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Biomedical subjects

P Ganz

Publications and source records attributed to P Ganz.

At least 55 records · Page 3Linked to original sources
PubMed1998

Effect of direct thrombin inhibition with Bivalirudin (Hirulog) on restenosis after coronary angioplasty.

The direct antithrombin, bivalirudin, did not reduce angiographic restenosis measured either as the dichotomous restenosis rate of 62% for bivalirudin and 58% for heparin (p = 0.70), or as the late loss in lumen diameter of 0.44 +/- 0.47 mm for bivalirudin and 0.39 +/- 0.53 mm for heparin (p = 0.62). Direct thrombin inhibition with bivalirudin neither reduces angiographic restenosis nor alters the impact of several established risk factors for restenosis.

Adult↗
PubMed1998

Rationale and design of the Myocardial Ischemia Reduction with Aggressive Cholesterol Lowering (MIRACL) study that evaluates atorvastatin in unstable angina pectoris and in non-Q-wave acute myocardial infarction.

The goal of the Myocardial Ischemia Reduction with Aggressive Cholesterol Lowering (MIRACL) study is to determine whether early, rapid, and profound cholesterol lowering therapy with atorvastatin can reduce early recurrent ischemic events in patients with unstable angina or non-Q-wave acute myocardial infarction. Within 1 to 4 days of hospitalization for one of these conditions, 2,100 patients will be randomly assigned to receive atorvastatin, 80 mg/day, or placebo in a double-blind design. Both groups receive dietary counseling. Over a 16-week follow-up period, the primary outcome measure is the time to occurrence of an ischemic event, defined as death, nonfatal acute myocardial infarction, cardiac arrest with resuscitation, or recurrent symptomatic myocardial ischemia requiring emergency rehospitalization. Secondary outcome measures are the time to occurrence and incidence of each of the primary outcome components, as well as nonfatal stroke, worsening angina, congestive heart failure requiring hospitalization, and need for coronary revascularization not anticipated before randomization. The sample size of 1,050 patients in each group is expected to provide 95% power to detect a 30% reduction in the primary outcome measure with a 5% level of significance. The results of the MIRACL study will determine the utility of profound cholesterol lowering as an early intervention in acute coronary syndromes.

Angina, Unstable↗
PubMed1998

Vitamin C improves endothelium-dependent vasodilation in patients with insulin-dependent diabetes mellitus.

OBJECTIVES: We sought to determine whether the antioxidant vitamin C improves endothelium-dependent vasodilation of forearm resistance vessels in patients with insulin-dependent diabetes mellitus. BACKGROUND: Endothelium-dependent vasodilation is impaired in patients with diabetes mellitus. Oxidatively mediated degradation of endothelium-derived nitric oxide contributes to abnormal endothelium-dependent vasodilation in animal models of diabetes mellitus. METHODS: The study group included 10 patients with insulin-dependent diabetes mellitus and 10 age-matched control subjects. Forearm blood flow was determined by venous occlusion plethysmography. Endothelium-dependent vasodilation was assessed by intraarterial infusion of methacholine (0.3 to 10 microg/min). Endothelium-independent vasodilation was assessed by intraarterial infusion of nitroprusside (0.3 to 10 microg/min). Forearm blood flow dose-response curves were determined for each drug infusion before and during concomitant infusion of vitamin C (24 mg/min). RESULTS: In diabetic subjects, endothelium-dependent vasodilation was augmented by the concomitant infusion of vitamin C (p = 0.001). Endothelium-independent vasodilation was not affected by the concomitant infusion of vitamin C (p = NS). In control subjects, vitamin C infusion did not affect endothelium-dependent vasodilation (p = NS). CONCLUSIONS: Vitamin C selectively restores the impaired endothelium-dependent vasodilation in the forearm resistance vessels of patients with insulin-dependent diabetes mellitus. These findings indicate that nitric oxide degradation by oxygen-derived free radicals contributes to abnormal vascular reactivity in humans with insulin-dependent diabetes mellitus.

Adult↗
PubMed1998

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.

Cholesterol, LDL↗
PubMed1998

Noninvasive assessment of transplant-associated arteriosclerosis.

