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P Ganz

Publications and source records attributed to P Ganz.

At least 19 recordsLinked to original sources
PubMed2001

Expression of the chemokine receptor CXCR3 and its ligand IP-10 during human cardiac allograft rejection.

BACKGROUND: Chemokines play an essential role in regulating the infiltration of leukocytes into allografts in experimental models. Little is known of their expression or function after human cardiac transplantation. METHODS AND RESULTS: We analyzed 169 sequential human endomyocardial biopsies by immunocytochemistry for infiltration by CD3(+) T cells and the expression of the chemokine receptors CCR1, CCR3, CCR5, and CXCR3. In both cross-sectional and longitudinal analyses, the expression of each of the chemokine receptors correlated with the degree of CD3(+) T-cell infiltration. In particular, the expression of CXCR3 was temporally and spatially associated with CD3(+) T-cell infiltrates and correlated with the histopathological diagnosis of acute rejection (OR, 11.73 and 4.05, respectively; P<0.001). Of 7 patients followed up longitudinally for 1 year, 4 with consecutive biopsies developed intimal thickening by intravascular ultrasound. In these patients, there was a trend for persistent expression of CD3- and CXCR3-expressing infiltrates in the later part of the first posttransplant year. The chemokines eotaxin, IP-10, lymphotactin, MCP-1, Mig, RANTES, and SDF-1 were examined in an additional 35 biopsies by RT-PCR. Eotaxin, lymphotactin, MCP-1, Mig, and SDF-1 were present in both normal and rejecting biopsies. However, the CXCR3 ligand IP-10, which was rarely expressed in normal biopsies, was markedly induced in acute rejection (OR, 19.43; P=0.01). CONCLUSIONS: The presence of CXCR3(+) T cells and the CXCR3 ligand IP-10 within endomyocardial biopsies is strongly associated with acute rejection. The CXCR3-IP-10 interaction warrants consideration as a therapeutic target in the management of cardiac allograft recipients.

Adult↗
PubMed2001

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.

Coronary Artery Disease↗
PubMed2001

Usefulness of intravascular ultrasound in preventing stenting of hazy areas adjacent to coronary stents and its support of support spot-stenting.

The uncertain significance of hazy areas at the margins of coronary stents may lead to further, at times unnecessary, stenting. However, the risk of restenosis increases substantially when additional stents are deployed. We used intravascular ultrasound (IVUS) to identify the causes of hazy segments adjacent to stents. We identified 13 cases with hazy regions adjacent to coronary stents and 20 controls without hazy regions matched by age, gender, and vessel stented. Hazy regions were defined from the angiogram as reduced contrast density without a clearly defined intimal tear, dissection, thrombus, or stenosis (> 50%). IVUS images were obtained from the reference, stent, and hazy and control regions adjacent to the stent. Computerized planimetery was used to measure the vessel, lumen, and plaque cross-sectional areas (CSAs), the maximum arc of calcium, and the eccentricity ratio (minimum:maximum lumen diameter). There were no significant differences between hazy and control segments in the vessel, lumen, and plaque CSAs. All lumen CSAs were >4.0 mm2. Compared with control regions, the hazy regions had calcified plaque more often (69% vs 25%; odds ratio [OR] 6.75, 95% confidence intervals [CI] 1.82 to 25.0]) and more frequent intimal tears (23% vs 0%, OR 6.67, 95% CI 1.98 to 35.0). Haziness was particularly associated with calcified plaque and eccentric lumen (p = 0.037). Thus, haziness at the margins of coronary stents is often caused by calcified plaque. IVUS can differentiate calcified plaques from intimal tears and thereby obviate unnecessary stenting.

Adult↗
PubMed2001

Effects of atorvastatin on early recurrent ischemic events in acute coronary syndromes: the MIRACL study: a randomized controlled trial.

