Vigabatrin directed against kindled seizures following cortical insult: impact on epileptogenesis and somatosensory recovery.

The anticonvulsant drug vigabatrin has not been found to be detrimental to the recovery process when administered following focal cortical insult. This finding is in contrast to the negative postinjury consequences of other anticonvulsant drugs (e.g., phenobarbital and diazepam) with more direct activation of the GABA/benzodiazepine receptor complex. Moreover, phenobarbital directed against kindled seizures affects functional recovery more adversely than either the drug or subconvulsive seizures alone. The purpose of the present study was to determine whether vigabatrin (150, 200, and 250 mg/kg) directed against kindled seizures would impact recovery from lesion-induced somatosensory deficits. Vigabatrin was coupled with daily electrical kindling of the amygdala during the first week after a unilateral anteromedial cortex (AMC) lesion. Somatosensory recovery was assessed using bilateral tactile stimulation tests. Animals receiving the highest dose of vigabatrin prior to electrical kindling (250 mg/kg vigabatrin/kindled) remained significantly impaired even after two months of testing relative to vehicle/kindled, kindled/250 mg/kg vigabatrin, which received vigabatrin after electrical kindling, and the 150, 200, and 250 mg/kg vigabatrin/nonkindled groups (p < 0.0001). In contrast, neither vigabatrin (at any of the doses tested) nor subconvulsive kindled seizures impacted the recovery process (p > 0.05) when administered alone (i.e., without the drug + seizure interaction). These data add to the accumulating experimental and clinical evidence suggesting that the neurobehavioral consequences of the interaction between anticonvulsant drugs and subclinical seizures after brain insult are detrimental to functional recovery.

Endothelium-derived nitric oxide regulates arterial elasticity in human arteries in vivo.

Arterial elasticity is determined by structural characteristics of the artery wall and by vascular smooth muscle tone. The identity of endogenous vasoactive substances that regulate elasticity has not been defined in humans. We hypothesized that NO, a vasodilator released constitutively by the endothelium, augments arterial elasticity. Seven healthy young men were studied. A 20-MHz intravascular ultrasound catheter was introduced through an arterial sheath to measure brachial artery cross-sectional area, wall thickness, and intra-arterial pressure. After control was established, indices of elasticity (pressure-area relationship, instantaneous compliance, and stress-strain, pressure-incremental elastic modulus (E(inc)), and pressure-pulse wave velocity relationships) were examined over 0 to 100 mm Hg transmural pressure obtained by inflation of an external cuff. Thereafter, the basal production of endothelium-derived NO was inhibited by N(G)-monomethyl-L-arginine (L-NMMA) (4 and 8 mg/min). Finally, nitroglycerin (2.5 and 12.5 microgram/min), an exogenous donor of NO, was given to relax the vascular smooth muscle. Elasticity was measured under all of these conditions. L-NMMA (8 mg/min) decreased brachial artery area (P=0.016) and compliance (P<0.0001) and increased E(inc) (P<0.01) and pulse wave velocity (P<0.0001). Nitroglycerin (12.5 microgram/min) increased brachial artery area (P<0.001) and compliance (P<0.001) and decreased pulse wave velocity (P=0.02). NO, an endothelium-derived vasodilator, augments arterial elasticity in the human brachial artery. Loss of constitutively released NO associated with cardiovascular risk factors may adversely affect arterial elasticity in humans.

Role of endothelin-1 in the active constriction of human atherosclerotic coronary arteries.

BACKGROUND: Atherosclerotic coronary arteries are prone to constriction but the underlying causes are incompletely understood. We tested the hypothesis that endothelin-1 (ET-1), a potent vasoconstrictor, contributes to the heightened tone of atherosclerotic human coronary arteries. METHODS AND RESULTS: In 8 patients with coronary artery disease (CAD) and 8 patients with angiographically smooth coronary arteries (normal), we infused BQ-123, an antagonist of the ET(A) receptor, into a major coronary artery (infused artery) at 40 nmol/min for 60 minutes. The infused artery in the CAD patients contained a >50% stenosis. Using quantitative angiography, we compared the dilation of the infused artery with another, noninfused coronary artery. To estimate the magnitude of the contribution of ET-1 to coronary tone, we compared the dilation to BQ-123 with that elicited by intracoronary nitroglycerin (200 microgram). BQ-123 induced significant dilation in the normal arteries (7.3% at 60 minutes, P<0.001 versus noninfused arteries) and a greater dilation in the CAD arteries (16.3% at 60 minutes, P<0.001 versus infused normal arteries). The dilation at stenoses was particularly pronounced (21.6% at 60 minutes, P<0.001 versus infused CAD arteries). Compared with the dilation from nitroglycerin, ET-1 contributed to 39% of the coronary tone in normal arteries, 74% of tone in CAD arteries, and 106% of tone at stenoses (P<0.01). CONCLUSIONS: ET-1 accounts for nearly all the resting tone in atherosclerotic coronary arteries, especially at stenoses. Inhibitors of ET-1, by relieving constriction, may significantly lessen the hemodynamic significance of coronary stenoses and thereby reduce myocardial ischemia.