BACKGROUND: Transplant-associated arteriosclerosis is the major limitation to long-term survival in the cardiac transplant recipient, and annual surveillance angiography is used in many centers to monitor its progression. Noninvasive methods would be preferable because angiography is invasive, costly, and insensitive; however, the reliability of such methods has been questioned. METHODS: All publications relating to the assessment of the cardiac allograft by noninvasive testing were identified through MEDLINE and a review of references from the published literature on transplant-associated arteriosclerosis. RESULTS: Resting and stress ECG, radionuclide scintigraphy, echocardiography, and positron emission tomography have all been used in cardiac transplant recipients with variable results. Most techniques are insensitive, but this limitation may be improved with pharmacologic stress imaging like dobutamine echocardiography. Although insensitive, some methods have good specificity (i.e., radionuclide scintigraphy). The noninvasive measurement of absolute coronary blood flow is promising as a specific and sensitive technique but is limited by availability and cost. CONCLUSIONS: In general, noninvasive techniques to assess transplant-associated coronary arteriosclerosis are limited by variable sensitivity and specificity. However, certain methods, such as dobutamine echocardiography and radionuclide scintigraphy, can provide important adjunctive physiologic information to angiography. Such techniques can therefore help to guide the care and treatment of the cardiac transplant recipient with allograft coronary arteriosclerosis.

Coronary Angiography↗
PubMed1998

Central role for CD40/CD40 ligand (CD154) interactions in transplant rejection.

Major advances have been made in understanding the expression and function of CD40 and its ligand CD154. It is now clear that CD40/CD154 interactions are critical in many aspects of the immune response, including T cell activation, T cell-dependent macrophage activation, T cell-B cell interactions and endothelial activation. Moreover, increasing evidence supports a central role for CD40/CD154 interactions in the immune processes of allograft rejection. Functional studies using blocking monoclonal antibodies have revealed beneficial effects of interupting CD40/CD154 co-stimulation in animal models of transplantation, particularly in association with interuption of the CD28/B7 pathway. A next step is to develop new therapeutic approaches to interrupting this pathway in humans, either through the development of receptor antagonists or through the understanding of intracellular signaling pathways utilized by these molecules.

Animals↗
PubMed1998

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.

Acute Disease↗
PubMed1997

CD40 and CD40 ligand (CD154) are coexpressed on microvessels in vivo in human cardiac allograft rejection.

BACKGROUND: CD40 is expressed by a wide variety of cells in the immune system, including endothelial cells. It binds to CD40 ligand ([CD40L] CD154), which was originally reported to be restricted in its expression to early-activated T cells. We report here the expression of CD40 and CD40L in human cardiac allografts. METHODS: A total of 123 consecutive biopsies from 11 human cardiac allograft recipients were analyzed by immunohistochemistry for the expression of CD40 and CD40L. The expression of CD40L was also examined in vitro in homogeneous cultures of umbilical vein endothelial cells by reverse transcriptase-polymerase chain reaction and by flow cytometry. RESULTS: CD40 was expressed at low levels, and CD40L was minimal or absent in histologically normal biopsies in the absence of CD3+ T-cell infiltrates. In rejection, the expression of CD40 increased on vascular endothelial cells and on graft-infiltrating leukocytes throughout biopsy specimens. Induced expression of CD40 was strongly associated with the presence of CD3+ T-cell infiltrates, acute rejection, and ischemic injury (P<0.05). CD40L was expressed in biopsies with rejection and was prominent on a subset of infiltrating leukocytes as well as on microvascular endothelial cells. In contrast to CD40, staining of endothelial CD40L was focal in most biopsies. Overall, the expression of CD40L correlated with the presence of CD3+ T-cell infiltrates and rejection (P<0.05), but not ischemic injury (P=0.9). To confirm that the endothelium can synthesize CD40L, we also evaluated the expression of endothelial CD40L in vitro. Cultured endothelial cells were found to express little constitutive CD40L that markedly increased after 24 hr of treatment with supernatants from phytohemagglutinin-activated peripheral blood mononuclear cells or by the cytokines tumor necrosis factor-alpha, interleukin-1a, interleukin-4, or interferon-gamma. CONCLUSION: Both CD40 and CD40L are expressed in vivo on infiltrating leukocytes and on microvascular endothelium in human cardiac allograft rejection. We suggest that endothelial cell CD40 and CD40L play a role in human cell-mediated immune responses such as cardiac allograft rejection.

Biopsy↗
PubMed1997

Role of endothelial dysfunction in coronary artery disease and implications for therapy.

Atherosclerosis is a complex process that is characterized by the accumulation of modified low-density lipoprotein (LDL), local inflammatory and immune responses, and reduced nitric oxide bioavailability within the arterial wall. These cellular changes lead to endothelial vasomotor dysfunction, plaque instability, and the development of clinical events such as stable angina and the acute coronary syndromes. The vascular endothelium plays a critical role in modulating both the inflammatory response and vasomotor abnormalities that occur in those with coronary artery disease or risk factors for disease. In these conditions, endothelial cells are activated by cytokines to express cellular adhesion molecules that facilitate the adhesion of leukocytes to the endothelium, and their migration into the subintimal space. Cytokines stimulate inflammatory and smooth muscle cells in the intima to produce degradative enzymes, including metalloproteinases that can weaken the fibrous cap of atherosclerotic lesions and make them vulnerable to rupture. Endothelial cells also regulate vascular tone by the synthesis of nitric oxide. Atherosclerosis and other conventional risk factors for coronary artery disease are associated with endothelial vasodilator dysfunction in the coronary epicardial and resistance vessels, which likely contributes to myocardial ischemia. Several studies have demonstrated that lowering serum total and LDL cholesterol reverses endothelial vasomotor dysfunction, reduces myocardial ischemia, and lowers the risk of the acute coronary syndromes or need for revascularization. Improving endothelial function, for example, by lowering blood cholesterol should now be regarded as a goal of therapy in the treatment of coronary artery disease.