CONTEXT: Patients experience the highest rate of death and recurrent ischemic events during the early period after an acute coronary syndrome, but it is not known whether early initiation of treatment with a statin can reduce the occurrence of these early events. OBJECTIVE: To determine whether treatment with atorvastatin, 80 mg/d, initiated 24 to 96 hours after an acute coronary syndrome, reduces death and nonfatal ischemic events. DESIGN AND SETTING: A randomized, double-blind trial conducted from May 1997 to September 1999, with follow-up through 16 weeks at 122 clinical centers in Europe, North America, South Africa, and Australasia. PATIENTS: A total of 3086 adults aged 18 years or older with unstable angina or non-Q-wave acute myocardial infarction. INTERVENTIONS: Patients were stratified by center and randomly assigned to receive treatment with atorvastatin (80 mg/d) or matching placebo between 24 and 96 hours after hospital admission. MAIN OUTCOME MEASURES: Primary end point event defined as death, nonfatal acute myocardial infarction, cardiac arrest with resuscitation, or recurrent symptomatic myocardial ischemia with objective evidence and requiring emergency rehospitalization. RESULTS: A primary end point event occurred in 228 patients (14.8%) in the atorvastatin group and 269 patients (17.4%) in the placebo group (relative risk [RR], 0.84; 95% confidence interval [CI], 0.70-1.00; P =.048). There were no significant differences in risk of death, nonfatal myocardial infarction, or cardiac arrest between the atorvastatin group and the placebo group, although the atorvastatin group had a lower risk of symptomatic ischemia with objective evidence and requiring emergency rehospitalization (6.2% vs 8.4%; RR, 0.74; 95% CI, 0.57-0.95; P =.02). Likewise, there were no significant differences between the atorvastatin group and the placebo group in the incidence of secondary outcomes of coronary revascularization procedures, worsening heart failure, or worsening angina, although there were fewer strokes in the atorvastatin group than in the placebo group (12 vs 24 events; P =.045). In the atorvastatin group, mean low-density lipoprotein cholesterol level declined from 124 mg/dL (3.2 mmol/L) to 72 mg/dL (1.9 mmol/L). Abnormal liver transaminases (>3 times upper limit of normal) were more common in the atorvastatin group than in the placebo group (2.5% vs 0.6%; P<.001). CONCLUSION: For patients with acute coronary syndrome, lipid-lowering therapy with atorvastatin, 80 mg/d, reduces recurrent ischemic events in the first 16 weeks, mostly recurrent symptomatic ischemia requiring rehospitalization.

Aged↗
PubMed2001

A comparative study of light transmission aggregometry and automated bedside platelet function assays in patients undergoing percutaneous coronary intervention and receiving abciximab, eptifibatide, or tirofiban.

Platelet inhibition is central to the efficacy of glycoprotein (GP) IIb-IIIa antagonist therapy, but is not routinely measured during percutaneous coronary intervention (PCI). Data directly comparing the antiplatelet effects of these agents are also limited. Therefore, we compared ex vivo platelet function by standard light transmission aggregometry (LTA) and two automated bedside platelet function assays in 36 patients undergoing PCI with GP IIb-IIIa inhibitors. At baseline and 10 min following clinically recommended bolus and infusion of abciximab (0.25 mg/kg, 0.125 microg/kg/min), eptifibatide (180 microg/kg, 2 microg/kg/min), or tirofiban (10 microg/kg, 0.1 microg/kg/min), we measured 20 microM ADP- and 1.9 mg/mL collagen-induced platelet aggregation using LTA. Platelet function was also assessed using the bedside Accumetrics Ultegra-Rapid Platelet Function Assay (RPFA) and the Xylum Clot Signature Analyzer (CSA). The degree of platelet inhibition, as assessed by LTA, varied significantly between the clinically recommended doses of these GP IIb-IIIa antagonists. RPFA measurements agreed closely with LTA for abciximab, but tended to overestimate the degree of platelet inhibition for small molecules. CSA demonstrated profoundly inhibited shear-induced platelet function, but lacked sensitivity to discriminate between agents. These findings may have implications for the results of trials comparing the efficacy of these agents in patients undergoing PCI.

Abciximab↗
PubMed2001

Is there a menopausal syndrome? Menopausal status and symptoms across racial/ethnic groups.