Vascular closure devices and the risk of vascular complications after percutaneous coronary intervention in patients receiving glycoprotein IIb-IIIa inhibitors.

Vascular closure devices offer advantages over traditional means of obtaining hemostasis after percutaneous coronary intervention (PCI) in terms of patient comfort and time to ambulation. We investigate whether such devices also reduce the risk of vascular complications in selected patient populations. We conducted a retrospective analysis of all patients who underwent PCI at our institution between January 1998 and December 1999. Of 3,151 consecutive patients, 3,027 were eligible to receive vascular closure devices. Of these, 1,485 received a closure device and 1,409 received glycoprotein IIb-IIIa antagonists. The overall vascular complication rate, as defined by the need for surgical repair or transfusion, or the development of arteriovenous fistula, pseudoaneurysm, or large hematoma, was 4.20%. By univariate analysis, the use of closure devices was associated with a lower vascular complication rate (3.03% vs 5.52%; p = 0.002) and a shorter length of hospital stay (2.77 vs 3.97 days, p <0.001). Multivariate analysis showed a significant reduction in vascular complications with closure devices (odds ratio 0.59, p = 0.007). For the subgroup of patients receiving glycoprotein IIb-IIIa antagonists, the use of closure devices was associated with an even more pronounced reduction in the risk of vascular complications (odds ratio 0.45, p <0.008). Thus, the use of closure devices in selected patients undergoing PCI is associated with a low rate of vascular complications and decreased length of stay. This benefit was most marked for patients receiving glycoprotein IIb-IIIa antagonists.

Pathophysiology of atherosclerosis: development, regression, restenosis.

There is now a very large number of patients with coronary artery disease who have also undergone percutaneous interventions such as coronary angioplasty. Atherosclerosis and restenosis are two distinct pathologic processes with different underlying pathophysiologic mechanisms, different natural histories, different clinical presentations, and treatment strategies. Management strategies to target both processes are currently poorly applied in clinical practice. The development of integrated management strategies to target atherosclerosis, as well as restenosis in the postprocedural period remains a priority.

Treating ambulatory ischemia in coronary disease by manipulating the cell biology of atherosclerosis.

Obstructive coronary artery disease is the most common cause of morbidity and mortality in the developed world. Our understanding of the pathobiology of coronary atherosclerosis provides us with new opportunities to reduce myocardial ischemia by interventions that address these mechanisms directly. These interventions include lipid-lowering therapies that improve local coronary vasomotion, inflammation, and the procoagulant state. These interventions have also been shown to result in important reductions in clinical events, including angina pectoris, myocardial ischemia and infarction, and death. Ambulatory electrocardiography provides a versatile and quantifiable measure of regional myocardial ischemia. Reductions in ischemia, as quantified by this diagnostic modality, are associated with improved clinical outcomes that may reflect improvements in the cellular pathophysiology of coronary atherosclerosis. This review discusses new information regarding the interactions between low-density lipoprotein cholesterol, the cell biology of atherosclerosis, and the activity of ischemia in patients with coronary artery disease.

Lack of compensatory enlargement at sites of coronary vasospasm: identification by ultrasound and successful treatment with stenting.

The case of a young man with spontaneous vasospasm at two sites in his left anterior descending coronary artery is described. Intravascular ultrasound demonstrated mild eccentric atherosclerosis with smaller total artery cross-sectional area (defined as the external elastic membrane) compared with reference segments. Impaired compensatory enlargement (remodeling) in response to mild atherosclerosis may derive from one or more biologic mechanisms that are also responsible for vasospasm. This characteristic is easily identified by intravascular ultrasound. In this case, coronary stenting of the vasospastic sites led to excellent long-term control of symptoms more than 1 year after intervention.

The comparative pathobiology of atherosclerosis and restenosis.

Percutaneous coronary interventions (PCIs) play an increasingly important role in the management of patients with coronary artery disease. However, these important procedures are complicated by restenosis in a sizeable number of patients. The pathobiology of atherosclerosis comprises a complex interaction among lipids, the endothelium, circulating and tissue inflammatory cells, platelets, and vascular smooth muscle cells. The superimposition of the mechanical and cellular consequences of PCIs on the abnormal substrate of atherosclerosis leads to a characteristic and distinct pathobiology that initiates and perpetuates restenosis. A clear understanding of the significant differences between atherosclerosis and restenosis will provide a rational basis for developing treatment plans that always address both problems. This article reviews and contrasts the pathobiology of atherosclerosis and restenosis and compares the mechanisms and time-course of these distinct entities.