Anticholesteremic Agents↗
PubMed1997

Bivalirudin compared with heparin during coronary angioplasty for thrombus-containing lesions.

OBJECTIVES: We investigated whether bivalirudin is more effective than heparin in preventing ischemic complications in high risk patients undergoing coronary angioplasty for thrombus-containing lesions detected by angiography. BACKGROUND: Heparin is administered during coronary angioplasty to prevent closure of the dilated vessel. Bivalirudin (Hirulog) is a direct thrombin inhibitor that can be safely substituted for heparin during angioplasty. Bivalirudin has several theoretic advantages over heparin as an anticoagulant agent. METHODS: We performed an observational analysis of the Hirulog Angioplasty Study in which 4,098 patients with unstable or postinfarction angina were randomized to receive either bivalirudin or heparin during coronary angioplasty. The study group for this analysis consisted of 567 patients who had thrombus-containing lesions on angiography. The primary end point was death, myocardial infarction, emergency coronary artery bypass graft surgery or abrupt vessel closure before hospital discharge. RESULTS: Patients with thrombus-containing lesions had a higher incidence of myocardial infarction (5.1% vs. 3.2%, p = 0.03) and abrupt vessel closure (13.6% vs. 8.3%, p < 0.001) than those without thrombus. In patients with thrombus-containing lesions, however, the incidence of the primary end point was not different between the bivalirudin and heparin treatment groups. Furthermore, no difference in the incidence of ischemic events at 6 months was seen between the treatment groups. CONCLUSIONS: Bivalirudin is not more effective than heparin in preventing ischemic complications in patients undergoing coronary angioplasty for thrombus-containing lesions detected by angiography. Other approaches, perhaps involving potent anti-platelet agents, should be considered for patients with thrombus-containing lesions.

Aged↗
PubMed1997

Vitamin C improves endothelium-dependent vasodilation in forearm resistance vessels of humans with hypercholesterolemia.

BACKGROUND: Endothelium-dependent vasodilation is impaired in humans with hypercholesterolemia. Oxidative degradation of endothelium-derived nitric oxide plays a major role in endothelial dysfunction in animal models of hypercholesterolemia. To assess whether this mechanism is relevant to humans, we studied the effect of vitamin C, an antioxidant, on vasodilator function in forearm resistance vessels of patients with hypercholesterolemia. METHODS AND RESULTS: We studied 11 hypercholesterolemic and 12 healthy control subjects. Forearm blood flow was determined by venous occlusion plethysmography. Endothelium-dependent vasodilation was assessed by intra-arterial infusion of methacholine (0.3 to 10 micrograms/min). Endothelium-independent vasodilation was measured by intra-arterial infusion of nitroprusside (0.3 to 10 micrograms/min) and verapamil (10 to 300 micrograms/min). Forearm blood flow dose-response curves were determined for each drug before and during coadministration of vitamin C (24 mg/min). In hypercholesterolemic subjects, endothelium-dependent vasodilation to methacholine was augmented by coinfusion of vitamin C (P = .001); in contrast, endothelium-independent vasodilation to nitroprusside and verapamil were not affected by coinfusion of vitamin C (P = .8 and P = .3, respectively). In control subjects, vitamin C administration did not alter endothelium-dependent vasodilation (P = .2). CONCLUSIONS: We conclude that vitamin C improves endothelium-dependent vasodilation in the forearm resistance vessels of patients with hypercholesterolemia. These findings suggest that nitric oxide degradation by oxygen-derived free radicals contributes to abnormal vascular reactivity in hypercholesterolemic humans.

Adult↗
PubMed1997

Heat changes in lipid membranes under sudden osmotic stress.

