Heart, brain and hypertension

Hypertension is one of the most important cardiovascular risk factors. Without therapy hypertension leads to stroke, coronary heart disease with angina pectoris and myocardial infarction, kidney failure and/or peripheral vascular disease. The association between blood pressure and these cardiovascular complications can be demonstrated over the entire blood pressure range. The risk of stroke, myocardial infarction, renal failure or peripheral vascular disease increases with increasing blood pressure. Additional cardiovascular risk factors such as hyperlipidemia, smoking and diabetes involve a further increase in risk. Today hypertension can be effectively treated. To that end, diuretics, betablockers, ACE-inhibitors or calcium antagonists can be used. Alpha receptor antagonists and angiotensin AT1 receptor antagonists are also of value. The antihypertensive effectiveness of these drugs is comparable but may vary in individual patients. During antihypertensive therapy, a reduction in cerebrovascular and cardiac complications has been demonstrated for alpha methyldopa, diuretics and betablockers. In these studies, fatal and non-fatal strokes were reduced by 42%, while the reduction in cardiac events was less pronounced (14%). The reasons for this greater efficacy of antihypertensive therapy in the cerebral circulation are not clear. Other risk factors may be particularly important in the pathogenesis of coronary artery disease (e.g. genetic factors, hyperlipidemia and others) or hypertensive vascular changes in the coronary circulation may not be as reversible as they are in the cerebral circulation. The well documented correlation between stroke, myocardial infarction and hypertension, as well as the proven efficacy of antihypertensive therapy in preventing cardiovascular events, underscores the importance of effective and sustained blood pressure control in these patients.     

Binding of xanthine oxidase to vascular endothelium. Kinetic characterization and oxidative impairment of nitric oxide-dependent signaling

Concentrations of up to 1.5 milliunits/ml xanthine oxidase (XO) (1.1 micrograms/ml) are found circulating in plasma during diverse inflammatory events. The saturable, high affinity binding of extracellular XO to vascular endothelium and the effects of cell binding on both XO catalytic activity and differentiated vascular cell function are reported herein. Xanthine oxidase purified from bovine cream bound specifically and with high affinity (Kd = 6 nM) at 4 degreesC to bovine aortic endothelial cells, increasing cell XO specific activity up to 10-fold. Xanthine oxidase-cell binding was not inhibited by serum or albumin and was partially inhibited by the addition of heparin. Pretreatment of endothelial cells with chondroitinase, but not heparinase or heparitinase, diminished endothelial binding by approximately 50%, suggesting association with chondroitin sulfate proteoglycans. Analysis of rates of superoxide production by soluble and cell-bound XO revealed that endothelial binding did not alter the percentage of univalent reduction of oxygen to superoxide. Comparison of the extent of CuZn-SOD inhibition of native and succinoylated cytochrome c reduction by cell-bound XO indicated that XO-dependent superoxide production was occurring in a cell compartment inaccessible to CuZn-SOD. This was further supported by the observation of a shift of exogenously added XO from extracellular binding sites to intracellular compartments, as indicated by both protease-reversible cell binding and immunocytochemical localization studies. Endothelium-bound XO also inhibited nitric oxide-dependent cGMP production by smooth muscle cell co-cultures in an SOD-resistant manner. This data supports the concept that circulating XO can bind to vascular cells, impairing cell function via oxidative mechanisms, and explains how vascular XO activity diminishes vasodilatory responses to acetylcholine in hypercholesterolemic rabbits and atherosclerotic humans. The ubiquity of cell-XO binding and endocytosis as a fundamental mechanism of oxidative tissue injury is also affirmed by the significant extent of XO binding to human vascular endothelial cells, rat lung type 2 alveolar epthelial cells, and fibroblasts.     

Hemodynamic effects of vasodilator agents in dogs with experimental ventricular septal defects

The ratio of pulmonary to systemic vascular resistance (Rp/Rs) largely determines the amount of left-to-right shunting and pulmonary to systemic flow rat (Qp/Qs) in the presence of a large isolated ventricular septal defect. The possibility that pharmacologic reduction of systemic vascular resistance with alpha-adrenergic receptor blockade or beta-adrenergic receptor stimulation would increase the ratio Rp/Rs, and therefore reduce the ratio Qp/Qs, was studied in dogs in which ventricular septal defects had been surgically created. Administration of phentolamine and phenoxybenzamine caused a 42% reduction in Rs and no reduction in Rp. Qs was unchanged and Qp declined by 24% and the ratio Qp/Qs fell by 32%. Infusion of the beta-adrenergic receptor stimulant isoproterenol also reduced Qp/Qs. However, this was accomplished as a result of an increase in Qs and at the expense of an increase in heart rate. As a decline in the ratio Qp/Qs has been shown to be beneficial to patients with large left-to-right shunts, pharmacologic reduction of systemic vascular resistance may prove to be helpful in treating congestive heart failure in those patients with large left-to-right shunts at the ventricular level who are refractory to the usual decongestive measures.     

