Permanent pacemaker insertion after CoreValve transcatheter aortic valve implantation: incidence and contributing factors (the UK CoreValve Collaborative).

BACKGROUND: Permanent pacemaker (PPM) requirement is a recognized complication of transcatheter aortic valve implantation. We assessed the UK incidence of permanent pacing within 30 days of CoreValve implantation and formulated an anatomic and electrophysiological model. METHODS AND RESULTS: Data from 270 patients at 10 centers in the United Kingdom were examined. Twenty-five patients (8%) had preexisting PPMs; 2 patients had incomplete data. The remaining 243 were 81.3±6.7 years of age; 50.6% were male. QRS duration increased from 105±23 to 135±29 milliseconds (P<0.01). Left bundle-branch block incidence was 13% at baseline and 61% after the procedure (P<0.001). Eighty-one patients (33.3%) required a PPM within 30 days. Rates of pacing according to preexisting ECG abnormalities were as follows: right bundle-branch block, 65.2%; left bundle-branch block, 43.75%; normal QRS, 27.6%. Among patients who required PPM implantation, the median time to insertion was 4.0 days (interquartile range, 2.0 to 7.75 days). Multivariable analysis revealed that periprocedural atrioventricular block (odds ratio, 6.29; 95% confidence interval, 3.55 to 11.15), balloon predilatation (odds ratio, 2.68; 95% confidence interval, 2.00 to 3.47), use of the larger (29 mm) CoreValve prosthesis (odds ratio, 2.50; 95% confidence interval, 1.22 to 5.11), interventricular septum diameter (odds ratio, 1.18; 95% confidence interval, 1.10 to 3.06), and prolonged QRS duration (odds ratio, 3.45; 95% confidence interval, 1.61 to 7.40) were independently associated with the need for PPM. CONCLUSION: One third of patients undergoing a CoreValve transcatheter aortic valve implantation procedure require a PPM within 30 days. Periprocedural atrioventricular block, balloon predilatation, use of the larger CoreValve prosthesis, increased interventricular septum diameter and prolonged QRS duration were associated with the need for PPM.

Effects of S-nitroso-glutathione in the human forearm circulation: evidence for selective inhibition of platelet activation.

OBJECTIVE: Nitric oxide (NO) is a vasodilator and inhibitor of platelet function. The clinical use of NO donors as inhibitors of platelet activation is limited by their concomitant hypotensive effect. S-nitroso-glutathione (GSNO) has a significant antiplatelet effect at doses that cause only a small decrease in blood pressure in rats. The aim of this study was to examine the antiplatelet and vasodilator properties of this nitrosothiol in the human forearm. METHODS: Forearm blood flow was measured by forearm occlusion plethysmography in five healthy males. Ex vivo platelet aggregation to ADP was performed in a platelet ionised calcium lumi-aggregometer. RESULTS: Intra-arterial infusion of GSNO (0.2, 1, and 5 nmol.min-1) resulted in inhibition of ADP (1-10 microM) induced platelet aggregation. This inhibition was submaximal for 0.2 and maximal for 1 and 5 nmol.min-1. However, the antiaggregatory effect observed at the lowest dose of GSNO was accompanied only by a threshold increase in forearm blood flow. CONCLUSIONS: These results show that GSNO is more effective as an inhibitor of platelet activation than as a vasodilator, suggesting that it is possible to achieve selective antiplatelet and potentially antithrombotic effects with NO donors.

A study of platelet activation during human cardiopulmonary bypass and the effect of S-nitrosoglutathione.

Cardiac surgery is complicated by the occurrence of post-operative bleeding due to platelet dysfunction. This is largely caused by platelet activation and consumption during cardiopulmonary bypass. Patients undergoing cardiac surgery requiring cardiopulmonary bypass were studied to determine whether early platelet changes due to bypass could be inhibited using the platelet-selective nitric oxide donor S-nitrosoglutathione (GSNO). Flow cytometry was used to measure platelet surface expression of P-selectin (an alpha-granule protein) and glycoproteins (GP) IIb/IIIa and Ib (mediators of aggregation and adhesion) before and 5 and 10 min after commencing cardiopulmonary bypass, in 6 controls and 6 patients receiving GSNO 50 microg/min. Platelet P-selectin expression increased during bypass both in controls and patients receiving GSNO. Glycoproteins IIb/IIIa and Ib fell during bypass in control and GSNO-treated patients. There was no difference between control and GSNO-treated groups. Thus no significant platelet inhibition by S-nitrosoglutathione was demonstrated under these conditions.

