Background: Transient Receptor Potential Canonical 1 (TRPC1) is a widely-expressed mammalian cationic channel with functional effects that include stimulation of cardiovascular remodelling. The initial aim of this study was to investigate variation in TRPC1-encoding gene transcripts.Results: Extensive TRPC1 transcript alternative splicing was observed, with exons 2, 3 and 5-9 frequently omitted, leading to variants containing premature termination codons. Consistent with the predicted sensitivity of such variants to nonsense-mediated decay (NMD) the variants were increased by cycloheximide. However it was notable that control of the variants by NMD was prominent in human embryonic kidney 293 cells but not human vascular smooth muscle cells. The cellular difference was attributed in part to a critical protein in NMD, up-frameshift-1 (UPF1), which was found to have low abundance in the vascular cells. Rescue of UPF1 by expression of exogenous UPF1 was found to suppress vascular smooth muscle cell proliferation.Conclusions: The data suggest: (i) extensive NMD-sensitive transcripts of TRPC1; (ii) inefficient clearance of aberrant transcripts and enhanced proliferation of vascular smooth muscle cells in part because of low UPF1 expression.

Radio-labeled red cell perfusion scan of the non-donorydonor forearmyhand was undertaken, 1- and 5-years post operation, in 12 patients who had received a radial artery graft during myocardial revascularisation. Results were analysed using a Wilcoxon Signed Rank test (P- value -0.05 was taken as statistically significant). Mean tissue perfusion (in millilitersy100 ml tissueymin) declined in the non-donor (y10.06%, Ps0.07) and donor (y6.65%, Ps0.15) forearm, respectively, compared to 1 year post radial artery harvest. The statistically significant observed difference in tissue perfusion between the non-donor (21.9"5.1) and donor (17.5"3.7) forearm (Ps0.0007) at 1 year was maintained at 5 years, non-donor and donor, 19.5"3.7 and 16.2"3.4 (Ps0.001), respectively. The same pattern in tissue perfusion was observed in the non-donorydonor hand. This study demonstrates that, over time, there is little recovery in perfusion in the donor forearmyhand from ulnar artery collateral circulation. There is a significant and persistent difference in tissue perfusion between the non- donorydonor forearmyhand at 5 years post radial artery harvest. Although no functional deficit or overt ischaemic events were recorded, these findings may influence the choice of conduit and the information given when obtaining consent in patients undergoing myocardial revascularisation.

Aim The aim of the study was to determine the potential for K(V)1 potassium channel blockers as inhibitors of human neoinitimal hyperplasia.Methods and results Blood vessels were obtained from patients or mice and studied in culture. Reverse transcriptase-polymerase chain reaction and immunocytochemistry were used to detect gene expression. Whole-cell patch-clamp, intracellular calcium measurement, cell migration assays, and organ culture were used to assess channel function. K(V)1.3 was unique among the K(V)1 channels in showing preserved and up-regulated expression when the vascular smooth muscle cells switched to the proliferating phenotype. There was strong expression in neointimal formations. Voltage-dependent potassium current in proliferating cells was sensitive to three different blockers of K(V)1.3 channels. Calcium entry was also inhibited. All three blockers reduced vascular smooth muscle cell migration and the effects were non-additive. One of the blockers (margatoxin) was highly potent, suppressing cell migration with an IC50 of 85 pM. Two of the blockers were tested in organ-cultured human vein samples and both inhibited neointimal hyperplasia.Conclusion K(V)1.3 potassium channels are functional in proliferating mouse and human vascular smooth muscle cells and have positive effects on cell migration. Blockers of the channels may be useful as inhibitors of neointimal hyperplasia and other unwanted vascular remodelling events.

