degenerative mitral regurgitation (DMR) is one cardiac manifestation of the multiorgan metabolic enzyme disorder Anderson-Fabry Disease (AFD). Although DMR is normally managed surgically, many patients with AFD are unsuitable for this. We present the first case of mitral transcatheter edge-to-edge repair in a patient with AFD.

In vivo morphologic comparison of saphenous vein grafts and native coronary arteries following non-ST elevation myocardial infarction.

OBJECTIVE: This study aimed to assess the pathophysiological differences between saphenous vein grafts (SVG) and native coronary arteries (NCA) following presentation with non-ST elevated myocardial infarction (NSTEMI). BACKGROUND: There is accelerated pathogenesis of de novo coronary disease in harvested SVG following coronary artery bypass (CABG) surgery, which contributes to both early and late graft failure, and is also causal in adverse outcomes following vein graft PCI. However in vivo assessment, with OCT imaging, comparing the differences between vein grafts and NCAs has not previously been performed. METHODS: We performed a retrospective, observational, analysis in patients who underwent PCI with adjunctive OCT imaging following presentation with NSTEMI, where the infarct-related artery (IRA) was either in an SVG or NCA. RESULTS: A total of 1550 OCT segments was analysed from thirty patients with a mean age of 66.3 (±9.0) years were included. The mean graft age of 13.9 (±5.6) years in the SVG group. OCT imaging showed that the SVG group had evidence of increased lipid pool burden (lipid pool quadrants, 2.1 vs 2.7; p = 0.021), with a reduced fibro-atheroma cap-thickness in the SVG group (45.0 µm vs 38.5 µm; p = 0.05) and increased burden of calcification (calcified lesion length = 0.4 mm vs 1.8 mm; p = 0.007; calcified quadrants = 0.2 vs 0.9; p = 0.001; arc of superficial calcium deposits = 11.6° vs 50.9°; p = 0.007) when compared to NCA. CONCLUSION: This OCT study has demonstrated that vein grafts have a uniquely atherogenic environment which leads to the development of calcified, lipogenic, thin-capped fibro-atheroma's, which may be pivotal in the increased, acute and chronic graft failure rate, and may underpin the increased adverse outcomes following vein graft PCI.

Transcatheter aortic valve implantation: current trends and future directions.

Transcatheter aortic valve implantation (TAVI) has been increasingly utilized for the treatment of severe symptomatic aortic stenosis in inoperable and high surgical risk patients. Recent advances in valve technology include repositionable scaffolds and smaller delivery systems, as well as improvement in periprocedural imaging. These advances have resulted in reduction of vascular complications, rates of paravalvular aortic regurgitation and periprocedural stroke and improved overall outcomes. Increasingly, TAVI is the preferred treatment for high-risk surgical patients with severe aortic stenosis. Consequently, there is growing interest for the use of TAVI in lower surgical risk patients. Furthermore, the role of TAVI has expanded to include valve-in-valve procedures for the treatment of degenerative bioprosthetic valves and bicuspid aortic valves. Questions remain in regard to the optimal management of concurrent coronary artery disease, strategies to minimize valve leaflet restriction and treatment of conduction abnormalities as well as identifying newer indications for its use.

Retrieval of a subintimal fractured guide wire from the brachial artery following saphenous vein graft stenting.

We present a case of a 58-year-old woman with diabetes mellitus with a history of angina, coronary artery bypass 24 years previously and who underwent retrieval of a fractured coronary buddy wire from the right brachial artery following attempted coronary intervention to a saphenous vein graft via the right radial route. Attempted removal of the guide wire had caused guide catheter-induced dissection of the vein graft in addition to a distal stent edge dissection before fracture in the brachial artery. The fractured end of the buddy wire was found to be in the subintimal space and could only be retrieved by advancing the wire into the subclavian artery by means of wrapping its free portion around the guiding catheter. Its fractured end could then be snared into the guiding catheter but could only be withdrawn from behind the stented segment in the vein graft by means of a trap balloon in the guiding catheter. Successful stenting of a guide catheter-induced dissection and distal stent edge dissection within the vein graft was then performed. This case highlights the hazards of deploying stents over buddy wires and of fractured guide wires in coronary intervention. © 2015 Wiley Periodicals, Inc.

Regulation of ß-adrenergic control of heart rate by GTP-cyclohydrolase 1 (GCH1) and tetrahydrobiopterin.

AIMS: Clinical markers of cardiac autonomic function, such as heart rate and response to exercise, are important predictors of cardiovascular risk. Tetrahydrobiopterin (BH4) is a required cofactor for enzymes with roles in cardiac autonomic function, including tyrosine hydroxylase and nitric oxide synthase. Synthesis of BH4 is regulated by GTP cyclohydrolase I (GTPCH), encoded by GCH1. Recent clinical studies report associations between GCH1 variants and increased heart rate, but the mechanistic importance of GCH1 and BH4 in autonomic function remains unclear. We investigate the effect of BH4 deficiency on the autonomic regulation of heart rate in the hph-1 mouse model of BH4 deficiency. METHODS AND RESULTS: In the hph-1 mouse, reduced cardiac GCH1 expression, GTPCH enzymatic activity, and BH4 were associated with increased resting heart rate; blood pressure was not different. Exercise training decreased resting heart rate, but hph-1 mice retained a relative tachycardia. Vagal nerve stimulation in vitro induced bradycardia equally in hph-1 and wild-type mice both before and after exercise training. Direct atrial responses to carbamylcholine were equal. In contrast, propranolol treatment normalized the resting tachycardia in vivo. Stellate ganglion stimulation and isoproterenol but not forskolin application in vitro induced a greater tachycardic response in hph-1 mice. ß1-adrenoceptor protein was increased as was the cAMP response to isoproterenol stimulation. CONCLUSION: Reduced GCH1 expression and BH4 deficiency cause tachycardia through enhanced ß-adrenergic sensitivity, with no effect on vagal function. GCH1 expression and BH4 are novel determinants of cardiac autonomic regulation that may have important roles in cardiovascular pathophysiology.

