Biomedical subjects
Publications and source records attributed to David S Celermajer.
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BACKGROUND: Restenosis remains an important limitation of PCI. Although local factors such as small vessel diameter and systemic factors such as diabetes explain some of its incidence, it nevertheless also occurs in low-risk patients. We hypothesize that endothelial dysfunction may be an independent risk factor in some of these cases. METHODS: 20 patients who had previously undergone PCI were studied at cardiac catheterization (10 with restenotic lesions were matched to 10 without restenosis). Infusion of multiple concentrations of acetylcholine (ACh) and nitroglycerine (GTN) were made via a 3F infusion catheter into the target artery. Following infusion, changes in diameter of segments proximal and distal to the PCI site were measured. RESULTS: There was a significant impairment in endothelium-dependent dilatation at the maximal dose of acetylcholine in those with restenosis compared to those without restenosis, both proximal and distal to the stented area (proximal; 11.5+/-7.0% versus -20.9+/-9.0% p<0.001, distal; 12.0+/-3.1% versus -17.8+/-8.1% p<0.001), but there was no difference in the response to GTN. There was a significant correlation between the endothelium-dependent dilatation response and the percent restenosis (r=-0.65, p=0.003). CONCLUSIONS: Coronary endothelium-dependent dilatation is reduced in subjects with restenosis in arterial segments separate from the stented lesion. This supports a hypothesis that endothelial dysfunction contributes to the development of restenosis, following percutaneous coronary intervention.
New generation multislice CT technology has changed the approach to non-invasive assessment of congenital heart disease, in both paediatric and adult patients. This is mainly because of rapid advances in spatial and temporal resolution and in post-processing capability. At Hôpital Necker-Enfants Malades, CT with multiplanar and three-dimensional reconstruction has become a routine examination in the evaluation of congenital heart disease planning surgery, complex interventional catheterisations and for follow-up. It has proved to be an invaluable diagnostic and decision-aiding methodology in these situations, as a complement to echocardiography and, increasingly, as a substitute for diagnostic angiography (which is usually associated with higher-dose radiation and longer sedation times, as well as occasional morbidity). This review illustrates the current status of 64-slice CT in congenital heart diseases, including assessment of the aorta, the coronary arteries, the pulmonary arteries, the systemic and pulmonary veins, and other intra- and extracardiac malformations.
OBJECTIVES: The purpose of this study was to investigate the influence of dietary fatty acids on the anti-inflammatory properties of high-density lipoproteins (HDL) and vascular function. BACKGROUND: The effect of dietary fatty acids on atherogenesis remains uncertain. METHODS: Fourteen adults consumed an isocaloric meal containing either a polyunsaturated or a saturated fat on 2 occasions. The effects of post-prandial HDL on endothelial cell expression of intercellular adhesion molecule-1 (ICAM-1) and vascular cell adhesion molecule-1 (VCAM-1) were determined. Flow-mediated dilation (FMD) and microvascular reactivity were assessed before and 3 and 6 h after the meal. RESULTS: Plasma triglycerides, insulin, and nonesterified fatty acids rose after the meals. The HDL collected 6 h after the saturated meal were less effective than HDL isolated from fasting plasma in terms of their ability to inhibit expression of ICAM-1 and VCAM-1, whereas HDL collected 6 h after the polyunsaturated meal had an inhibitory activity that was greater than that of HDL collected from fasting plasma (p < 0.004 and p = 0.01 for comparison of effect of meals on ICAM-1 and VCAM-1, respectively). Post-hyperemic microvascular flow significantly increased at 3 h after the polyunsaturated meal by 45 +/- 14% and by 21 +/- 11% after the saturated meal. The FMD decreased 3 h after the saturated meal by 2.2 +/- 0.9% (p< 0.05 compared with baseline) and by 0.9 +/- 1% after the polyunsaturated meal. CONCLUSIONS: Consumption of a saturated fat reduces the anti-inflammatory potential of HDL and impairs arterial endothelial function. In contrast, the anti-inflammatory activity of HDL improves after consumption of polyunsaturated fat. These findings highlight novel mechanisms by which different dietary fatty acids may influence key atherogenic processes.
