bluuebunny/crossref_metadata_2025 huggingface dataset:
Chondroitin Sulfate Anticoagulant Activity Is Linked to Water Transfer
Authors: McGee Maria , Wagner William D.
Published: August 2003

Objective—

Changes in chondroitin sulfate (CS) proteoglycan (PG) during atherosclerosis are associated with chronic inflammatory changes and increased incidence of thrombosis. To explore how glycosaminoglycan changes could influence the thrombogenicity of atherosclerotic lesions, water-transfer reactions were examined during activation of antithrombin by CS.

Methods and Results—

Advanced type IV atherosclerotic lesions prone to thrombosis contained CSPG (versican) with undersulfated CS relative to CS of the adjacent healthy aorta. Approximately 11% of the CS disaccharide in versican from healthy arteries was oversulfated, but this proportion decreased markedly to 3% in atherosclerotic lesions. Oversulfated CS functionally bound antithrombin with a dissociation constant of 3.3±1.9 μmol/L. Measured by osmotic stress (OS) techniques with an ≈26-Å probe, the reaction was linked to transfer of ≈2500 mol water per mole of coagulation factor Xa inhibited. Under OS, the anticoagulant efficiency of CS was 1.3 (μmol/L)
−1
· s
−1
, ≈5- and 15-fold higher than heparan sulfate efficiency measured under OS and standard conditions, respectively.

Conclusions—

Decreased sulfation of high molecular weight CSPG in the advancing atherosclerotic lesions may predispose the lesions to thrombosis by disrupting osmotic regulation, limiting avidity for antithrombin and decreasing activation efficiency.
Using Mice to Dissect Genetic Factors in Atherosclerosis
Authors: Allayee Hooman , Ghazalpour Anatole , Lusis Aldons J.
Published: August 2003

The genes that contribute to common, complex forms of atherosclerosis remain largely unknown. Genetic studies in humans have, for the most part, focused on identifying genes that predispose to the traditional risk factors, such as lipid levels and blood pressure, but apart from rare, single-gene disorders, there have been few successes to date. The use of mice to dissect the complex genetic etiology of atherosclerosis offers a viable alternative to human studies, because experimental parameters, such as environment, breeding scheme, and detailed phenotyping, can be controlled. Herein we review how mouse genetics can lead to the identification of genes, some of which would otherwise not have been considered as candidates for atherosclerosis, and provide an overview of the prospects for successful gene discovery in the future.
Genetic Backgrounds but Not Sizes of Atherosclerotic Lesions Determine Medial Destruction in the Aortic Root of Apolipoprotein E–Deficient Mice
Authors: Shi Weibin , Brown Morry D. , Wang Xuping , Wong Jack , Kallmes David F. , Matsumoto Alan H. , Helm Gregory A. , Drake Thomas A. , Lusis Aldons J.
Published: August 2003

Objective—

Destruction of the elastic media is the most striking histologic feature of atherosclerotic aortic aneurysms. Apolipoprotein E–deficient (apoE
−/-
) mice fed a Western diet develop advanced atherosclerotic lesions in the aorta. We sought to assess the integrity of atherosclerotic aortic walls in 2 apoE
−/-
strains, C57BL/6 (B6) and C3H/HeJ (C3H) that differ markedly in atherosclerosis susceptibility.

Methods and Results—

C3H.apoE
−/-
mice developed much smaller atherosclerotic lesions than did B6.apoE
−/-
mice after being fed a Western diet for 16 weeks, but the C3H.apoE
−/−
mice exhibited destruction of the elastic media, including erosion, fragmentation, and focal dilatation beneath plaques. Gelatin and casein zymography showed proteolytic activity of matrix metalloproteinases (MMPs) −9, −2, and −12 in aortic tissues and of MMP-9 and −12 in macrophages from both strains. However, C3H.apoE
−/-
mice showed significantly increased MMP-2 and −12 activity in aortas and macrophages compared with those from B6.apoE
−/-
mice. MMP-9 activity was comparable in aortic tissues of the 2 strains, but it was significantly higher in macrophages from C3H.apoE
−/-
than from B6.apoE
−/-
mice.