High rate of acute rejections in renal allograft recipients with thrombophilic risk factors

Inherited and acquired thrombophilic disorders predispose patients for thromboembolic and probably other occlusive vascular events that occur when additional risk factors play in concert. Because acute rejections in renal transplant recipients may reflect vascular events, and an impairment of the fibrinolytic system in immunosuppressed patients has been previously described, the implications of genetic or acquired risk factors of thrombophilia for the occurrence of early acute rejections after kidney transplantation were evaluated. The following risk factors of thrombophilia were determined in 97 patients after cadaveric kidney transplantation: factor V Leiden mutation, protein S, protein C, and antithrombin deficiency. In a retrospective analysis, the prevalence of acute rejections, the histologic classification when rejection episodes had been confirmed by biopsy, and other vascular complications were evaluated. In 21 of the 97 patients, an inherited or acquired risk factor of thrombophilia was detected. Prevalence of acute rejections was 71% in the first 6 mo after transplantation in patients with a thrombophilic disorder and significantly higher compared with patients without thrombophilia (41%; P = 0.017). The distribution of classic risk factors associated with acute rejections, such as number of human leukocyte antigen mismatches or percentage of panel-reactive antibodies, was similar in patients with and without thrombophilia. In the eight patients with thrombophilia and histologically proven acute rejection, four patients had an acute vascular rejection, and in two patients a vascular involvement was suspected. Furthermore, prevalence of cerebral or coronary vascular disease, or venous thromboembolic complications, was significantly higher in patients with a thrombophilic clotting defect (67%) compared with patients with normal hemostasis parameters (28%; P < 0.002). It is concluded that renal allograft recipients with thrombophilia are at risk of developing an acute rejection or other vascular event. Although the determination of thrombotic risk factors was performed at least 3 mo after an acute rejection episode, it can be presumed that acute rejection episodes are associated with subsequent coagulatory abnormalities with further consequences for transplant survival. Thus, pretransplant evaluation of genetic and acquired risk factors of thrombophilia is recommended.     

Selection of patients for cardiac evaluation before peripheral vascular operations

PURPOSE: This study evaluated the value of preoperative cardiac screening with dipyridamole thallium scintigraphy and radionuclide ventriculography in vascular surgery patients. METHODS: From July 1, 1989, to Dec. 31, 1991, we routinely (irrespective of the patient's cardiac history or symptomatology) performed dipyridamole thallium scintigraphy (DTS) and radionuclide ventriculography (RVG) in 394 patients being considered for an elective vascular operation. Patients with reversible defects on DTS underwent coronary arteriography. RESULTS: DTS results were normal in 146 patients (37%), showed a fixed defect in 75 (19%), and showed a reversible defect in 173 (44%). Patients with and without a history of angina or myocardial infarction had identical rates of reversible defects. Normal left ventricular function (> 50%) was noted in 76% of the patients; 17% had moderate dysfunction (35% to 50%) and 7% had a low ejection fraction (< 35%). The finding of severe coronary artery disease led to cardiac revascularization in 17 patients who had no prior history of cardiac disease and in 13 patients with a history of angina or myocardial infarction. Two deaths and nine major complications were associated with coronary arteriography and cardiac revascularization. Vascular procedures (144 aortic, 53 carotid, 146 infrainguinal) were ultimately performed in 343 patients, with a mortality rate of 1.7% (3.5% aortic, 0% carotid, and 0.7% infrainguinal bypass). The nonfatal perioperative myocardial infarction rate was 2.0%. We monitored all 394 patients for cardiovascular events, with a mean follow-up of 40 months. Patients who underwent cardiac revascularization had a 4-year survival rate of 75%, which was similar to those with a normal DTS. Late cardiac events were significantly more frequent in patients who had either a reversible DTS or RVG < 35%. CONCLUSIONS: Routine cardiac screening of vascular surgery patients had similar impact on patients irrespective of their prior history or current symptoms suggesting coronary artery disease. Routine screening did not result in substantial benefit. Screening studies such as DTS or RVG may be most useful as part of an overall risk versus benefit assessment in patients without active symptoms of coronary artery disease who have less compelling indications for vascular intervention (claudication, moderate-sized aortic aneurysms, or asymptomatic carotid disease).     

