General anaesthesia vs. conscious sedation for transfemoral aortic valve implantation: a single UK centre before-and-after study.

Reported data suggest that 99% of transfemoral, transcatheter aortic valve implantations in the UK are performed under general anaesthesia. This before-and-after study is the first UK comparison of conscious sedation vs. general anaesthesia for this procedure. Patients who underwent general anaesthesia received tracheal intubation, positive pressure ventilation, radial arterial and central venous access and urinary catheterisation. Anaesthesia was maintained with propofol or sevoflurane. Patients who received conscious sedation had a fascia iliaca and ilioinguinal nerve block and low-dose remifentanil infusion, without invasive monitoring or urinary catheterisation. Recruitment took place between August 2012 and July 2015, with a 6-month crossover period between November 2013 and June 2014. A total of 88 patients were analysed, evenly divided between the two groups. Patients receiving conscious sedation had a shorter anaesthetic time (mean (SD) 121 (28) min vs. 145 (41) min; p < 0.001) and recovery room time (110 (50) min vs. 155 (48) min; p = 0.001), lower requirement for inotropes (4.6% vs 81.8%; OR (95% CI) 0.1 (0.002-0.050); p < 0.001) and a lower incidence of malignant dysrhythmia (0% vs 11.4%; p = 0.020). Conscious sedation appears a feasible alternative to general anaesthesia for this procedure and is associated with a reduced requirement for inotropic support and improved efficiency.

Transcatheter aortic valve insertion: anaesthetic implications of emerging new technology.

Transcatheter aortic valve insertion is a new development that potentially offers a number of advantages to patients and healthcare providers. These include the avoidance of sternotomy and cardiopulmonary bypass, and much faster discharge from hospital and return to functional status. The procedure itself however is quite complex, and presents significant demands in planning and implementation to the multidisciplinary team. Anaesthetic input is essential, and patient care in the perioperative period can be challenging. Early results have shown a significant mortality and morbidity rate, but the majority of procedures to date have been carried out in elderly patients with multiple comorbidities, making comparison with surgical aortic valve replacement inappropriate. Long-term outcomes are not yet known, but randomized controlled trials should allow this procedure and its application to be properly assessed.

Angiotensin converting enzyme insertion/deletion polymorphism does not influence postcardiac transplantation hypertension onset or progression.

BACKGROUND: The angiotensin converting enzyme insertion deletion polymorphism (ACE I/D) has been associated with much cardiovascular pathology, including posttransplantation hypertension. Hypertension is a significant cause of morbidity and mortality after cardiac transplantation. We investigated the influence of the ACE I/D polymorphism on posttransplantation hypertension. METHODS: A total of 211 heart transplant recipients and 154 corresponding donors were genotyped for the ACE I/D polymorphism by polymerase chain reaction. ACE enzymatic activity was measured by spectrophotometric kinetic analysis. Sitting systolic and diastolic blood pressures were recorded at 3 consecutive visits, and the mean was calculated. Clinical data, including demographics and medication, were collected for all recipients. Results were analyzed by the chi-square test and analysis of variance, taking a p value of <0.05 to be significant. RESULTS: A total of 41.7% of the subjects were hypertensive (diastolic blood pressure >90 mm Hg) at the time of the study, with 79.6% taking at least one antihypertensive agent. We found no difference between the number of antihypertensive agents, cyclosporin dose and level, renal function, or systolic blood pressure for the different recipient or donor genotypes. We also found no significant correlation between ACE enzymatic activity and systolic or diastolic blood pressure. CONCLUSIONS: Our study of 211 recipients and 154 corresponding donors is the largest investigation of this polymorphism in a cardiac transplantation population. We found no apparent relationship between the ACE genotype (of either donor or recipient) and systemic hypertension (absolute measurements and the number or dose of antihypertensive agents used).

A novel polymorphism of the gene encoding furin, a TGF-beta1 activator, and the influence on cardiac allograft vasculopathy formation.