BACKGROUND: Evidence suggests that delayed re-endothelialization is responsible for in-stent thrombosis. Probucol inhibits neointimal thickening in animals via enhanced re-endothelialization and is the only oral drug that consistently inhibits restenosis after coronary angioplasty in humans. Here, we examined the effects of probucol on re-endothelialization and neointimal formation in a stent model. METHODS AND RESULTS: New Zealand White rabbits were fed a hypercholesterolemic diet with probucol (1%) or without (control) (n=11 each) for 6 weeks. At 2 weeks, endothelial denudation and stenting of the iliac artery was performed. Iliac arteries were harvested at week 6, and stented segments sectioned and analyzed. Compared with control, probucol increased in-stent re-endothelialization (74+/-6% in controls versus 93+/-3% in probucol-treated; P=0.008), and decreased average luminal stenosis (58+/-27 versus 31+/-16%; P=0.01) and stent depth (619+/-310 versus 314+/-158 microm; P=0.009). Compared with control, probucol also decreased accumulation of macrophages in the neointima. Furthermore, none of the probucol-treated rabbits had in-stent thrombosis, whereas four of eleven control rabbits showed thrombosis (P=0.04). CONCLUSIONS: Probucol demonstrates anti-restenotic and appears to have anti-thrombotic properties that are likely related to its ability to promote in-stent re-endothelialization.
OBJECTIVE: We sought to investigate the effect of particular deformations of aortic arch shape on blood pressure response in children who had undergone successful repair of coarctation of the aorta. METHODS: We studied normotensive patients (aged 15.1 +/- 5.8 years) who had undergone coarctation surgery by means of simple (n = 43) or extended (n = 32) end-to-end anastomosis. All patients underwent systematic exercise testing during follow-up, as well as magnetic resonance imaging. Three types of aortic arch geometry were evident on magnetic resonance imaging: gothic arch with angular geometry and an increased height/width ratio of the arch, crenel arch with a rectangular shape, and normal arch with a smooth rounded shape. For each subject's arch, the continuous variable height/width ratio was calculated. RESULTS: Exercise-induced hypertension was more frequent in patients with gothic arch, with a prevalence of 83% at 15 years after surgical intervention (95% confidence interval, 69%-97%) versus 25% (95% confidence interval, 0%-50%) in those with crenel and 21% (95% confidence interval, 10%-46%) in those with normal arch geometry (P < .001). The cumulative incidence of exercise-induced hypertension as a function of aortic arch geometry was significantly higher in patients with gothic arch geometry throughout follow-up. On multivariate analysis, both gothic arch geometry and higher height/width ratio were significantly correlated with exercise-induced hypertension. CONCLUSION: An angulated gothic arch is independently associated with abnormal blood pressure response. This deformation of the aortic arch identifies a subgroup of subjects with postoperative coarctation at high risk of hypertension in young adult life.
AIMS: Bosentan is efficacious in idiopathic pulmonary arterial hypertension, and the variants associated with connective tissue disease, but not currently approved for treatment of pulmonary arterial hypertension due to Eisenmenger's syndrome. We sought to evaluate its effect in adults with Eisenmenger's syndrome. METHODS: We administered bosentan on the basis of compassionate use in 23 patients with Eisenmenger's syndrome, aged 37 plus or minus 14 years. Of the patients, 17 had never received specific treatment for pulmonary arterial hypertension, five were transitioned from treprostinil, and one from beraprost to bosentan. We measured functional class, saturation of oxygen, haemoglobin levels and six-minute walk distance at baseline, one, six months and at most recent follow-up. RESULTS: Baseline functional class was IV in three, III in fifteen, and II in five patients. At follow-up, with a mean of 15 plus or minus 10 months, 13 of the 23 patients (57%) had improved by at least one functional class, from a median baseline of III to II (p equal to 0.016), mean saturation of oxygen at rest had increased from 81% to 84% (p equal to 0.001), and levels of haemoglobin had decreased from 178 plus or minus 26 grams per litre to 167 plus or minus 19 grams per litre (p equal to 0.001). Overall, the six-minute walk distance did not change from baseline of 335 metres. The distance walked by those not previously receiving specific therapy, however, improved from 318 plus or minus 129 to 345 plus or minus 123 metres (p equal to 0.03). CONCLUSION: Treatment of adults with Eisenmenger's syndrome using bosentan significantly improved functional class, saturation of oxygen at rest, and decreased levels of haemoglobin. Treatment with bosentan was associated with improvement in six-minute walk distance in those not previously receiving specific therapy. In patients already in receipt of specific therapy, transition to bosentan resulted in no clinical deterioration.
Epidemiological studies suggest a link between fetal/early infant nutrition and adult coronary artery disease. In the present study, we examined the effects of altering nutrition during gestation, lactation and juvenile life on aortic structure and function in rats. Wistar rat dams were fed either a control or low-protein diet throughout pregnancy, or a low-protein diet for the final 7 days of gestation only. At 21 days post-partum, male pups were weaned on to a control, low-protein or high-fat diet. At 12 weeks, the offspring rats were killed. In 46 rats, aortic sections were mounted and stained to assess media thickness and elastin content. In a further 38 rats, aortic rings were suspended in an organ bath and vascular reactivity was tested with dose-response curves to the endothelium-dependent dilator acetylcholine and the endothelium-independent dilator sodium nitroprusside. Rats exposed to maternal protein restriction while in utero had a significantly decreased aortic wall thickness compared with control rats (P=0.005). Total elastin content of the aorta was also decreased by both maternal low-protein (P=0.02) and early postnatal low-protein (P=0.01) diets. Neither maternal nor postnatal low-protein or high-fat diets, however, resulted in any significant changes in arterial dilator function. In conclusion, fetal undernutrition in rats, induced via a maternal low-protein diet, causes a decrease in aortic wall thickness and elastin content without altering aortic dilator function. These changes in vascular structure may amplify aging-related changes to the vasculature and contribute to the pathophysiology of the putative link between impaired fetal growth and adult cardiovascular disease.