To the editor: I thank Mr Munsch for his enjoyable and informative article1 in the February issue of Heart , and think that it highlights an important topic. Multidisciplinary meetings are an integral part of cardiovascular practice and cardiologists and cardiac surgeons have long worked closely together, perhaps more so than other medical specialties with their respective surgical colleagues. This …

It is probably fair to say that the relationship between cardiologists and cardiac surgeons is currently a little strained. True, there has always seemed to be something of an edge to this relationship, but the ongoing “turf wars” in coronary revascularisation have apparently increased the tension. The question is, does this tension serve to benefit patients with coronary disease, or would a better understanding of what “the other side” does allow us to make the right decisions and give the right advice to our patients? The aim of this article, therefore, is to highlight some of the areas where uncertainty may arise, and hopefully provide cardiology trainees with some additional insights into the surgical management of patients with coronary artery disease. In depth treatment is clearly not possible here and further reading is suggested in the bibliography. #### Key points 1: Evidence base for coronary artery surgery Coronary artery bypass graft surgery (CABG) is carried out either to relieve symptoms or improve prognosis. It has been compared against medical treatment in three large randomised trials: the Coronary Artery Surgery Study (CASS), the Veterans Administration Study, and the European Coronary Surgery Study. There have also been several smaller trials and several large registries. These studies took place during the 1970s and therefore have clear shortcomings when applied to current practice:

Stromal interaction molecule 1 (STIM1) is a predicted single membrane-spanning protein involved in store-operated calcium entry and interacting with ion channels including TRPC1. Here, we focus on endogenous STIM1 of modulated vascular smooth muscle cells, which exhibited a nonselective cationic current in response to store depletion despite strong buffering of intracellular calcium at the physiological concentration. STIM1 mRNA and protein were detected and suppressed by specific short interfering RNA. Calcium entry evoked by store depletion was partially inhibited by STIM1 short interfering RNA, whereas calcium release was unaffected. STIM1 short interfering RNA suppressed cell migration but not proliferation. Antibody that specifically bound STIM1 revealed constitutive extracellular N terminus of STIM1 and extracellular application of the antibody caused fast inhibition of the current evoked by store depletion. The antibody also inhibited calcium entry and cell migration but not proliferation. STIM1 interacted with TRPC1, and TRPC1 contributed partially to calcium entry and cationic current. However, the underlying processes could not be explained only by a STIM1-TRPC1 partnership because extracellular TRPC1 antibody suppressed cationic current only in a fraction of cells, TRPC1-containing channels were important for cell proliferation as well as migration, and cell surface localization studies revealed TRPC1 alone, as well as with STIM1. The data suggest a complex situation in which there is not only plasma membrane-spanning STIM1 that is important for cell migration and TRPC1-independent store-operated cationic current but also TRPC1-STIM1 interaction, a TRPC1-dependent component of store-operated current, and STIM1-independent TRPC1 linked to cell proliferation.

In vascular injury, the mechanisms responsible for contractile smooth muscle phenotype is altered, leading to vascular smooth muscle cell (VSMC) proliferation and vascular diseases such as neointimal hyperplasia. Analysis of mouse VSMC mRNA revealed the selective upregulation of KCNA3 gene (encoding KV1.3) when the cells switch phenotype. We here provide evidence for its role in vascular proliferation. Using a linear wound assay, we show that KV1.3 blockers margatoxin and correolide compound C inhibited cell motility in both mouse and human VSMC. Furthermore KV1.3 protein is selectively localised to smooth muscle cells grown in situ as neointimal formations in human saphenous veins obtained at coronary artery bypass surgery. Application of KV1.3 blockers reduced the neointimal formation and inhibited a voltage-dependent potassium current in human VSMC. We previously showed that downregulated REST transcription factor during phenotypic switching enables KCNN4 expression (Cheong et al, 2005). Here we reveal that KCNA3 also has a REST binding site and that there is enhanced KCNA3 expression in response to dominant-negative REST mutant. These data indicate that KV1.3 is upregulated in VSMC proliferation and that existing blockers of KV1.3 might have a therapeutic role in diseases caused or exacerbated by VSMC proliferation. Funded by the BHF, MRC and Wellcome Trust.