Lipid-lowering therapy after coronary revascularization.

Atherosclerosis is often asymptomatic, unrecognized, and undertreated. Lumen irregularities are important angiographic findings that should be addressed aggressively through risk factor modification, medical therapy, and coronary revascularization. Both angiographic and clinical benefits have been demonstrated with lipid reduction therapy in randomized clinical trials. Coronary revascularization is indicated for symptom relief and improvement in quality of life in patients with acute coronary syndromes at "intermediate" and "high" risk of subsequent death or myocardial infarction. In patients following percutaneous coronary intervention (PCI), future cardiac events may be related to lumen renarrowing or to progression of atherosclerotic disease at sites remote from the site of coronary revascularization. The time course of restenosis is relatively self-limiting, generally occurring within 6-12 months after the procedure. Clinical events occurring > 1 year after PCI generally relate to new lesions or progression of existing atherosclerotic disease. Patients with diabetes mellitus may be at higher risk for late coronary events than nondiabetic patients. In post-coronary artery bypass surgery (CABG) patients, the majority of late events relate to degeneration of saphenous vein grafts. Lipid lowering therapy after coronary revascularization has been shown to prevent clinical events related to plaque instability and inhibit progression of saphenous vein graft disease. Thus, there are 2 goals in management of patients with symptomatic coronary artery disease: (1) to relieve the flow-limiting stenosis, and (2) to prevent future clinical events with aggressive lipid lowering and modification of other risk factors. Patients, specialists, and primary care physicians each need to take accountability for this risk-factor modification.

Atherogenic lipids and endothelial dysfunction: mechanisms in the genesis of ischemic syndromes.

Atherogenic lipids, particularly oxidized low-density lipoprotein, are responsible for a wide range of cellular dysfunctions within the vessel wall. The effects on endothelial cells disrupt normal control of vasomotion, with a reduction of effective nitric oxide activity, the development of a procoagulant surface, chronic low-grade inflammation, and abnormal cell growth. These changes are central not only in the development of atherosclerosis but also in the evolution of both stable and unstable ischemic syndromes. There is growing evidence that these abnormal changes in cell function respond rapidly to changes in the atherogenic lipids. Certain cell functions can improve within hours or days of cholesterol lowering.

Plasma alpha-tocopherol and coronary endothelium-dependent vasodilator function.

BACKGROUND: In the presence of atherosclerosis, the coronary endothelial vasomotor response to acetylcholine is frequently abnormal but is variable between patients. We tested the hypothesis that the plasma concentration of alpha-tocopherol is associated with the preservation of nitric oxide-mediated endothelium-dependent vasomotion. METHODS AND RESULTS: We studied 15 men and 6 women (mean age 61+/-10 years) at coronary angiography who were not taking vitamin supplements. Coronary endothelium-dependent and -independent vasomotion was assessed by intracoronary infusions of acetylcholine and nitroglycerin. The vasomotor responses were compared with the plasma concentration of alpha-tocopherol and the plasma alpha-tocopherol concentration relative to total lipid (total cholesterol plus triglycerides). The mean plasma alpha-tocopherol was 25.6+/-6.1 micromol/L, total cholesterol 193+/-27 mg/dL, triglycerides 115+/-66 mg/dL, and alpha-tocopherol to total lipid 4. 2+/-0.9 micromol. L(-1). (mmol/L)(-1). The mean vasomotor response to acetylcholine was -1% (range -33% to 28%) and to nitroglycerin 22% (range 0% to 54%). Plasma alpha-tocopherol was significantly correlated with the acetylcholine response (r=0.49, P<0.05) but not the nitroglycerin response (r=0.13, P>0.05). The acetylcholine response remained significant after adjustment for other potential sources of oxidant stress (total cholesterol, diabetes mellitus, smoking, angina class) (P<0.01). The relative concentration of alpha-tocopherol to total lipid was not related to endothelial function (r=0.24, P=0.3, n=20). CONCLUSIONS: alpha-Tocopherol may preserve endothelial vasomotor function in patients with coronary atherosclerosis. This effect may be related primarily to the action of alpha-tocopherol in the vascular wall. Further studies that assess the impact of alpha-tocopherol supplementation as therapy of endothelial dysfunction are justified.

The influence of basal nitric oxide activity on pulmonary vascular resistance in patients with congestive heart failure.