BACKGROUND: Coronary vasculopathy (CV) is an important determinant of survival following cardiac transplantation. We have previously shown that G915C polymorphism of the Transforming Growth Factor-beta1 (TGF-beta1) gene strongly influences CV development. Furin is a proprotein convertase enzyme important in TGF-beta1 activation. We investigated for polymorphism within the promoter region of the gene for furin (fur). Allelic variation of the fur gene, in conjunction with TGF-beta1 polymorphism, was subsequently related to the development of CV. METHODS AND RESULTS: The fur gene promoter region (position -1199 to +39) was analysed by SSCP and sequencing. A C/T single nucleotide substitution polymorphism at position -231* was identified. Using PCR the fur and TGFB1 genotypes were identified in 115 cardiac transplant recipients. CV was diagnosed at routine surveillance post-transplant coronary angiography. Fur polymorphism had no influence on vasculopathy development; median time to diagnosis, *C/C homozygotes, 2.27 years (2.10-4.32), *C/T heterozygotes 2.97 years (2.09-4.24), *T/T homozygotes 2.65 years (2.33-4.08), (P=0.95). Allelic variation did not influence Kaplan Meier actuarial analysis of disease onset (P=0.54). Ninety-three percent of recipients were high TGF-beta1 producers. We used fur polymorphism to substratify patients with the +915*G/G TGFB1 (high producing) allele. Fur polymorphism did not influence CV development within this TGF-beta1 high producer cohort, when analysed by time to first diagnosis and Kaplan Meier testing. CONCLUSIONS: We have described a novel polymorphism at position -231* in the gene encoding furin. The fur -231* single nucleotide polymorphism in isolation, or in conjunction with TGFB1 polymorphism, is not useful as a genetic risk marker for cardiac transplant associated coronary vasculopathy.

Donor and recipient-transforming growth factor-beta 1 polymorphism and cardiac transplant-related coronary artery disease.

BACKGROUND: Transforming growth factor-beta1 (TGF-beta1) has been implicated in the pathogenesis of coronary vasculopathy following cardiac transplantation. The TGFB1 gene contains polymorphisms at positions +915* (Arg25Pro) and +869* (Leu10Pro) which may influence TGF-beta1 expression. We investigated the relationship between the development of coronary vasculopathy and the prevalence of these alleles in a cardiac transplant population. METHODS: Vasculopathy was diagnosed at routine surveillance post-transplant coronary angiography. Using sequence-specific polymerase chain reaction we identified the TGFB1 +915* and +869* genotypes in 147 cardiac transplant recipients and 134 cardiac donors. RESULTS: TGFB1 +915*C allele carriers (low producers) made up 10.5% of the recipient population but were significantly less likely to develop coronary vasculopathy (P=0.03). Median time to diagnosis was 6.0 years (3.9-8.72) in +915*C allele carriers compared to 2.75 years (2.10-4.22) in *G/G homozygotes (p=0.002). Pre- and 1 year post-transplant clinical variables were equivalent between the two groups. Multivariate analysis identified the recipient +915*G/G genotype (hazard ratio 2.96 (95% CI, 1.09-9.98); p=0.039), donor age (hazard ratio 1.05 (95% CI, 1.02-1.09); p=0.008) and number of acute rejection episodes of ISHLT grade 3 or greater in the first year (hazard ratio 1.12 (95% CI, 1.01-1.23); p=0.03) as significant predictors of vasculopathy. The recipient TGFB1 +869*, and both alleles in the donor, had no influence on vasculopathy development. CONCLUSIONS: Recipient TGFB1 +915* genotype influences the development of cardiac transplant-related coronary vasculopathy. This gives an important insight to the pathophysiology of the disease. On the contrary, donor TGFB1 +915* and TGFB1 +869* polymorphisms do not appear to be important and cannot be used as genetic risk factors.

Influence of interleukin-10 polymorphism on the development of coronary vasculopathy following cardiac transplantation.

BACKGROUND: Interleukin-10 (IL-10), an important anti-inflammatory cytokine has been implicated in the pathogenesis of acute rejection and long term graft tolerance. Polymorphism in the IL-10 promoter at positions -1082, -819 and -592, correlates with IL-10 production. Haplotype inheritance of these alleles determines whether individuals are high, intermediate, or low producers of IL-10. We investigated the effect of this polymorphism on the development of cardiac transplant vasculopathy (CV). METHODS: CV was defined at routine surveillance coronary angiography as any abnormality in 1 or more epicardial vessels. Recipient and donor DNA was amplified by PCR using primers to the 3 allele sites. After identifying the phenotype by electrophoresis, freedom from CV was analysed by Kaplan-Meier and the log rank test. RESULTS: One hundred and forty eight recipients and 135 donors were studied. High, intermediate and low producers made up 26.4, 47.3 and 26.3% of recipients and 35.6, 48.2 and 16.2% of donors (P=0.42). No significant differences were noted between the phenotype groups. The recipient and donor genotypes, when considered in isolation, had no effect on the freedom from CV; recipients: P=0.85; donors: P=0.52. When the recipient and donor genotypes were combined for an individual patient the freedom from CV was again unaffected; high producing IL-10 allele in donor or recipient: P=0.76, low producing IL-10 allele in donor or recipient: P=0.51. Increasing donor age and acute rejection episodes and the presence of a high producing TGF-beta1 phenotype were independent risk factors for CV. CONCLUSIONS: Polymorphism of the IL-10 promoter region fails to predict the development of CV and cannot be used as a genetic risk marker. This may be due to the effects of immunosuppressive treatment.