Adjunctive therapy in epilepsy with new antiepileptic drugs: is it of any value?

A total of 97 patients were recruited into a prospective, follow-up study after they were prescribed an adjunctive antiepileptic drug. The patients were followed up over a 6-month period. The interview included questions on Quality of Life, side-effects, adverse events and seizure frequency and severity. We operationally defined patients 'satisfaction' as (i) still on new drug; (ii) experiencing no side-effects (iii) experiencing no adverse events and (iv) had a greater than 50% reduction in seizures. A total of 13 patients (17%) reported being 'satisfied' according to our operational definition.     

HMG-CoA reductase inhibition by atorvastatin reduces neointimal inflammation in a rabbit model of atherosclerosis

OBJECTIVES: To study the effect of the 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA)-reductase inhibitor atorvastatin on the potential mechanisms involved in the recruitment of monocytic cells into the vessel wall. BACKGROUND: Inhibitors of HMG-CoA-reductase reduce cardiovascular mortality though the mechanisms yet elucidated. Most ischemic events are secondary to disruption of atherosclerotic plaques highly infiltrated by macrophages. METHODS: Atherosclerosis was induced in the femoral arteries of rabbits by endothelial damage and atherogenic diet for 4 weeks. Then, animals were switched to standard chow and randomized to receive either no treatment or atorvastatin (5 mg/kg/d) and killed after 4 weeks. RESULTS: Atorvastatin induced a significant reduction in serum lipids and in lesion size. Arterial macrophage infiltration was abolished by the treatment, and monocyte chemoattractant protein-1 (MCP-1) was significantly diminished in the neointima and in the media. Nuclear factor kappa-B (NF-kappaB) was activated in the 60% of the lesions, both in macrophages and vascular smooth muscle cells (VSMC), of the untreated group while only in 30% of the atorvastatin group. NF-kappaB activity was also lower in the uninjured aorta and liver of treated compared with untreated rabbits. In cultured VSMC, MCP-1 expression and NF-kappaB activity induced by tumor necrosis factor alpha were downregulated by atorvastatin. CONCLUSIONS: In a rabbit atherosclerosis model, atorvastatin diminishes the neointimal inflammation, and this could contribute to the stabilization of the atherosclerotic plaque. This may be an additional explanation for the reduction of acute ischemic events in patients treated with statins.     

Is coronary angiography necessary for vascular surgery patients who have positive results of dipyridamole thallium scans?

PURPOSE: Because dipyridamole thallium (DT) scanning is a useful predictor of perioperative cardiac events, a positive results of a DT scan is frequently the basis for performing more invasive cardiac evaluation and for consideration for performing coronary revascularization procedures before performing peripheral vascular surgery. The rationale for this approach has been that the treatment of anatomically significant coronary artery disease would lower the risk of performing a subsequent vascular operation. However, the benefit of performing aggressive diagnostic and therapeutic cardiac procedures in such patients remains unproved. To examine this issue, data from patients who underwent coronary angiography because of thallium redistribution were compared with data from matched control subjects who underwent peripheral vascular operations without further cardiac evaluation. METHODS: The medical records of 70 consecutive patients who underwent coronary angiography because of the presence of two or more segments of redistribution on DT scan were reviewed and compared with 70 other patients matched with respect to age, gender, peripheral vascular operation, and number of segments of redistribution on DT scan who did not undergo additional cardiac evaluation. RESULTS: DT scans were performed on 934 preoperative peripheral vascular surgery patients to help in the assessment of operative risk. Ischemic responses, defined as two or more segments of redistribution, were observed in 297. Of these, 70 underwent cardiac catheterization and 25 underwent coronary revascularization procedures. Adverse outcomes affected 46% of the coronary angiography group and 44% of the control group (p = NS). Patients who underwent coronary angiography and were considered for myocardial revascularization had fewer cardiac events with a subsequent vascular operation than did the control subjects. However, any possible benefit from invasive cardiac evaluation was offset by the three deaths and two myocardial infarctions (MIs) that complicated the cardiac evaluation. There was no significant difference between the angiography group and the matched control subjects with respect to perioperative nonfatal MI (13% vs 9%), fatal MI (4% vs 3%), late nonfatal MI (16% vs 19%), or late cardiac death (10% vs 13%). In long-term follow-up, MIs occurred later in patients who underwent coronary angiography than the control subjects (p = 0.049), but this difference was not associated with an improvement in the overall survival rate. CONCLUSIONS: The risks of extended cardiac evaluation and treatment did not produce any improvement in either the perioperative or the long-term survival rate. For most vascular surgery patients who have a positive result of a DT scan, coronary angiography does not provide any additional useful information.     