S-nitrosoglutathione inhibits platelet activation and deposition in coronary artery saphenous vein grafts in vitro and in vivo.

OBJECTIVE: To investigate platelet activation and deposition in human saphenous vein and internal mammary artery grafts following coronary artery bypass in vitro and in vivo, as well as inhibition of activation by the platelet selective nitric oxide donor S-nitrosoglutathione (GSNO). DESIGN: Controlled in vitro and in vivo studies. SETTING: Tertiary cardiac centre. PATIENTS: 24 patients undergoing coronary artery bypass surgery requiring vein and artery grafts. INTERVENTIONS: In vitro: human platelet rich plasma was perfused through segments of vein and artery, with or without GSNO 10(-6) M, and the platelet count was measured in the effluent. In vivo: indium-111 labelled antibody against the platelet alpha granule protein GMP-140 was injected at the end of coronary bypass grafting and gamma counts were compared between vein and artery grafts with or without systemic infusion of GSNO (40 nmol/min). RESULTS: In vitro: platelet count in perfused vein (< 70% of baseline) decreased more than in artery segments (89-94% of baseline) (p < 0.001). The platelet count was unchanged with GSNO in vein and artery segments. In vivo: gamma counts were greater at all time points over vein than artery grafts (p < 0.05), and were reduced by infusion of GSNO (p < 0.05). CONCLUSIONS: Platelet activation is greater in vein than in artery grafts in vitro and in vivo. Activation, which contributes to early vein graft failure, was inhibited by GSNO.

Non-invasive cardiac investigations in patients awaiting renal transplantation.

Patients with chronic renal failure undergoing renal transplantation have a high prevalence of cardiovascular disease. Invasive investigation may identify those at risk of cardiac death during or after renal transplantation, but which patients should undergo cardiac catheterization is currently not clear. In 95 patients awaiting renal transplantation we assessed the ability of echocardiography and exercise electrocardiography to identify patients at risk of cardiac death. Echocardiography identified impaired left ventricular (LV) systolic function in 20%, severe in 8%. Of the patients with severe LV dysfunction, 25% died before transplantation. Of those undergoing exercise electrocardiography, 44% did not achieve 85% of maximum predicted heart rate. No coronary artery disease requiring intervention was identified by exercise testing. These findings indicate that echocardiography, but not exercise electrocardiography, should be part of the assessment for renal transplantation.

Development and validation of a Bayesian index for predicting major adverse cardiac events with percutaneous transluminal coronary angioplasty.

OBJECTIVE: To create a risk model for predicting major adverse complicating events of percutaneous transluminal coronary angioplasty (PTCA), and to test the accuracy of the model on a prospective cohort of patients SETTING: Tertiary cardiac centre METHODS: Available software can predict probabilities of events using Bayes's theorem. To establish the accuracy of these predictive tools, a Bayes table was created to evaluate major adverse complicating events (MACE)-death, emergency coronary artery bypass grafting (CABG), or Q wave infarct occurring during the in-patient episode-on the first 1500 patients in the department PTCA database (development group); the predictive value of this model was then tested with the subsequent 1000 patients (evaluation group). The following probabilities were assessed to determine their association with MACE: age, sex, left ventricular function, American Heart Association lesion morphology classification, cardiogenic shock, previous CABG, diabetes, hypertension, multivessel PTCA. MAIN OUTCOME MEASURES: To establish the discriminatory ability of the predictive index, calibration plots and receiver operating characteristic (ROC) curves were obtained to compare the development and evaluation groups. RESULTS: The ROC curve plotted to determine the discriminatory value of the Bayesian table created from the development group (n = 1500) in predicting MACE in the evaluation group (n = 1000) showed a moderately predictive area under the curve of 0.76 (SEM 0.07). This predictive accuracy was confirmed with separately constructed calibration plots. CONCLUSIONS: Accurate predictions of MACE can be identified in populations undergoing percutaneous intervention. The database used allows operators to obtain consent from patients appropriately from their own experience rather than from other published data. If a national PTCA database existed along similar lines, individual operators and interventional centres could compare themselves with nationally available data.

Transradial artery coronary angiography and intervention in patients with severe peripheral vascular disease.