OBJECTIVES:To define best practice standards for mitral valve repair surgery.DESIGN:Development of standards for process and outcome by consensus.SETTING:Multidisciplinary panel of surgeons, anaesthetists, and cardiologists with interests and expertise in caring for patients with severe mitral regurgitation.MAIN OUTCOME MEASURES:Standards for best practice were defined including the full spectrum of multidisciplinary aspects of care.RESULTS:19 criteria for best practice were defined including recommendations on surgical training, intraoperative transoesophageal echocardiography, surgery for atrial fibrillation, audit, and cardiology and imaging issues.CONCLUSIONS:Standards for best practice in mitral valve repair were defined by multidisciplinary consensus. This study gives centres undertaking mitral valve repair an opportunity to benchmark their care against agreed standards that are challenging but achievable. Working towards these standards should act as a stimulus towards improvements in care.

In a screen of potential lipid regulators of transient receptor potential (TRP) channels, we identified sphingosine-1-phosphate (S1P) as an activator of TRPC5. We explored the relevance to vascular biology because S1P is a key cardiovascular signaling molecule. TRPC5 is expressed in smooth muscle cells of human vein along with TRPC1, which forms a complex with TRPC5. Importantly, S1P also activates the TRPC5-TRPC1 heteromultimeric channel. Because TRPC channels are linked to neuronal growth cone extension, we considered a related concept for smooth muscle. We find S1P stimulates smooth muscle cell motility, and that this is inhibited by E3-targeted anti-TRPC5 antibody. Ion permeation involving TRPC5 is crucial because S1P-evoked motility is also suppressed by the channel blocker 2-aminoethoxydiphenyl borate or a TRPC5 ion-pore mutant. S1P acts on TRPC5 via two mechanisms, one extracellular and one intracellular, consistent with its bipolar signaling functions. The extracellular effect appears to have a primary role in S1P-evoked cell motility. The data suggest S1P sensing by TRPC5 calcium channel is a mechanism contributing to vascular smooth muscle adaptation.

Radio-labeled red cell perfusion scan of the non-donor/donor forearm/hand was undertaken, 1- and 5-years post operation, in 12 patients who had received a radial artery graft during myocardial revascularisation. Results were analysed using a Wilcoxon Signed Rank test (P-value <0.05 was taken as statistically significant). Mean tissue perfusion (in milliliters/100 ml tissue/min) declined in the non-donor (-10.06%, P=0.07) and donor (-6.65%, P=0.15) forearm, respectively, compared to 1 year post radial artery harvest. The statistically significant observed difference in tissue perfusion between the non-donor (21.9+/-5.1) and donor (17.5+/-3.7) forearm (P=0.0007) at 1 year was maintained at 5 years, non-donor and donor, 19.5+/-3.7 and 16.2+/-3.4 (P=0.001), respectively. The same pattern in tissue perfusion was observed in the non-donor/donor hand. This study demonstrates that, over time, there is little recovery in perfusion in the donor forearm/hand from ulnar artery collateral circulation. There is a significant and persistent difference in tissue perfusion between the non-donor/donor forearm/hand at 5 years post radial artery harvest. Although no functional deficit or overt ischaemic events were recorded, these findings may influence the choice of conduit and the information given when obtaining consent in patients undergoing myocardial revascularisation.

Occlusive vascular disease is a widespread abnormality leading to lethal or debilitating outcomes such as myocardial infarction and stroke. It is part of atherosclerosis and is evoked by medical procedures including angioplasty and grafting of saphenous vein in bypass surgery. A causative factor is the switch in smooth muscle cells to an invasive and proliferative mode, leading to neointimal hyperplasia. Here we reveal the importance to this process of TRPC1, a homologue of Drosophila Transient Receptor Potential. Human vein samples obtained during coronary artery bypass graft surgery commonly exhibited an intimal structure containing smooth muscle cells which expressed more TRPC1 than the medial layer cells. Veins were organ-cultured to allow growth of neo-intimal smooth muscle cells over a 2-week period. To explore the functional relevance of TRPC1 we used a specific E3-targeted antibody to TRPC1 and chemical blocker 2-aminoethoxydiphenyl borate. Both agents significantly reduced neointimal growth in human vein, or proliferation of A7r5 smooth muscle cells in culture. The data suggest up-regulated TRPC1 is a general feature of smooth muscle cells in occlusive vascular disease and that TRPC1 inhibitors have potential as protective agents against human vascular failure. Work supported by Wellcome Trust, British Heart Foundation and Nuffield Hospitals.