Increased pulmonary resistance may reduce survival and treatment options in patients with congestive heart failure. Nitric oxide (NO) is a determinant of normal pulmonary resistance vessel tone. We tested the hypothesis that loss of NO function contributes to increased pulmonary vascular resistance index (PVRI) in congestive heart failure. Pulmonary arterial resistance vessel function was studied in 25 conscious adults. Three groups were studied: 8 controls, 9 patients with congestive heart failure and normal PVRI, and 8 patients with congestive heart failure and raised PVRI. Segmental arterial flow was determined with a Doppler wire and quantitative angiography. NG-monomethyl-L-arginine (L-NMMA) was used to inhibit NO, whereas phenylephrine was used as an endothelium-independent control. The response to inhibition of NO with L-NMMA was less in patients with congestive heart failure and elevated PVRI than in patients with congestive heart failure and normal PVRI (p <0.05). The difference in response between the congestive heart failure groups was specific to NO-dependent regulation because the response to the endothelium-independent constrictor phenylephrine was not different (p = 0.92). There was no difference in response to L-NMMA between controls and patients with congestive heart failure and normal PVRI. The response to L-NMMA correlated to PVRI. In adults with congestive heart failure, NO appears to play an important role in maintaining normal pulmonary resistance.

Current concepts in cardiovascular pathology: the role of LDL cholesterol in plaque rupture and stabilization.

Emerging evidence is redefining traditional concepts of coronary atherosclerosis. Recent data indicate that severe stenoses, the traditional focus of attention, do not cause most coronary events. Rather, interest has increased in the often less stenotic but more vulnerable lesions that are characterized by thin fibrous caps, large lipid accumulations, large numbers of macrophages, and depletion of smooth muscle cells. Such lesions appear prone to rupture, which allows the blood to come into contact with the highly thrombogenic material in the lipid core of the plaque, thereby precipitating thrombosis. The fibrous cap may become weakened through decreased synthesis of the extracellular matrix or increased degradation of the matrix. The cytokine interferon-gamma, produced by T-lymphocytes, inhibits the ability of smooth muscle cells to synthesize collagen, a structurally important component of the fibrous cap. A family of enzymes known as matrix metalloproteinases can degrade all major constituents of the vascular extracellular matrix: collagen, elastin, and proteoglycans. Additional studies on the biochemical mechanisms of atherosclerosis may provide a fuller understanding of the ways in which lipid-lowering therapy can confer clinical benefit.

Inflammation, the endothelium, and the acute coronary syndromes.

Disruption of atherosclerotic plaques with associated thrombus is responsible for the majority of the acute coronary syndromes. Plaque instability is related closely to the degree of inflammation. Inflammatory cells within the plaque produce cytokines that inhibit collagen production by vascular smooth muscle cells and increase the production of metalloproteinases, which degrade the extracellular matrix in the fibrous cap. The recruitment of inflammatory cells into the vessel wall occurs in a coordinated sequence of events involving the expression of cellular adhesion molecules on the surface of activated endothelial cells and the production of chemoattractants, and occurs in part in response to oxidation of low-density lipoprotein within the vessel wall. The cellular adhesion molecules are shed into the circulating blood in several disease states, including clinically evident atherosclerosis. The acute-phase reactants C-reactive protein and interleukin-6, and markers of the fibrinolytic state (plasminogen activator inhibitor-1 and tissue plasminogen activator), are also elevated in the acute coronary syndromes and in healthy individuals at increased risk for developing coronary artery disease. These markers may reflect vascular inflammation and thereby the stability of atherosclerotic plaques. Their measurement may pinpoint the mechanisms of benefit of cholesterol-lowering therapy and other interventions designed to reduce coronary risk, and potentially could offer a new method for monitoring coronary risk factor reduction in patients.

Cell dysfunction in atherosclerosis and the ischemic manifestations of coronary artery disease.

Many of the cellular mechanisms and dysfunctions that underlie atherosclerotic plaque formation have been identified, including adverse interactions between atherogenic lipids and the arterial endothelium, loss of endothelium-dependent dilation, accumulation of inflammatory cells and mediators of inflammation in the intima of the arteries, and a decline in anticoagulant defenses. Several studies have shown that these mechanisms, which appear to be active throughout the pathogenesis and progression of atherosclerosis, are reversible within days, weeks, or months with effective lipid-lowering therapy. In addition, the findings of large-scale trials of 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors suggest that the rapid improvement observed in trial participants is attributable to a reversal of endothelial and vascular wall dysfunctions rather than to a reduction in plaque size. The accumulated evidence indicates that improved endothelial function can benefit patients who have angina pectoris and/or are at risk for myocardial infarction. Current understanding of the cellular mechanisms of atherogenesis also suggests avenues of future research to refine treatment approaches and further improve outcomes for patients with coronary artery disease.