BACKGROUND: Traditionally, cardiac catheterization in patients with severe aorto-iliac disease has been performed using a brachial arteriotomy. This approach is associated with significant vascular and neuronal complications and requires considerable training to achieve an adequate level of expertise. Improvement and miniaturization of catheter equipment now allows the radial artery to be used for coronary investigation and intervention. The lack of important structures close to the radial artery, a good collateral ulnar artery circulation and its superficial position suggests that these procedures should have a low complication rate. The purpose of this study was to assess the efficacy and safety of percutaneous transradial diagnostic and interventional coronary catheterization in patients with severe peripheral vascular disease. PATIENTS AND METHODS: We undertook a non-randomized prospective analysis of 75 patients who had transradial artery diagnostic and interventional coronary catheterization in whom femoral angiography was impossible or relatively contraindicated (22 patients with severe claudication and absent femoral pulses, 24 patients with previous aorto-iliac surgery or intervention, 20 patients with a failed femoral approach, 9 patients with an aortic aneurysm). Three patients had an absent ulnar artery and were excluded. RESULTS: Radial artery cannulation was successful in 73/75 (97%) cases. Seventy-one (95%) patients had a successful diagnostic study. There was a high incidence of 3 vessel disease (73%), and the majority of patients (64%) were referred for coronary bypass surgery. Twelve patients underwent successful follow-on intervention including the insertion of 9 intracoronary stents. Adequate haemostasis was achieved within 20 min after diagnostic angiography and 60 min after interventional procedures. One patient had a forearm haematoma with paraesthesia of the hand which settled with conservative treatment. At 4-6 weeks, all patients had normal hand sensation and function (100%) with a palpable pulse present in 59/62 (96%). All patients undergoing diagnostic angiography were discharged on the same day, and patients undergoing intervention were discharged the following day. CONCLUSIONS: Transradial coronary investigation and intervention can be performed with a high degree of success and a low complication rate with early mobilization and discharge in patients with severe peripheral vascular disease. We suggest that the percutaneous transradial technique should be considered as an alternative to the Sones' technique in these patients.

Successful percutaneous transluminal coronary angioplasty for acute myocardial infarction in von Willebrand's disease.

An elderly woman with mild von Willebrand's disease presented with acute myocardial infarction. Percutaneous transluminal coronary angioplasty, to mechanically disrupt the thrombus without anticoagulation, was successfully undertaken. Haemostatic cover was also avoided.

Intravascular ultrasound-guided stenting in long lesions: an insight into possible mechanisms of restenosis and comparison of angiographic and intravascular ultrasound data from the MUSIC and RENEWAL trials.

The high restenosis rates in long stents may be related to suboptimal stent deployment. In an attempt to understand the potential components associated with restenosis in long stents, this study compares angiographic and intravascular ultrasound (IVUS) data from the MUSIC and RENEWAL studies where IVUS was used to optimize stent deployment in short (< 15 mm) and long (> 20 mm) coronary lesions, respectively. The RENEWAL study, a randomized trial, compared the NIR stent and Wallstent in long (> 20 mm) coronary lesions and used on-line visual IVUS criteria to optimize stent expansion. Detailed analysis of IVUS data was performed off line. Angiographic and IVUS data from this study was compared to that from the MUSIC study. Initial stent deployment was deemed optimal by the operator after visual angiographic and IVUS assessment in 50 of 70 lesions. In the remaining 20 lesions further balloon inflations were required to optimize stent apposition that led to an average gain in minimal in-stent luminal area (MISA) of 15.9% (P < 0.01). Off-line IVUS data analysis showed that the number reaching "MUSIC criteria" for optimal stent deployment preredilatation was 8 (11.4%) of 70 and 14 (20%) of 70 postredilatation. The ratio of MISA/MRAprox (mean proximal reference area) was 0.69 in RENEWAL. At 6-month follow-up, the angiographic restenosis rate in RENEWAL was 36% and target lesion revascularization (TLR) rate was 7.8%, compared with MUSIC's 9.7% and 4.5%, respectively. In conclusion, angiographic assessment of stent deployment in long lesions is limited. On-line visual IVUS with further balloon inflations to improve stent apposition led to a significant gain in MISA, but the MISA/MRAprox ratio remained suboptimal. Therefore, suboptimal stent deployment due to constraint by lesion resistance may be an important mechanism underlying the high restenosis rates in long stents.