Tumour necrosis factor alpha gene polymorphism: a predisposing factor to non-ischaemic myocardial dysfunction?

BACKGROUND: Tumour necrosis factor alpha (TNF alpha) is implicated in the pathophysiology of heart failure. Plasma TNF alpha is raised in patients with myocardial dysfunction in proportion to the symptoms. OBJECTIVE: To determine whether this genetic variant is over represented in heart transplant recipients. PATIENTS: 175 heart transplant recipients and a control group of 212 healthy volunteers were studied. The reason for transplantation was severe symptomatic myocardial dysfunction in all cases. METHODS: The TNF alpha genotype was determined by polymerase chain reaction and gel electrophoresis. The populations were compared for their fit to Hardy-Weinberg equilibrium by calculating the expected frequencies of each genotype and comparing them to the observed values. A chi(2) test was used to determine the significance of the difference between the observed and expected values. RESULTS: No differences were found in the frequency of the TNF2 allele between all heart transplant recipients taken together (54/175, 31%) and healthy volunteers (58/212, 27%). A higher proportion of TNF2 allele carriers was present in cardiac recipients with a pretransplant diagnosis of viral mediated or idiopathic heart failure than in those with ischaemic myocardial dysfunction (26/69 (37.7%) v 28/106 (26.4%), p = 0.03). PATIENTS with a non-ischaemic aetiology had a higher prevalence of TNF2 than healthy volunteers (26/69 (37.7%) v 58/212 (27%), p = 0.05). CONCLUSIONS: The TNF2 allele is overrepresented in patients with end stage non-ischaemic myocardial dysfunction. This may represent a genetic predisposition in a small subset of patients who could respond favourably to anti-TNF alpha treatment.

Influence of tumor necrosis factor-alpha gene-308 polymorphism on the development of coronary vasculopathy after cardiac transplantation.

BACKGROUND: Tumor necrosis factor-alpha (TNF-alpha) has been implicated in cardiovascular disease. Polymorphism of the TNF-alpha gene promoter region (position -308) influences an individual's production of TNF-alpha. This affects susceptibility to acute rejection after cardiac transplantation. Because the highest serum levels of TNF-alpha have been found in recipients with cardiac transplant vasculopathy and because TNF-alpha blockade can prevent the disease in rabbits, we investigated the effect of TNF-alpha promoter polymorphism on the development of vasculopathy in human cardiac allograft recipients. METHODS: Using sequence-specific primers to the TNF-alpha gene and polymerase chain reaction, the genotypes of 147 cardiac transplant recipients and 134 heart donors were identified. An association was sought between the presence of high-producing (A homozygotes, GA heterozygotes) or low-producing (G homozygotes) TNF-alpha genotype and the development of coronary vasculopathy, diagnosed by routine surveillance coronary angiography. RESULTS: We found that 31.9% of recipients and 27.0% of donors were high TNF-alpha producers. The presence of the high-producing TNF-alpha allele led to an earlier diagnosis of vasculopathy; 3.42 years (+/- 91.3 days) vs 3.84 years (+/- 76.3 days) for high- and low-producing cardiac graft recipients, respectively; 3.52 years (+/- 87.3 days) vs 3.78 years (+/- 77.4 days) for high- and low-producing donor grafts, respectively. However, neither of these differences were significant. By Kaplan Meier actuarial analysis and log-rank test, TNF-alpha polymorphism had no effect on the freedom from vasculopathy when considering either recipient (p = 0.99) or donor (p = 0.86) TNF-alpha genotype. Multivariate analysis identified increasing donor age and the number of acute rejection episodes of International Society for Heart and Lung Transplantation grade 3 or greater as independent risk factors for vasculopathy in both the recipient and donor cohorts. CONCLUSIONS: Polymorphism at position -308 in the promoter region of the TNF-alpha gene fails to predict the development of cardiac transplant-related vasculopathy and cannot be used as a genetic risk marker. This may be because of the effects of immunosuppressive treatment.