Objective To study the “learning curve” associated with independent practice in coronary artery surgery. Design Retrospective analysis of prospectively collected data. Setting All NHS centres in north west England that carry out cardiac surgery in adults. Participants 18 913 patients undergoing coronary artery surgery for the first time between April 1997 and March 2003, 5678 of whom were operated on by 15 surgeons in the first four years after their consultant appointment. Main outcome measures Observed and predicted mortality (EuroSCORE) for surgeons in their first, second, third, and fourth years after appointment as a consultant compared with figures for established surgeons. Results Overall mortality decreased over the six years of study (P = 0.01). Of the patients operated on by established surgeons or newly appointed consultants, 265/13 235 (2.0%) and 109/5678 (1.9%), respectively, died (P = 0.71). There was a progressive decrease in observed mortality with time after appointment as a consultant from 2.2% in the first year to 1.2% in the fourth year (P = 0.049). This result remained significant after adjustment for time and case mix (P = 0.019). Conclusions Mortality in patients operated on by newly appointed consultant surgeons is similar to mortality in patients operated on by established surgeons. There are significant decreases in crude and risk adjusted mortality in the four years after appointment. These findings should influence the nature of practice in newly appointed surgeons.

This study was designed to measure the degree to which hand and forearm blood flow is reduced following harvesting of the radial artery in myocardial revascularization surgery and determine whether there is an effect on hand function. Twenty patients who had the radial artery used for myocardial revascularization underwent bilateral blood flow assessment of hands and forearms using Technetium-99m human serum albumin and clinical evaluation of hand function. Mean tissue perfusion in ml/100 ml/min ±SD was as follows: donor hand 21.9±5.6, non-donor hand 25.5±6.1 (P=0.00043), donor arm (hand and forearm) 17.5±3.7 and non-donor arm (hand and forearm) 21±5.1 (P=0.000681). No clinical evidence of hand claudication was detected. This study suggests that removal of the radial artery reduces the tissue perfusion of the hand and forearm but does not affect hand function in the short term. The use of radial artery grafts in patients at risk of developing peripheral vascular disease should be carefully considered

The symptomatic presentation of an unruptured sinus of Valsalva aneurysm is rare. A 48 year old man with a history of treated hypothyroidism, and a five year history of ileocolonic Crohn’s disease of chronic low grade activity presented with a profound left hemiplegia. He was in sinus rhythm and normotensive. Cardiac auscultation was repeatedly normal. Computed tomography of the head performed early in the course of the illness was reported as normal. Duplex Doppler examination of the carotid arteries performed six months later revealed no significant atheroma. There was complete resolution of the neurological deficit over a period of months. A year later he presented with chest pain suggestive of myocardial ischaemia. Computed tomography, magnetic resonance imaging, transthoracic and transoesophageal echocardiography, and cardiac catheterisation pointed to a sinus of Valsalva aneurysm protruding into the left ventricular outflow tract. In view of the previous neurological event and ongoing chest pain suggestive of myocardial ischaemia, the lesion was resected. The patient made a good recovery and postoperative transoesophageal echocardiography showed normal aortic valve function with no residual regurgitation. This is the first reported case of pure left ventricular outflow tract extension of an unruptured left sinus aneurysm. The presentation with ischaemic cardiac pain does not seem to be explained by conventional mechanisms.

Gastric mucosal tonometry was used to determine the adequacy of gastrointestinal perfusion in 10 patients undergoing elective myocardial revascularization. Patients were prospectively randomized to receive either pulsatile or nonpulsatile flow during cardiopulmonary bypass. All patients showed a reduction in gastric mucosal perfusion during bypass, manifested by a reduction in the gastric mucosal pH, which occurred independently of variations in the arterial pH. In the group of patients receiving nonpulsatile flow, this reduction was significantly greater (p < 0.05). Cardiopulmonary bypass using nonpulsatile flow is associated with the development of a gastric mucosal acidosis, which may have implications for the development of postoperative complications.