In recent years, research on menopausal symptomalogy has focused on identifying symptom groupings experienced by women as they progress from premenopausal to postmenopausal status. However, most of these studies have been conducted among Caucasian women from western cultures. This leaves open the question of whether the findings from these studies can be extended to women of other racial/ethnic groups or cultures. Furthermore, many of the previous studies have been conducted on relatively small samples. This paper addresses the diversity of the menopause experience by comparing symptom reporting in a large cross-sectional survey of women aged 40-55 years among racial/ethnic groups of women in the United States (Caucasian, African-American, Chinese, Japanese, and Hispanic). Evaluation of the extent to which symptoms group together and consistently relate to menopausal status across these five samples provides evidence for or against a universal menopausal syndrome. The specific research questions addressed in this paper are: (1) How does the factor structure of symptoms among mid-aged women compare across racial/ethnic groups? (2) Is symptom reporting related to race/ethnicity or menopausal status? and (3) Does the relation between menopausal status and symptoms vary across racial/ethnic groups? Analyses are based on 14,906 women who participated in the multi-ethnic, multi-race, multi-site study of mid-aged women called the Study of Women's Health Across the Nation (SWAN). Study participants completed a 15-min telephone or in-person interview that contained questions on a variety of health-related topics. Items of interest for these analyses include symptoms, menstrual history (to assess menopausal status), health status, and sociodemographics. Factor analysis results showed that across all five racial/ethnic groups, two consistent factors emerged; one consisting of clearly menopausal symptoms -- hot flashes and night sweats -- and the other consisting of psychological and psychosomatic symptoms. Results of regression analyses showed racial/ethnic differences in symptom reporting, as well as differences by menopausal status. Controlling for age, education, health, and economic strain, Caucasian women reported significantly more psychosomatic symptoms than other racial/ethnic groups. African-American women reported significantly more vasomotor symptoms. Perimenopausal women, hormone users, and women who had a surgical menopause reported significantly more vasomotor symptoms. All of these groups, plus postmenopausal women, reported significantly more vasomotor symptoms than premenopausal women. The pattern of results argues against a universal menopausal syndrome consisting of a variety of vasomotor and psychological symptoms.

Black or African American↗
PubMed2001

Role of vascular remodeling in the pathogenesis of early transplant coronary artery disease: a multicenter prospective intravascular ultrasound study.

BACKGROUND: Luminal narrowing in transplant coronary artery disease is thought to be primarily caused by intimal proliferation, and the role of vascular remodeling is less certain. METHODS AND RESULTS: We studied cardiac allografts from 83 prospectively recruited patients immediately and 1 year after transplant using intravascular ultrasound in a multicenter study. We measured coronary artery dimensions in 310 angiographically matched segments (175 were also fully matched by ultrasound criteria). At 1 year, lumen area changed by -1.8 +/- 3.7 mm(2) (p < 0.0001, 14% of baseline lumen area). Thirty-three percent of this luminal loss was due to intimal thickening and 67% to vessel shrinkage. Shrinkage also occurred (-0.9 +/- 3.2 mm(2), 7% of baseline total area) in segments free of detectable intimal disease at baseline and at 1 year. Using the mean baseline total vessel area (13.9 mm(2)) as the cutoff, we divided the cohort into the large and the small coronary-segment groups. The large-segment group (n = 176) shrank more (-2.6 +/- 4.4 vs. -0.03 +/- 2.8 mm(2), p < 0.0001), but intimal growth was similar in both groups (0.8 +/- 2.2 vs. 0.4 +/- 1.3 mm(2), p = not significant). Analysis of the 175 fully ultrasound matched sub-cohort showed similar results. Changes in intimal area, total vessel area, and lumen area were similar in segments with (n = 132) and segments without (n = 178) pre-existing donor disease. Despite overall shrinkage, change in total vessel area positively correlated with change in intimal area (r = 0.29, p < 0.0001). CONCLUSION: In large coronary segments, coronary artery shrinkage plays an important role in the loss of luminal diameter early after cardiac transplantation, whereas new intimal growth occurs in both large and small segments. Pre-existent donor disease does not aggravate these processes. Compensatory remodeling with increasing intimal growth retards the rate of lumen loss. As is intimal thickening, shrinkage and compensatory remodeling are important pathogenic mechanisms in transplant coronary artery disease.