Conclusions—

Data indicate that genetic backgrounds but not sizes of atherosclerotic lesions determine medial destruction in the aortic root of apoE
−/-
mice and that an increase in MMP proteolytic activity might contribute to the medial destruction of aortic walls in C3H.apoE
−/-
mice.
Intramural Plasminogen Activator Inhibitor Type-1 and Coronary Atherosclerosis
Authors: Sobel Burton E. , Taatjes Douglas J. , Schneider David J.
Published: August 2003

Altered expression of plasminogen activator inhibitor type-1 in vessel walls, reviewed here, might affect coronary atherogenesis. Upregulation might exacerbate vasculopathy by potentiating thrombosis and by inhibiting vascular smooth muscle cell migration, resulting in attenuation of thickness of elaborated fibrous caps implicated in the vulnerability of atheroma to rupture.
Small, Dense HDL Particles Exert Potent Protection of Atherogenic LDL Against Oxidative Stress
Authors: Kontush Anatol , Chantepie Sandrine , Chapman M. John
Published: August 2003

Objectives—

The relationship of the structural and functional heterogeneity of HDL particles to protection of LDL against oxidative stress is indeterminate.

Methods and Results—

HDL subfractions of defined physicochemical properties were isolated by density gradient ultracentrifugation from normolipidemic human serum (n=8), and their capacity to protect LDL from oxidation was evaluated. Under mild oxidative stress induced by AAPH or Cu(II), HDL subfractions (at equal cholesterol or protein concentration or equal particle number) significantly decreased LDL oxidation rate (−20% to −85%) in the propagation phase (234 nm), which was prolonged by up to 82% with decreased maximal diene formation. Antioxidative activity of HDL subfractions increased with increment in density, as follows: HDL2b<HDL2a<HDL3a<HDL3b<HDL3c (confirmed by thiobarbituric acid–reactive substance content and LDL electrophoretic mobility). Concordantly, antioxidative activity of small HDL prepared by FPLC was significantly higher (+56%) than that of large HDL. Antioxidative action of HDL subfractions was primarily associated with inactivation of LDL lipid hydroperoxides. The potent protective activity of small HDL could not be accounted for exclusively by enzymatic activities (PON1, platelet-activating factor acetylhydrolase, and lecithin-cholesterol acyltransferase).

Conclusions—

Small, dense HDL exhibit potent antioxidant activity, which may arise from synergy in inactivation of oxidized LDL lipids by enzymatic and nonenzymatic mechanisms, in part reflecting distinct intrinsic physicochemical properties.
Influence of the HDL Receptor SR-BI on Lipoprotein Metabolism and Atherosclerosis
Authors: Trigatti Bernardo L. , Krieger Monty , Rigotti Attilio
Published: August 2003

The scavenger receptor class B type I (SR-BI) was the first molecularly well-defined cell-surface HDL receptor to be described. SR-BI mediates selective HDL cholesterol uptake by formation of a productive lipoprotein/receptor complex, which requires specific structural domains and conformation states of apolipoprotein A-I present in HDL particles. SR-BI is abundantly expressed in several tissues, including the liver, where its expression is regulated by various mechanisms, including the transcriptional activity of nuclear receptors. The importance of SR-BI in overall HDL cholesterol metabolism and its antiatherogenic activity in vivo has been definitively established by SR-BI gene manipulation in mice. Remarkably, SR-BI/apolipoprotein E double-knockout mice develop complex coronary artery disease, myocardial infarction, and heart failure. Additional studies should help to define the importance of SR-BI in human health and disease.
C-Reactive Protein Concentration and Cardiovascular Disease Risk Factors in Children
Authors: Ford Earl S.
Published: August 2003

Background—

C-reactive protein is an emerging risk factor for cardiovascular disease. Although the relations between C-reactive protein and other risk factors for cardiovascular disease have been extensively studied in adults, the relations in children are not well understood.