OBJECTIVES: Diabetes has a major impact on the long-term outcome following percutaneous coronary intervention, being a major risk factor for restenosis. We aimed at assessing the clinical, hemodynamic and angiographic factors that predict outcome in this high-risk group. METHODS: Diabetic patients who underwent percutaneous coronary intervention during the period 1996-2000 were identified retrospectively, and their medical records, hemodynamic data and angiograms studied at the time of their procedure. Angiographic data were analyzed to determine procedural factors, quantitative angiographic results of their percutaneous coronary intervention and severity and extent scores of coronary artery disease. Clinical follow-up was obtained in 99.7% to a mean time of 782+/-153 days after percutaneous coronary intervention. RESULTS: A total of 327 consecutive diabetic patients underwent percutaneous coronary intervention on 389 lesions. The overall procedural success rate was 96.2%; however, during follow-up, 40.2% of patients had an adverse cardiac event. The strongest independent predictors of adverse outcome were presence of renal disease, need for medical diabetic treatment, and the extent of coronary artery disease as assessed by the extent score, but not the duration of diabetes or glycemic control. Other factors, which are often predictive of short-term outcome in a general population, such as vessel diameter, lesion length, and severity of coronary artery disease, were not predictive of outcome. CONCLUSIONS: In patients with type 2 diabetes mellitus, the extent of the coronary arteries involved with atheroma as well as systemic factors such as renal involvement are the best predictors of long-term outcome following percutaneous coronary intervention.
Obesity and its related metabolic diseases, including type 2 diabetes, are associated with alterations in the circulating levels of various peptides. These include the adipocytokines (peptides released by adipocytes which circulate, such as leptin, adiponectin and resistin), and other peptides whose levels are altered in association with obesity (such as ghrelin, neuropeptide Y, interleukin-1 beta and tumour necrosis factor-alpha). While the primary action of these peptides is linked with the regulation and maintenance of energy balance and metabolism, many of them have also been shown to possess vasoactive, inflammatory and other properties that influence vascular biology, vascular physiology and atherogenesis. As such, they may form an important mechanistic link between obesity and cardiovascular disease. In this review, we will outline the vasoactive properties of adipocytokines and other obesity-related peptides. In particular, as pharmacotherapies suggested to achieve weight loss will alter the pathways associated with these peptides, such treatments might have either beneficial or deleterious effects on the incidence and progression of cardiovascular disease.
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Danshen (Salvia miltiorrhiza) and Gegen (Radix puerariae) are two herbs used in traditional Chinese medicine, most commonly for their putative cardioprotective and anti-atherosclerotic effects. In this study, we investigated the effect of a preparation of these herbs on two key processes in the early stages of atherosclerosis; macrophage lipid loading and monocyte adhesion to endothelial cells. Human monocyte derived macrophages (HMDMs) were treated with 0.1-1.0 mg/ml of the herbal mixture in aqueous buffers and loaded with acetylated LDL (AcLDL) (50 microg/ml) for 72 h, and analyzed for cholesterol (C) and cholesteryl esters (CE), via HPLC. Human endothelial cell monolayers were also treated with 0.1-1.0 mg/ml of the herbal mixture and monocyte adhesion measured. Cell adhesion molecules E-selectin, ICAM-1 and VCAM-1 were assessed via ELISA. Compared to control conditions, the herbal mixture induced a significant dose-related decrease in the total cholesterol (free and esterified) in the HMDMs (p<0.001 by ANOVA). By contrast, the herbs also induced an increase in ICAM-1 expression (p<0.001) and monocyte adhesion at higher concentrations (p<0.05). In conclusion, treatment of cells with this preparation of Danshen and Gegen, a commonly used Chinese health supplement, results in a dose-related suppression of AcLDL uptake by human macrophages, and an increase in the level of ICAM-1 expression and adhesion of monocytes to endothelial cells. These herbs therefore show the ability to modulate key early events in atherosclerosis.