Cholesterol reduction and clinical benefit. Are there limits to our expectations?

Encouraging intervention trials drive our expectations toward more aggressive cholesterol-lowering therapies, lower target levels, and less severe hypercholesterolemia. Available studies may predict which patients, degrees of total cholesterol (TC) reduction, and baseline and target levels of TC provide the most clinical benefit. Data were pooled from seven primary and nine secondary controlled trials with major coronary heart disease (CHD) events as primary endpoints. The analysis showed that we can expect large reductions in CHD from TC reduction in primary and secondary prevention. However, the reduction is much larger in subjects with high TC and/or previous CHD events. The percent reduction in CHD increased exponentially with increasing percent TC reductions, which predicted > 70% of the change in CHD. Consequently, we cannot expect cost-effective clinical benefits from mean reductions in TC > 15 (LDL cholesterol > 20%). The TC level at the study endpoint correlated with CHD incidence irrespective of the study group and explained almost 45% of CHD incidence. The relationship was progressive and leveled off at a TC level below about 150 mgdL (3.9 mmol/L) (LDL cholesterol approximately equal to 110 mg/dl [approximately equal to 2.8 mmol/L]). Little extra clinical benefit can be expected from further reductions. We can expect an average 2% reduction in CHD events per percent reduction in TC. We can also expect a 2-fold greater clinical benefit among subjects with high initial TC levels than among those with low levels. Finally, we can expect that the cholesterol-attributable risk is reset to that predicted by the TC level achieved within 4 to 6 years.     

Atherosclerotic vascular complications in diabetic transplant candidates

Serious vascular complications limit the success of renal transplantation in diabetic patients. Nearly half of diabetic transplant recipients die within 3 years after transplantation from a vascular complication. However, it has been difficult to determine before transplantation which patients are likely to do poorly. Because atherosclerosis is a systemic disease, we hypothesized that diabetic transplant candidates with pretransplant coronary artery disease would be at high risk for vascular complications even if asymptomatic at the time of pretransplant evaluation. Our hypothesis was that insulin-dependent (IDDM) transplant candidates with coronary artery disease identified with pretransplant coronary angiography would have an increased number of vascular events (amputation, cerebral vascular accident [CVA], or myocardial infarction [MI]) within 3 years of follow-up. We prospectively studied 198 consecutive diabetic transplant candidates grouped on the basis of coronary artery disease. Group 1 patients had no stenosis that was 50% or greater, group 2 patients had one or more stenoses between 50% and 74%, and group 3 patients had one or more stenoses of 75% or greater. During median follow-up of 41 months, 64 patients experienced 98 amputations, 28 MIs, and seven CVAs. At 36 months of follow-up, 55% of group 3 patients, 30% of group 2 patients, and 11% of group 1 patients had experienced a vascular event (P < 0.001). Cox regression confirmed the association of coronary artery disease with subsequent vascular events. Patients with coronary artery disease had a sevenfold increased risk of amputation and a fourfold increased risk of myocardial infarction. Six of seven CVAs occurred in patients with coronary artery disease. We conclude that coronary artery disease identified at pretransplant evaluation is associated with an increased risk of noncoronary vascular complications within 3 years after evaluation.     