Myocardial calcium-independent nitric oxide synthase activity is present in dilated cardiomyopathy, myocarditis, and postpartum cardiomyopathy but not in ischaemic or valvar heart disease.

OBJECTIVE: To determine the activity of the calcium-dependent constitutive (cNOS) and calcium-independent inducible nitric oxide (iNOS) synthases in heart tissue from patients with different cardiac diseases. PATIENTS AND DESIGN: Endomyocardial biopsy specimens were obtained from patients with dilated hearts (by echocardiography and ventriculography) and normal coronary arteries (by selective angiography). Recognised clinical, radiological, and histopathological criteria were used to diagnose non-inflammatory dilated cardiomyopathy (DCM) (n = 6), inflammatory cardiomyopathy (ICM) (n = 5), and peripartum cardiomyopathy (PPCM) (n = 3). Comparative groups were chosen with similarly dilated hearts caused by ischaemic (n = 5) or valvar disease (n = 4), and, in addition, non-dilated hearts with ischaemic (n = 5) and valvar (n = 3) disease. Venous blood was taken at the time of myocardial biopsy for assay of plasma tumour necrosis factor alpha (TNF alpha). RESULTS: Myocardial tissue from patients with DCM, ICM, and PPCM showed considerable iNOS activity (16.8 (2.7) pmol citrulline/mg protein/min) with little or no cNOS activity (1.3 (0.9) pmol citrulline/mg protein/min). In contrast, myocardial tissue from patients with both dilated and non-dilated hearts of ischaemic or valvar aetiology showed cNOS and little, if any, iNOS activity (dilated--cNOS 11.7 (2.4) and iNOS 0.8 (0.6) pmol citrulline/mg protein/min; non-dilated--cNOS 12.1 (1.8) and iNOS 1.4 (0.8) pmol citrulline/mg protein/min). Plasma TNF alpha was detectable only in patients with inflammatory DCM. CONCLUSIONS: These results support the hypothesis the generation of nitric oxide by iNOS accounts for some of the dilatation and impaired contractility associated with inflammatory and non-inflammatory dilated cardiomyopathy and peripartum cardiomyopathy.

A randomised trial of endoluminal reconstruction comparing the NIR stent and the Wallstent in angioplasty of long segment coronary disease: results of the RENEWAL Study.

BACKGROUND: The role of coronary stents in reducing the incidence of acute complications and late restenosis after angioplasty has been established in randomized studies focusing on simple, short coronary lesions. The development of long coronary stents has provided a safe and predictable means of treating long coronary lesions, but this carries with it a higher risk of restenosis. By comparing the outcome of treating long lesions with two different stent types, we aimed to assess the influence of stent design rather than the nature of long lesions per se on the relatively high restenosis rates in this subgroup. METHODS: This study was designed to assess procedural complications and 6-month restenosis rates in a randomized trial comparing a slotted tube stent with a self-expanding stent for the treatment of long coronary lesions. Randomization of vessels to either stent occurred after successful balloon angioplasty. Intravascular ultrasound (IVUS) was used to assess and optimize stent deployment. The patients were restudied angiographically and by IVUS at 6 months. RESULTS: A total of 82 patients (85 vessels) were recruited (slotted tube stent, n = 44 vessels; self-expanding stent, n = 41 vessels). Successful deployment occurred in 41 (100%) of 41 of the self-expanding stent group and 41 (93%) of 44 of the slotted tube stent group. There was no difference in lesion length between the two groups (slotted tube stent, 26.6 +/- 6.9 [SD] mm; self-expanding stent, 28.7 +/- 9.8 [SD] mm; P = .2), but the mean length of the self-expanding stent was greater than that of the slotted tube stent (41.6 +/- 18.8 [SD] mm vs 35.4 +/- 16.2 [SD] mm, respectively; P < .05). There was no significant difference in the rate of major events between the two groups at 6-month follow-up. The angiographic restenosis rate at follow-up was less in the slotted tube stent group, but this did not reach statistical significance (26% vs 46%, respectively; P = .1) and the target lesion revascularization rate was similar for both groups (7.9% vs 7.7%, respectively; P = .8). IVUS assessment of plaque/stent ratios suggested a greater plaque burden in the self-expanding stent compared with the slotted tube stent at follow-up (0.42 +/- 1.2 [SD] vs 0.3 +/- 0.08 [SD]), but this was not statistically significant (P = .1). CONCLUSIONS: Long stents can be safely and successfully deployed in long segment coronary disease, with an acceptable 6-month target lesion revascularization rate. Our results showed a trend toward lower angiographic restenosis and a lesser in-stent plaque burden at follow-up in the slotted tube stent compared with the self-expanding stent. This suggests that stent design may influence the restenotic process in long coronary lesions.