Closed lipid vesicles act as osmometers increasing or decreasing their volume under the influence of osmotic gradients. The enthalpy changes accompanying membrane compression or expansion have not been measured yet, and first results obtained with high-sensitivity titration calorimetry are reported here. Phospholipid vesicles suspended in and in equilibrium with an electrolyte or nonelectrolyte with a defined initial concentration of c(i), were injected into a solution with a final concentration of c(f), and the heat changes were monitored with a titration microcalorimeter. Osmotic compression (delta c = c(f) - c(i) > 0) produced an exothermic heat change with deltaH approximately -500 +/- 100 cal/mol and osmotic expansion (delta c < 0) an endothermic heat change with deltaH approximately 1000 +/- 200 cal/mol; both results normalized to a concentration gradient of delta c = 1 M NaCl. The heats of compression and expansion varied linearly with the lipid content and the size of the osmotic gradient but were independent of the vesicle size. The cubic thermal expansion coefficient alpha(v) which equals (1/V)(deltaV/deltaT)p could be derived and was found to be 1.25 x 10(-3) and 2.5 x 10(-3) K(-1) for the compressed and expanded bilayer vesicles, respectively. The entropy changes associated with compression and expansion could be estimated. Compression of the membrane led to a negative entropy change and increased the hydrocarbon chain order. Expansion of the membrane was accompanied by a positive entropy change which can be explained, in part, by more disordered hydrocarbon chains. Vesicle expansion and compression thus appear to be asymmetric as far as the thermodynamic driving force is concerned.

Calorimetry↗
PubMed1997

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.

Animals↗
PubMed1997

Effect of cholesterol reduction on myocardial ischemia in patients with coronary disease.

BACKGROUND: Cholesterol lowering is associated with a reduction in cardiovascular morbidity and mortality. This study sought to determine whether cholesterol lowering also results in a reduction of myocardial ischemia during daily life. METHODS AND RESULTS: We enrolled 40 patients with proven coronary artery disease, total serum cholesterol between 191 and 327 mg/dL, and at least one episode of ST-segment depression on ambulatory ECG monitoring. Twenty patients were randomized to an American Heart Association Step 1 diet plus placebo (placebo group) and 20 to the same diet plus lovastatin (treatment group). Serum cholesterol and LDL cholesterol levels and ambulatory monitoring were repeated after 4 to 6 months of therapy. The two groups were comparable with respect to baseline characteristics, number of episodes of ST-segment depression, and baseline serum cholesterol levels. The treatment group had lower mean total and LDL cholesterol levels at study end and experienced a significant reduction in the number of episodes of ST-segment depression compared with the placebo group. ST-segment depression was completely resolved in 13 of 20 patients (65%) in the treatment group versus 2 of 20 (10%) in the placebo group. The treatment group exhibited a highly significant reduction in ischemia (P < .001). By logistic regression, treatment with diet and lovastatin was an independent predictor of ischemia resolution. CONCLUSIONS: Cholesterol lowering with lovastatin appears to be effective in eliminating myocardial ischemia during daily life in a significant proportion of patients.

Aged↗
PubMed1997

Atherogenic lipids, vascular dysfunction, and clinical signs of ischemic heart disease.

LDL is oxidized in vascular endothelial cells to a highly injurious product that results in characteristic cell dysfunction(s) in large arteries and resistance vessels. The characteristic dysfunctions (ie, loss of dilation, constriction, thrombosis, and inflammation) operate before and throughout the development of atherosclerosis and particularly during plaque rupture. Although oxidized LDL appears to induce these cell/vessel wall dysfunctions in a time- and concentration-dependent manner, Tamai and colleagues have shown that this interaction can be dynamic in that a reduction in lipids restores endothelium-dependent vasomotor function almost immediately. The same intervention (ie, lipid lowering) also appears to stabilize atheroma in the long term, improves endothelium-dependent vasomotion over months, and results in a reduction in clinical signs of risk in coronary heart disease (ie, ischemia and the need for revascularization). The above leads us to some important but unanswered questions. Can we rely on clinical measures of arterial vasomotor dysfunction to represent the other important cell dysfunctions (eg, inflammation, abnormal growth) while monitoring the response to therapeutic interventions? How can we effectively inhibit oxidation of LDL in the arterial wall, and is this useful in reversing the many cell dysfunctions and clinical sequelae of coronary atherosclerosis? What is the time course for restoration of endothelial dysfunction in the atherosclerotic epicardial coronary arteries in patients with effective lipid-lowering therapy? The intracellular responses to oxidized LDL are so numerous (loss of vasodilation, loss of anticoagulant mechanisms, abnormal inflammation, and growth) that targeting therapies to specific pathways may prove difficult. Parallel efforts in basic physiological and clinical research have resulted in remarkable progress that has improved outcomes in patients with coronary heart disease. We expect that many of the characteristic cell/vessel wall dysfunctions that result from adverse interactions with risk factors are dynamic and can be manipulated in a relatively short time frame. Treatment of atherogenic lipids with other risk factors must be further refined and may well become the cornerstone for effective management of angina, unstable syndromes, and ischemia in addition to the control of important outcomes such as myocardial infarction and coronary death.

Cholesterol, LDL↗