Vascular and glomerular changes in the ageing kidney

Glomerular size, shape and number were examined in 44 human kidneys obtained at necropsy. Intrarenal vascular appearances were assessed histologically and by post-mortem angiography. The mean cross-sectional area of glomeruli varied nearly three-fold and glomerular number varied more than three-fold when kidneys from different adult subjects were compared but kidneys from the same subject resembled one another in glomerular size and number. A significant negative correlation existed in the adult between glomerular number and dimensions. Glomerular numbers in the few immature kidneys studied were similar to those in adult kidneys but glomeruli were smaller. Glomerular numbers tended to decline as age and severity of age-related vascular changes increased but correlation was poor. The possibility remains that glomerular involution in the senescent kidney occurs independently of events in the vessels. In men, but not in women, totally hyalinised glomeruli were observed more frequently with increasing age but their presence did not appear to be related to the degree of vascular change. In the senescent kidney, glomerular lobulations tended to disappear. This, together with glomerular loss, must result in a reduction in the area available for filtration. Assessments of total glomerular surface area should take account of glomerular shape and dimensions as well as numbers.     

Vascular lesions in children: percutaneous MR imaging-guided interstitial Nd:YAG laser therapy--preliminary experience

PURPOSE: To investigate the use of magnetic resonance (MR) imaging to guide interstitial laser therapy of deep hemangiomas and vascular malformations in children. MATERIALS AND METHODS: Sixteen children aged 3 months to 16 years with symptomatic vascular lesions underwent percutaneous laser treatment. MR imaging guidance of the laser applicator and online thermomonitoring with MR imaging were performed with a 0.2-T open MR system. Follow-up studies were performed 2 days and 6 weeks after thermotherapy. RESULTS: Interactive positioning of the laser applicator was possible in all patients. Online thermomonitoring was possible in 122 of 137 therapy spots (89%). There was a good correlation between volumes of coagulated tissue on intraprocedural T1-weighted images and volumes of coagulated tissue on follow-up T2-weighted images. At 6-week follow-up, MR imaging demonstrated a reduction in lesion size in 10 patients (mean reduction, 72%) and an increase in lesion size in two patients (mean increase, 134%). Clinical symptoms improved in 14 of 16 patients (88%). CONCLUSION: MR imaging-guided laser therapy appears to be a safe and potentially effective minimally invasive treatment for selected children with vascular lesions.     

Radiation therapy and breast cancer

OBJECTIVE: To evaluate the benefits of a policy of performing screening blood tests in new patients with arterial disease referred to the vascular outpatients department. METHODS: Clinical audit over a 12-month period of all new referrals with arterial disease to the vascular outpatients department at the Leicester General Hospital. RESULTS: Two hundred and seventy-two patients had at least one blood test performed at their outpatient visit. All of these patients had a full blood count performed, of which 21 results (21%) were abnormal. Further investigation of patients with abnormal results revealed one case of bladder cancer, one case of leukaemia and one patient with polycythaemia. Urea and electrolytes were measured in 269 patients (99%). Of these, 26 (10%) were expectedly abnormal in patients with known renal impairment. A further 27 patients (10%) were identified to have some degree of unrecognised renal impairment. Serum non-fasting glucose was measured in 252 patients (93%). There were 11 unexpectedly raised results, but further investigation of these patients only diagnosed one of these patients as diabetic. Serum cholesterol was measured in 201 patients (74%). One hundred and thirty-two patients (66%) had an abnormally raised serum cholesterol level. Of these, only 12 patients (6%) were known to have hyperlipidaemia. CONCLUSIONS: Screening new patients with arterial disease in vascular outpatients does identify significant abnormalities, in particular renal impairment and hyperlipidaemia. Correction of these abnormalities may reduce the morbidity associated with contrast induced nephrotoxic acute renal failure, and also contribute to secondary prevention of vascular events associated with raised lipids.     

Meta-analysis of antiaggregant therapy trials. Proposal of an additional reading key]

The efficacy of drug treatment is conventionally assessed by clinical trials. In these studies, experimental design, data analysis and interpretation of results are based on statistical methods. It is difficult to relate to a specific patient the data obtained from statistically analysed studies of population. In our opinion the statistical parameter NNT (Number of patients Needed to Treat) indicates the effectiveness of a treatment taking into consideration the basal risk as well as the risk reduction after therapy. We applied the NNT parameter to data taken from the metaanalysis Antiplatelet Trialists' Collaboration concerning secondary prevention of adverse vascular events with antiplatelet drugs. We focused on the long-term effect of antiplatelet therapy on the adverse events reduction; in the first year of treatment we observed a NNT value of 37, in the second year a NNT value of 59 and in the third year a NNT value of 200; in the fourth year we found absence of effect. The NNT parameter allows us to evaluate immediately the economic consequences of therapeutic strategies and the clinical impact of a long-term treatment.     

Is atherosclerosis an arginine deficiency disease?

