A J de Belder

A nitric oxide donor improves uterine artery diastolic blood flow in normal early pregnancy and in women at high risk of pre‐eclampsia

The utero-placental vascular adaptations of normal and complicated pregnancies can be investigated in an accurate, reproducible and non-invasive manner using Doppler ultrasound [I]. In the normal non-pregnant state the flow velocity waveform (FVW) of the main uterine artery shows little diastolic flow with a postsystolic notch, a pattern indicative of high resistance to flow. Between 12 and 18 weeks gestation there is a physiological change from this pattern with increased diastolic flow and disappearance of the notch. A persistence of the high resistance pattern beyond 20 weeks gestation is associated with the subsequent development of pre-eclampsia and fetal growth retardation [2]. The presence of a post-systolic notch and resistance index > 0.6 (RI = peak systolic velocity-end diastolic velocity/end diastolic velocity) has a sensitivity of 70% and a specificity of 90% for the prediction of proteinuric pregnancy-induced hypertension [2]. The generation of nitric oxide (NO) from L-arginine by the vascular endothelium plays a key role in the control of vascular tone [3]. There is histological [4] and functional [5] evidence for endothelial cell dysfunction in pre-eclampsia. Thus, i t is likely that the synthesis of endothelial derived factors, such as NO and prostacyclin, is also impaired in this condition [6,7]. I f this is the case then the blood flow changes that characterise pre-eclampsia may be altered favourably by supplementation with endothelial derived factors. To investigate this hypothesis we have studied the effect of intravenous glyceryl trinitrate (GTN), a donor of NO in oitio, and prostacyclin (PGI2), an arachidonic acid metabolite, on uterine artery blood flow during pregnancy. This study was approved by the local research ethics committee and informed consent obtained from all

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.

Expression of nitric oxide synthase in ulcerative colitis

Abstract. 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 gut 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.

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 α granule protein GMP-140 was injected at the end of coronary bypass grafting and γ 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: γ 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.

Megakaryocytes From Patients With Coronary Atherosclerosis Express the Inducible Nitric Oxide Synthase

Endothelial and platelet generation of nitric oxide (NO) plays an important role in the regulation of hemostasis. Alterations in NO biosynthesis are described in atherosclerosis. We have investigated the NO pathway in megakaryocytes and platelets from patients with atherosclerosis and age-matched control subjects. Megakaryocytes and platelets were isolated from patients with severe coronary atherosclerosis (n = 19) and normal coronary arteries (n = 9) as demonstrated by selective angiography. Constitutive (Ca(2+)-dependent) and inducible (Ca(2+)-independent) NO synthase (cNOS and iNOS, respectively) activities were measured by using the citrulline assay and by immunostaining techniques using an anti-peptide antibody to iNOS. Megakaryocytes from patients with atherosclerosis expressed significantly greater amounts of iNOS (1.28 +/- 0.46 pmol citrulline.mg-1.min-1) than cNOS (0.29 +/- 0.40 pmol.mg-1.min-1). In contrast, megakaryocytes from patients with normal coronary arteries expressed significantly more cNOS (1.48 +/- 0.23 pmol.mg-1.min-1) than iNOS (0.49 +/- 0.40 pmol.mg-1.min-1). Platelets isolated from both groups showed no significant difference in cNOS expression, and no iNOS was seen in either group. Immunostaining confirmed the presence of the iNOS in megakaryocytes. These results suggest there is a link between the expression of iNOS in the megakaryocyte and atherosclerosis.

Itraconazole and anti-tuberculosis drugs

Changing to an enteral feed in which over three-quarters of the carbohydrate was provided as polysaccharide successfully prevented any further recurrence. Clearly, the nature of colonic luminal substrate is important in the pathogenesis of this disorder, an occurrence which you point out has parallels in the animal kingdom. Hans Krebs drew attention to this curious happening with respect to ethanol production and it seems that several species may spend their days in a potentially pleasant state of inebriation. For example, bullfinches and hawfinches can become intoxicated when feeding on the willow catkin, which contains a readily fermented nectar. Most intriguing is the observation that African elephants are exposed to large amounts of ethanol after feeding on the decaying fruit of the marula tree. With its well recognised effects on libido and fertility, could repeated ethanol intoxication be a factor in the long-term survival of the African elephant, and was this the real cause of the demise of the dinosaur?

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 Bayess 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.

Consent procedure for coronary angioplasty is haphazard

Editor—A legal case highlighted the importance of patients giving fully informed consent for medical procedures.1 Doctors must inform the patient of significant risks, but what represents a significant risk for particular procedures is not precisely defined.2 Coronary angioplasty carries a risk of death in hospital and of emergency coronary artery bypass grafting of 0.7% and 1.1% respectively.3 To assess current British practice when informed consent is obtained for coronary angioplasty we conducted a telephone survey of 25 centres in England, Scotland, and Wales that regularly …

Should primary angioplasty be available for all patients with an ST elevation myocardial infarction

For the acute myocardial infarction patient, percutaneous coronary intervention is clearly superior to thrombolysis for many clinical end points, yet widespread availability of PCI services is still far from being realised