Adult↗
PubMed2001

Endothelial function and coronary artery disease.

The endothelium produces a number of vasodilator and vasoconstrictor substances that not only regulate vasomotor tone, but also the recruitment and activity of inflammatory cells and the propensity towards thrombosis. Endothelial vasomotor function is a convenient way to assess these other functions, and is related to the long-term risk of cardiovascular disease. Lipids (particularly low density lipoprotein cholesterol) and oxidant stress play a major role in impairing these functions, by reducing the bioavailability of nitric oxide and activating pro-inflammatory signalling pathways such as nuclear factor kappa B. Biomechanical forces on the endothelium, including low shear stress from disturbed blood flow, also activate the endothelium increasing vasomotor dysfunction and promoting inflammation by upregulating pro-atherogenic genes. In contrast, normal laminar shear stress promotes the expression of genes that may protect against atherosclerosis. The sub-cellular structure of endothelial cells includes caveolae that play an integral part in regulating the activity of endothelial nitric oxide synthase. Low density lipoprotein cholesterol and oxidant stress impair caveolae structure and function and adversely affect endothelial function. Lipid-independent pathways of endothelial cell activation are increasingly recognized, and may provide new therapeutic targets. Endothelial vasoconstrictors, such as endothelin, antagonize endothelium-derived vasodilators and contribute to endothelial dysfunction. Some but not all studies have linked certain genetic polymorphisms of the nitric oxide synthase enzyme to vascular disease and impaired endothelial function. Such genetic heterogeneity may nonetheless offer new insights into the variability of endothelial function.

Animals↗
PubMed2001

Relationship of clinical presentation and calcification of culprit coronary artery stenoses.

Coronary artery calcification is increased in the presence of atherosclerosis. However, there is great variability in the calcification of individual coronary stenoses, and the clinical significance of this finding remains unknown. We tested the hypothesis that culprit lesions associated with myocardial infarction or unstable angina are less calcified than are stenoses associated with stable angina. The study consisted of 78 patients who underwent intravascular ultrasound imaging of culprit stenoses after the placement of a stent. Seventeen patients presented with stable angina; 43, with unstable angina; and 18, with myocardial infarction. The extent of coronary calcification was measured by the angle of its arc and was quantified with a computer-based protractor. The arc of calcium was measured in the stented area at the point of maximal calcification and also as an average of the calcification found at proximal, middle, and distal stent segments. The maximal arc of calcium decreased progressively from patients with stable angina (91+/-10 degrees ) to those with unstable angina (59+/-8 degrees ) and to those with myocardial infarction (49+/-11 degrees, P=0.014). Similarly, the average arc of calcium was greatest (32+/-7 degrees ) in patients with stable angina, less (15+/-4 degrees ) in patients with unstable angina, and least (10+/-5 degrees ) in patients with acute myocardial infarction (P=0.014). These associations remained significant after adjustment for other factors that potentially affect arterial calcification. Acute coronary syndromes are associated with a relative lack of calcium in the culprit stenoses compared with stenoses of patients with stable angina. These findings have implications for the understanding of the biology of acute coronary syndromes as well as for the identification of coronary stenoses by methods that rely solely on the presence of calcium.

Angina Pectoris↗
PubMed2001

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.

Adult↗
PubMed2000

Relation between endothelial dysfunction and the acute coronary syndrome: implications for therapy.

Endothelial dysfunction is present in patients with atherosclerosis, even in the early stages of disease, before plaque formation. Thus, it is a useful marker for early cardiovascular disease. In recent studies, statin therapy has been shown to improve endothelial function by increasing production of nitric oxide, a key vasodilator, from the endothelium. The improvement in endothelial function occurs by lipid lowering as well as by nonlipid mechanisms. These effects begin early in treatment, supporting prompt initiation of statin therapy. The functional benefits that result from an improvement in endothelial dysfunction include enhanced myocardial perfusion, reduced duration and burden of transient myocardial ischemia, and reduced angina pectoris. As dysfunctional endothelium encourages the recruitment of leukocytes into the arterial wall and thereby predisposes to inflammation and plaque disruption, improvement in endothelial function leads to plaque stabilization.