Neuropeptide Y reduces acetylcholine release and vagal bradycardia via a Y2 receptor-mediated, protein kinase C-dependent pathway.

The co-transmitter neuropeptide Y (NPY), released during prolonged cardiac sympathetic nerve stimulation, can attenuate vagal-induced bradycardia. We tested the hypothesis that NPY reduces acetylcholine release, at similar concentrations to which it attenuates vagal bradycardia, via pre-synaptic Y2 receptors modulating a pathway that is dependent on protein kinase A (PKA) or protein kinase C (PKC). The Y2 receptor was immunofluorescently colocalized with choline acetyl-transferase containing neurons at the guinea pig sinoatrial node. The effect of NPY in the presence of various enzyme inhibitors was then tested on the heart rate response to vagal nerve stimulation in isolated guinea pig sinoatrial node/right vagal nerve preparations and also on (3)H-acetylcholine release from right atria during field stimulation. NPY reduced the heart rate response to vagal stimulation at 1, 3 and 5 Hz (significant at 100 nM and reaching a plateau at 250 nM NPY, p<0.05, n=6) but not to the stable analogue of acetylcholine, carbamylcholine (30, 60 or 90 nM, n=6) which produced similar degrees of bradycardia. The reduced vagal response was abolished by the Y2 receptor antagonist BIIE 0246 (1 microM, n=4). NPY also significantly attenuated the release of (3)H-acetylcholine during field stimulation (250 nM, n=6). The effect of NPY (250 nM) on vagal bradycardia was abolished by the PKC inhibitors calphostin C (0.1 microM, n=5) and chelerythrine chloride (25 microM, n=6) but not the PKA inhibitor H89 (0.5 microM, n=6). Conversely, the PKC activator Phorbol-12-myristate-13-acetate (0.5 microM, n=7) mimicked the effect of NPY and significantly reduced (3)H-acetylcholine release during field stimulation. These results show that NPY attenuates vagal bradycardia via a pre-synaptic decrease in acetylcholine release that appears to be mediated by a Y2 receptor pathway involving modulation of PKC.

Reactive oxygen species and autonomic regulation of cardiac excitability.

Sympathetic hyper-activity and diminished parasympathetic activity are a consequence of many primary cardiovascular disease states and can trigger arrhythmias. Emerging evidence suggests that reactive oxygen species (ROS) including nitric oxide, superoxide, and peroxynitrite may contribute to cardiac sympathovagal imbalance in the brainstem, peripheral neurons, and in cardiomyocytes since all experience increased oxidative stress as a result of cardiac disease processes and aging. This article reviews the roles of ROS in autonomic dysfunction and arrhythmia. In addition, novel research directed toward finding targets for modulating sympathovagal balance in cardiac disease is discussed.

Cardiac neurobiology of nitric oxide synthases.

Nitric oxide (NO) is a potent modulator of cardiac and vascular regulation. Its role in cardiac-autonomic neural signaling has received much attention over the last decade because of the ability of NO to alter cardiac sympathovagal balance to favor more anti-arrhythmic states. Complexity and controversy have arisen, however, because of the numerous sources of NO in the brain, peripheral nerves, and cardiomyocytes, all of which are potential regulators of cardiac excitability and calcium signaling. This review addresses the integrative role of NO as a relatively ubiquitous signaling molecule with respect to cardiac neurobiology. The present idea, that divergent NO-signaling pathways from multiple sources within the heart and nervous system converge to modulate cardiac excitability and impact on morbidity and mortality in health and disease, is discussed.

Cardiac nitric oxide: emerging role for nNOS in regulating physiological function.

Emerging evidence shows that neuronal nitric oxide synthase (nNOS) plays several diverging roles in modulating cardiac function. This review examines the nitric oxide (NO) pathway and the regulatory mechanisms to which nNOS signalling is sensitive. These mechanisms are diverse and include regulation of gene expression, posttranscriptional regulation, protein trafficking, allosteric modulation of nNOS and redox modification to alter NO bioavailability once synthesised. Functionally, alteration in nNOS-NO signalling in the heart may correlate with different cardiac regulatory states. The idea of this being associated with exercise-trained states and myocardial disease is discussed.

Cholinergic control of heart rate by nitric oxide is site specific.

Parasympathetic control of heart rate involves the exocytotic release of acetylcholine and muscarinic receptor regulation of pacemaking currents. Endogenous nitric oxide can potentially regulate all of these processes; however, recent work suggests that the main functional role of nitric oxide lies in the modulation of acetylcholine release.