The real cost of aspirin.

Aspirin is a widely used drug and perceived by most physicians to be inexpensive. High rates of concurrent gastroprotective agents are reported from a study of cardiology outpatients. Aspirin takers are more likely to also be taking a proton pump inhibitor, H(2) antagonist, or antacid than non-aspirin takers. They are more than 10 times as likely to be experiencing upper gastrointestinal symptoms. Although aspirin is inexpensive, it is emphasised that the overall cost implications for therapy can be significant and it is suggested that it may be more appropriate to consider the use of alternative antiplatelet agents in patients who tolerate aspirin poorly.

Polymorphism of the transforming growth factor-beta 1 gene correlates with the development of coronary vasculopathy following cardiac transplantation.

BACKGROUND: Expression of transforming growth factor-beta1 (TGF-beta1) is central to vascular repair due to its effects on smooth muscle cell, monocyte/macrophage, leucocyte, and extracellular matrix accumulation and proliferation. Genetic polymorphism at position +915 of the TGF-beta1 gene determines the degree of cytokine production in response to injury. We investigated this allelic variation on the development of cardiac transplant-related coronary vasculopathy (CV). METHODS: Using sequence-specific primers to the TGF-beta1 gene region of interest, a polymerase chain reaction (PCR) and gel electrophoresis identified the genotype in 129 cardiac transplant recipients. An association was sought between the presence of a high- (GG) or low/intermediate-producing (CC/GC) genotype and the development of coronary vasculopathy diagnosed by coronary angiography. RESULTS: C allele carriers made up 10.9% of the recipient population but were significantly less likely to develop coronary vasculopathy (p = 0. 0361). Mean time to diagnosis was 1240.5 days in G homozygotes relative to 2266.5 days in C allele carriers (p = 0.002). Pre- and 1-year posttransplant clinical variables were equivalent between the 2 groups. Multivariate analysis identified the GG genotype (p = 0. 042, hazard ratio 3.01, [95% CI, 1.056-10.99]), donor age (p = 0.002, hazard ratio 1.063, [95% CI, 1.029-1.097]), and number of acute-rejection episodes of grade 3 or greater in the first year (p = 0.029, hazard ratio 1.11, [95% CI, 1.05-1.26]) as significant predictors of vasculopathy. CONCLUSION: This study demonstrates a correlation between a high-producing TGF-beta1 genotype and an earlier onset of cardiac-transplant coronary vasculopathy. This gives an important insight into the pathophysiology of cardiac transplant vasculopathy and suggests new treatment options.

Impact of stenting on coronary angioplasty procedures.

OBJECTIVE: To compare patient selection and outcome of coronary angioplasty procedures before and after the widespread availability and use of stents. SUBJECTS AND METHODS: Group 1 consisted of 252 consecutive patients and group 2 comprised 389 patients who underwent angioplasty between April 1993 and March 1994, and April 1995 and March 1996, respectively, in a tertiary cardiothoracic centre. Clinical variables were collected before the procedures. Endpoints included in-hospital death, the need for repeat coronary angiography, repeat angioplasty, and coronary artery bypass surgery. Lesions were classified under American Heart Association/American College of Cardiology criteria in 100 randomly selected patients from each group. RESULTS: 311 and 482 angioplasty procedures were performed in patients from groups 1 and 2, respectively. One or more stents were deployed in nine (4%) and 179 (46%, p < 0.01) patients, respectively. The success rate was higher in group 2 than in group 1 patients (483/523 (92%) v 274/372 (88%), respectively, p < 0.05). There were significantly more single vessel angioplasty procedures (198/252 (79%) v 272/389 (70%), p < 0.05), type A lesions (30/116 (26%) v 19/130 (15%), p < 0.05), patients with stable angina (220/252 (87%) v 311/389 (80%), p < 0.05), and fewer acute myocardial infarction patients (1/252 (0%) v 12/389 (3%), p < 0.05) treated in group 1 than in group 2, respectively. Similar numbers of angioplasty were performed in the left anterior descending, left circumflex, and right coronary arteries. There were no significant differences in the in-hospital mortality or the need for repeat coronary angiography, angioplasty, or bypass surgery at 24 hours or six months after the initial procedure. CONCLUSION: Patients undergoing angioplasty in the stenting era had features associated with an increased risk of complication. Despite this, the primary success rate was higher, and the complication rate and the need for subsequent revascularisation were similar in the two groups, supporting the widely held clinical impression that stenting has made a valuable impact on the practice of angioplasty.