Acute Disease↗
PubMed2000

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.

Animals↗
PubMed2000

Binding of Nisin Z to bilayer vesicles as determined with isothermal titration calorimetry.

Nisin Z, a 34-residue lantibiotic, is secreted by some lactic acid bacteria and exerts its antibacterial activity against various Gram-positive bacteria by permeabilizing the cell membrane. It is a cationic amphiphilic peptide with several unusual dehydro residues and thioether-bridged lanthionines. Isothermal titration calorimetry was used to provide a quantitative thermodynamic description for nisin Z adsorption to and penetration into negatively charged and neutral lipid bilayers. The binding of the cationic peptide (electric charge z approximately 3.8) to anionic membranes was found to be dominated by electrostatic forces which could be described with the Gouy-Chapman theory. For biologically relevant conditions with a membrane surface potential of -40 mV, the peptide concentration near the membrane surface increases by about 2-3 orders of magnitude compared to the bulk concentration. The binding step proper, i.e., the transition from the lipid-water interface into the membrane, is almost exclusively driven by the high surface concentration. Binding can be described by a partition equilibrium of the form X(b) = KC(M) = KC(p,f) exp(-z(p)psi(0)F(0)/RT), where C(M) is the peptide surface concentration, C(p,f) the bulk concentration, and psi(0) the membrane surface potential. The intrinsic partition coefficient (K = 1.8 M(-)(1)) is remarkably small, indicating a correspondingly small hydrophobic energy contribution to the binding process. The electrostatic model was confirmed with nisin Z mutants in which valine-32 was replaced with either lysine (V32K) or glutamate (V32E), increasing or decreasing the electric charge by 1 unit. The extent of peptide binding increased for V32K and decreased for V32E as predicted by the electrostatic theory. In contrast, electrostatic effects were almost negligible for the binding of nisin Z to neutral membranes. However, the binding isotherms were characterized by a distinctly larger intrinsic binding constant K(0) of approximately 540 M(-)(1) and an enhanced hydrophobic free energy of binding. The binding of nisin Z to sonicated lipid vesicles is exothermic with a DeltaH degrees of ca. -9 and -3.4 kcal/mol for charged and neutral membranes, respectively.

Amino Acid Sequence↗
PubMed2000

Effect of cholesterol-lowering therapy on coronary endothelial vasomotor function in patients with coronary artery disease.

BACKGROUND: Improved endothelial function may contribute to the beneficial effects of cholesterol-lowering therapy. METHODS AND RESULTS: In this randomized, double-blind study, we compared the effect of 6 months of simvastatin (40 mg/d) treatment with that of placebo on coronary endothelial vasomotor function in 60 patients with coronary artery disease. Simvastatin lowered LDL-cholesterol by 40+/-12% from 130+/-28 mg/dL (P<0.001). Peak intracoronary acetylcholine infusion produced epicardial coronary constriction at baseline in both the simvastatin (-17+/-13%) and placebo (-24+/-16%) groups. After treatment, acetylcholine produced less constriction in both groups (-12+/-19% and -15+/-14%, respectively, P=0.97). The increase in coronary blood flow during infusion of the peak dose of substance P was blunted at baseline in both the simvastatin (42+/-50%) and placebo (55+/-71%) groups, reflecting impaired endothelium-dependent dilation of coronary microvessels. After treatment, the flow increase was 82+/-81% in the simvastatin group and 63+/-53% in the placebo group (P=0.16). CONCLUSIONS: Six months of cholesterol-lowering therapy has no significant effect on coronary endothelial vasomotor function in the study population of patients with coronary artery disease and mildly elevated cholesterol levels. These findings suggest that the effects of cholesterol lowering on endothelial function are more complex than previously thought.

Adult↗