Nitric oxide synthase activities in human myocardium.

Myocardial constitutive and inducible nitric oxide (NO) synthase activities were measured in right ventricular tissue from 17 patients with dilated cardiomyopathy (DCM). A significant activity of inducible enzyme was accompanied by a low activity of the constitutive NO synthase. Thus, the myocardium has the capacity to express both NO synthases. NO may have a physiological as well as a pathological role in the human myocardium.

Expression of nitric oxide synthase in ulcerative colitis.

Nitric oxide (NO) is generated from L-arginine by a family of enzymes called the NO synthases. Previous investigators have proposed that the expression of this inducible enzyme (iNOS) may account for the characteristic vasodilatation, oedema and impairment of get motility seen in active ulcerative colitis. Using a specific antibody to iNOS, we have investigated the distribution of this enzyme in colonic tissue from patients with histologically proven ulcerative colitis. Eight patients with ulcerative colitis expressed calcium-independent citrulline activity (9.96 +/- 2.34 pmol citrulline mg-1 protein min-1) and showed immunoreactivity to the iNOS antibody within the inflammatory infiltrate of the lamina propria, and also within the cytoplasm of the epithelial cells lining the colon. Five age-matched controls showed no calcium-independent citrulline activity (0.2 +/- 0.08 pmol citrulline mg-1 protein min-1) and no immunoreaction to the antibody. We conclude that this enzyme is present in colonic tissue including the epithelium from patients with active colitis. Inhibition of this enzyme may provide a novel therapeutic option for patients with active ulcerative colitis.

Induction of myocardial nitric oxide synthase by Coxsackie B3 virus in mice.

BACKGROUND: Inducible nitric oxide synthase (iNOS) expression is regulated by cytokines. This study investigated whether Coxsackie group B virus (CVB) myocarditis resulted in an environment suitable for induction of NOS in the murine heart. MATERIALS AND METHODS: Myocardium was removed from mice infected with CVB3 and from controls. Histology, reverse transcriptase polymerase reaction (RT-PCR) for murine iNOS, NOS enzyme activity and immunohistochemistry were assessed. RESULTS: Histology revealed severe myocarditis 7 days after infection with CVB3 but not in controls. RT-PCR using primers for murine iNOS detected iNOS mRNA in infected mice but not in controls. Calcium-independent NOS activity increased by day 5 after infection with a peak at day 7. Calcium-dependent NOS activity was present throughout, with a trend to lower levels during peak calcium-independent activity. Immunohistochemistry revealed iNOS to be localized to inflammatory cells rather than to myocytes. CONCLUSION: This study demonstrates the development of calcium-independent NOS activity and de novo gene transcription for iNOS in the murine myocardium in response to CVB3 infection. The nitric oxide produced at such high output may act at times as part of the immune defence as an antiviral agent and may be toxic to host tissue.

Inhibition of platelet activity by S-nitrosoglutathione during coronary angioplasty.

Platelet activation is associated with acute vessel occlusion and chronic restenosis after percutaneous transluminal coronary angioplasty (PTCA). Organic nitrates, which act by releasing the vasodilator and anti-platelet agent nitric oxide (NO), have a predominantly vasodilator action and cause hypotension at doses required to inhibit platelet activation. S-nitrosoglutathione (GSNO) is an NO donor with a preferential action on platelets. We investigated platelet activation in patients undergoing PTCA and the effect of GSNO. Blood was sampled from the coronary sinus to measure platelet surface expression of P-selectin and glycoprotein IIb/IIIa as indices of platelet activation. In 7 control patients, PTCA caused a rise in platelet surface expression of P-selectin and glycoprotein IIb/IIIa, which was maximal 5 minutes after PTCA, indicating increased platelet activation despite treatment with aspirin, glyceryl trinitrate, and heparin. 6 patients received an intracoronary infusion of GSNO, starting 10 min before PTCA. GSNO significantly inhibited the PTCA-induced increase in platelet surface expression of P-selectin and glycoprotein IIb/IIIa without altering blood pressure. These findings show that platelets are activated following PTCA and that GSNO can prevent this activation.