To conclude, an impairment of the NO synthase pathway may be one of the earliest events in atherogenesis. A reduction in NO synthesis and/or activity may contribute to the initiation and progressive of atherosclerosis. Derangement of the NO synthase pathway may occur by several mechanisms, including lipoproptein-induced alterations in signal transduction; increases in superoxide anion elaboration (and degradation of NO); reduced affinity of NOS for L-arginine; and/or elevated levels of circulating antagonists. NO is a potent vasodilator, a regulator of vascular structure, and an inhibitor of endothelial interactions and circulating blood elements. A loss of endothelial NO activity may contribute to the abnormal vasomotion observed in coronary artery disease, as well as the progression of atherosclerosis. Strategies to enhance NO synthesis and/or activity may be useful in maintaining cardiovascular health.     

Dietary L-arginine reduces the progression of atherosclerosis in cholesterol-fed rabbits: comparison with lovastatin

BACKGROUND: We investigated whether L-arginine induces regression of preexisting atheromatous lesions and reversal of endothelial dysfunction in hypercholesterolemic rabbits, whether similar effects can be obtained by cholesterol-lowering therapy with lovastatin, and which mechanism leads to these effects. METHODS AND RESULTS: Rabbits were fed 1% cholesterol for 4 weeks and 0.5% cholesterol for an additional 12 weeks. Two groups of cholesterol-fed rabbits were treated with L-arginine (2.0% in drinking water) or lovastatin (10 mg/d) during weeks 5 through 16. Systemic nitric oxide (NO) formation was assessed as the urinary excretion rates of nitrate and cGMP in weekly intervals. Cholesterol feeding progressively reduced urinary nitrate excretion to approximately 40% of baseline (P<.05) and increased plasma concentrations of asymmetrical dimethylarginine (ADMA), an endogenous NO synthesis inhibitor. Dietary L-arginine reversed the reduction in plasma L-arginine/ADMA ratio and partly restored urinary excretion of nitrate and cGMP (each P<.05 vs cholesterol) but did not change plasma cholesterol levels. L-Arginine completely blocked the progression of carotid intimal plaques, reduced aortic intimal thickening, and preserved endothelium-dependent vasodilator function. Lovastatin treatment reduced plasma cholesterol by 32% but did not improve urinary nitrate or cGMP excretion or endothelium-dependent vasodilation. Lovastatin had a weaker inhibitory effect on carotid plaque formation and aortic intimal thickening than L-arginine. L-Arginine inhibited but lovastatin potentiated superoxide radical generation in the atherosclerotic vascular wall. CONCLUSIONS: Dietary L-arginine improves NO-dependent vasodilator function in cholesterol-fed rabbits and completely blocks the progression of plaques via restoration of NO synthase substrate availability and reduction of vascular oxidative stress. Lovastatin treatment has a weaker inhibitory effect on the progression of atherosclerosis and no effect on vascular NO elaboration, which may be due to its stimulatory effect on vascular superoxide radical generation.     

Secondary prevention of arteriosclerosis

Secondary prevention of arteriosclerosis tries to inhibit progression of the atherosclerotic process. Therapeutic measures focus on modification of cardiovascular risk factors and antithrombotic treatment. Hypercholesterolemia is the main risk factor for coronary artery disease. The risk of a coronary event is correlated to the plasma cholesterol level. Lowering plasma cholesterol results in reduction of vascular morbidity and mortality. Cigarette smoking is the predominant risk factor for peripheral arterial occlusive disease (PAOD). Smoking cessation reduces progression of PAOD and lowers cardiovascular morbidity and mortality. The preventive effect of antihypertensive therapy in hypertensive patients is most pronounced for cerebrovascular events. Antihypertensive measures improve prognosis after stroke and myocardial infarction. The increased cardiovascular risk in diabetics is in part explained by hyperglycemia and hyperinsulinemia, but also depends on coexisting dyslipidemia and hypertension. Intensive treatment of elevated blood glucose levels, dyslipidemia and hypertension are important preventive measures. Aspirin is highly effective in secondary prevention of vascular events. For the coronary arteries, low-dose aspirin is well established. Whether low-dose aspirin is equally effective for reducing progression of arteriosclerosis in the cerebrovascular and in the peripheral vessels is questionable. Ticlopidine serves as an alternative to aspirin; however, neutropenia may occur, which requires supervision of the patient.     