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Percutaneous transluminal coronary angioplasty (PTCA) of chronic total occlusions (CTO) is not performed routinely in some centres due to concerns of low procedural success rates and high rates of short-term complications. This retrospective study examines the safety of PTCA to CTO in 100 consecutive cases compared to 100 matched controls. Success rate was 79% for CTO versus 98% for controls (p<0.001), however 5% of CTO patients had a cardiac enzyme rise compared to 13% of controls (p<0.05) and 0% of CTO patients compared to 6% of controls had a significant enzyme rise (p=0.03). These results suggest that PTCA to CTO can be carried out successfully in the majority of patients with only a relatively small risk of myocardial necrosis.
BACKGROUND: Investigation for cardiac source of embolus (CSE) is one of the commonest referrals for transthoracic echocardiography (TTE) of hospital inpatients, but has a relatively low-diagnostic yield. We sort to investigate whether 12-lead ECG might be useful in screening patients to obviate the need for TTE, in a subset of patients referred for echocardiographic investigation of cardiac source of embolus. METHODS: We collected ECG and echo data for 400 consecutively referred inpatients for TTE investigation of possible cardiac source of embolus. We analysed this data for evidence of cardiac source of embolism on TTE in patients with a normal or abnormal ECG. RESULTS: 41/400 (10%) subjects had possible CSE identified on TTE. Diagnostic yield for CSE was higher for those with abnormal compared with normal ECG (17% versus 6%, p<0.001). Of 232/400 (58%) patients with a normal ECG, 200 had a normal TTE (86%). Of the 32 with normal ECG and abnormal TTE, echo found a possible embolic source in 13. Of those 168 (42%) with an abnormal ECG, TTE was normal in 73 and abnormal in 95, of whom 28 patients had an echo that identified a possible cardio-embolic source. ECG, therefore, had a sensitivity of 68%, specificity of 61%, positive predictive value of 0.17 and negative predictive value of 0.94 for detecting possible cardiac sources of embolus. CONCLUSIONS: Although TTE is a relatively low-yield investigation for the detection of cardiac source of embolus, 12-lead ECG is not sufficiently sensitive to identify the approximately 10% of patients in whom echo will demonstrate a diagnostic abnormality.
Hypoxia increases and hyperoxia decreases experimental atherosclerosis, but it is unclear if repetitive hypoxic and hyperoxic insults affect intimal thickening after arterial injury. Rabbits on 2% cholesterol diet for 6 weeks underwent balloon injury to the abdominal aorta (AA) after week 3, and were then exposed to normoxia (n = 6), or 12 h daily of intermittent repetitive hypoxia (n = 6) or hyperoxia (n = 6). After week 6, damaged AA and undamaged thoracic aorta (TA) were assessed for intimal thickening and lipid content. Compared with normoxia, hypoxia and hyperoxia did not alter the rise in serum cholesterol related to cholesterol feeding. However, compared to normoxia, hypoxia markedly increased the intima-to-media ratio in AA (1.18 +/- 0.09 versus 1.96 +/- 0.14, P < 0.01) and TA (0.15 +/- 0.02 versus 0.41 +/- 0.01, P < 0.01) whereas hyperoxia had no effect on AA disease and increased intimal thickening in TA (0.26 +/- 0.03, P < 0.01). Hyperoxia promoted positive arterial remodeling in both TA and AA, resulting in larger luminal size. The cholesterol content in AA was increased by hypoxia and decreased by hyperoxia, but decreased by both treatments in TA. Lipophilic antioxidants and the proportion of arterial lipids that was oxidized were not altered by hypoxia or hyperoxia. These results suggest that intermittent repetitive hyperoxia is not protective and intermittent repetitive hypoxia promotes arterial disease in normal and injured arteries independent of lipid peroxidation.
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Obstructive sleep apnea (OSA) is characterized by repetitive episodes of hypoxia and is associated with an increase in cardiovascular disease. We, therefore, investigated the effect of repetitive hypoxia on two key early events in atherogenesis; lipid loading in foam cells and monocyte adhesion to endothelial cells. Human macrophages were loaded with acetylated low-density lipoproteins. During lipid loading, the cells were exposed to 30 min cycles of 2%/21% oxygen or control (room air, 5% CO(2) incubator). Human umbilical vein endothelial cells (HUVECs) were also exposed to 30 min cycles of repetitive hypoxia or control conditions and monocyte adhesion measured. Cell adhesion molecules E-selectin, ICAM-1 and VCAM-1 were measured by ELISA. Repetitive hypoxia increased cholesteryl ester uptake by macrophages (127+/-5% compared to controls; p=0.003). By contrast, monocyte adhesion to HUVECs and cell adhesion molecule expression were unchanged by exposure to repetitive hypoxia, compared to controls (p >0.1). Repetitive hypoxia, at levels relevant to tissues such as the arterial wall, enhances lipid uptake into human macrophages. This may contribute to accelerated atherosclerosis in OSA patients.