Interaction of Chlamydia pneumoniae and human alveolar macrophages: infection and inflammatory response

Our laboratory developed an isolated perfused superior mesenteric arterial vascular bed preparation to study and correlate vascular smooth-muscle mechanics with associated biochemical events. This preparation provides consistent dose-dependent contractile responses, contains most of the superior mesenteric artery as well as first-, second-, and third-generation arterioles, and has been used for concurrent functional and biochemical analysis of vascular smooth muscle. Preparations isolated from Sprague-Dawley rats produced rapid, dose-related vasoconstrictor responses to norepinephrine (NE) and KCl, while appearing to be unresponsive to periarterial nerve stimulation. Endothelial relaxations to bolus doses of acetylcholine (ACh) in the presence of a constant infusion of NE (10 microM) were limited, producing reductions of perfusion pressures of <25%. Receptor-binding studies conducted to evaluate alpha1-adrenoceptor subtypes revealed high- and low-affinity binding sites composing 91 and 9% of the overall population, respectively. A 60-s time course for contractile response and inositol 1,4,5-triphosphate (IP3) production revealed a significant but transient increase of IP3 that paralleled the contractile response generated by using bolus injections of NE (30 microg). This preparation offers the capacity to conduct perfusion studies investigating vasoconstrictor responses, as well as biochemical studies including receptor-binding and second-messenger assays in the same tissue.     

Effects of etomidate administration on cerebral collateral flow

OBJECTIVE: Augmentation of blood flow to collateral-dependent tissue (CDT) as a result of selective vasodilation of collateral vessels has been shown to occur with various stimuli after middle cerebral artery occlusion. Etomidate, a carboxylated imidazole derivative, is a nonbarbiturate anesthetic that is used clinically both as an anesthetic and as a neuroprotective agent. The effect etomidate has on collateral cerebral vessels is unknown. The purpose of our studies was to test whether etomidate selectively augmented cerebral blood flow (CBF) to CDT during ischemia as an additional mechanism of neuroprotection. METHODS: A left craniotomy was performed in each of 14 dogs, with the animals under halothane anesthesia. A branch of the middle cerebral artery was occluded and cannulated distally for determination of CDT using a "shadow flow" technique. CBF and vascular pressures were measured and used to calculate vascular resistance. An etomidate infusion (0.1 mg/kg of body weight/min administered intravenously) was started, and CBF and vascular pressures were measured at 10 and 40 minutes. Hypotension was then induced, and CBF and pressures were again measured. RESULTS: CBF was significantly reduced in all regions of the brain, including CDT, when etomidate was infused. CDT showed a 53.7% reduction in flow, whereas normal CBF was reduced by at least 63.4%. During hypotension, blood flow to CDT was reduced by an additional 42.7%, whereas normal cerebrum was reduced by at least 22.7%. Vascular resistance was increased in all vessels during etomidate infusion. CONCLUSION: The neuroprotective effects of etomidate do not seem to be through the augmentation of collateral or global CBF.     

Automated interpretation of myocardial SPECT perfusion images using artificial neural networks

The purpose of this study was to develop a computer-based method for automatic detection and localization of coronary artery disease (CAD) in myocardial bull's-eye scintigrams. METHODS: A population of 135 patients who had undergone both myocardial 99mTc-sestamibi rest-stress scintigraphy and coronary angiography within 3 mo was studied. Different image data reduction methods, including pixel averaging and two-dimensional Fourier transform, were applied to the bull's-eye scintigrams. After a quantitative and qualitative evaluation of these methods, 30 Fourier components were chosen as inputs to multilayer perceptron artificial neural networks. The networks were trained to detect CAD in two vascular territories, using coronary angiography as gold standard. A "leave one out" procedure was used for training and evaluation. The performance of the networks was compared to those of two human experts. RESULTS: One of the human experts detected CAD in one of two vascular territories, with a sensitivity of 54.4% at a specificity of 70.5%. The sensitivity of the networks was significantly higher at that level of specificity (77.2%, p = 0.0022). The other expert had a sensitivity of 63.2% at a specificity of 61.5%. The networks had a sensitivity of 77.2% (p = 0.038) at this specificity level as well. The differences in sensitivity between human experts and networks for the other vascular territory were all less than 6% and were not statistically significant. CONCLUSION: Artificial neural networks can detect CAD in myocardial bull's-eye scintigrams with such a high accuracy that the application of neural networks as clinical decision support tools appears to have significant potential.