Methods and Results—

Data from 2846 boys and girls 3 to 17 years of age who participated in the National Health and Nutrition Examination Survey, 1999 to 2000, a cross-sectional survey of the US population, were used. In univariate analyses, significant associations were observed between C-reactive protein concentration—measured with a high-sensitivity assay—and age, body mass index, systolic blood pressure, and triglyceride concentrations in both sexes. In multiple linear regression analyses, body mass index was the best predictor of C-reactive protein concentration. Age was positively associated with C-reactive protein concentration among boys 3 to 17 years of age. Some race or ethnic differences were present as well among boys 8 to 17 years of age and girls 8 to 11 years of age. Systolic blood pressure was positively associated with C-reactive protein among girls 12 to 17 years of age.

Conclusions—

Among the sociodemographic and cardiovascular disease risk factors, body mass index was the best predictor of C-reactive protein concentration in children.
Role of the Exercise Pressor Reflex in Rats With Dilated Cardiomyopathy
Authors: Smith Scott A. , Mammen Pradeep P.A. , Mitchell Jere H. , Garry Mary G.
Published: August 2003

Background—

In heart failure, there is a sympathetically mediated hyperkinetic cardiovascular response to exercise that limits tolerance to physical activity. Alterations in skeletal muscle morphology and metabolism have led to the hypothesis that the exercise pressor reflex (EPR) becomes hyperactive after the development of cardiomyopathy and contributes to the exaggerated circulatory response elicited.

Methods and Results—

To test this hypothesis, Sprague-Dawley rats were divided into the following groups: control, sham, and dilated cardiomyopathy (DCM, induced by ischemic injury). Using transthoracic echocardiography, left ventricular fractional shortening was 47±2%, 44±1%, and 24±2% in control, sham, and DCM rats, respectively. Activation of the EPR by electrically induced static muscle contraction resulted in significantly larger increases in mean arterial pressure and heart rate in DCM animals (32±2 mm Hg, 13±1 bpm) compared with control (20±1 mm Hg, 8±1 bpm) and sham (20±2 mm Hg, 8±1 bpm) rats. Comparable results were obtained with selective stimulation of the mechanically sensitive component of the EPR by passive muscle stretch. The augmentations in EPR and mechanoreflex activity in DCM occurred progressively over a 10-week period, becoming greater as the severity of left ventricular dysfunction increased.

Conclusions—

In DCM, the potentiated cardiovascular response to static muscle contraction is mediated, in part, by an exaggerated EPR. The muscle mechanoreflex contributes significantly to the EPR dysfunction that develops.
Preterm Birth Attenuates Association Between Low Birth Weight and Endothelial Dysfunction
Authors: Norman Mikael , Martin Helena
Published: August 2003

Background—

Low birth weight predisposes to later coronary disease. To further elucidate the mechanisms behind this association and their timing, vascular endothelial function—a key factor in early pathophysiology of atherosclerosis—was studied in 54 infants born either before the third trimester or at term.

Methods and Results—

All subjects were studied at 3 months of postnatal age. A laser-Doppler technique was used to measure skin perfusion before and after transdermal iontophoresis of acetylcholine (ACh; an endothelium-dependent vasodilator). In infants born at term (n=19; birth weight range: 2230 to 4205 g), maximum perfusion after ACh was 109±8 perfusion units (PU, mean±SEM) in normal–birth weight controls compared with 56±13 PU among those who had been small for gestational age at birth (
P
<0.01). In infants born preterm (n=35; birth weight range, 722 to 1868 g), ACh induced similar perfusion responses among subjects appropriate for gestational age (113±16 PU) and in those small for gestational age at birth (109±19 PU).

Conclusions—

Impairment in human endothelial function associated with low birth weight occurs or emerges late in pregnancy. Very preterm birth attenuates this association. Different gene–environment interactions in the third trimester may contribute to this finding.
Short QT Syndrome
Authors: Gaita Fiorenzo , Giustetto Carla , Bianchi Francesca , Wolpert Christian , Schimpf Rainer , Riccardi Riccardo , Grossi Stefano , Richiardi Elena , Borggrefe Martin
Published: August 2003

Background—

A prolonged QT interval is associated with a risk for life-threatening events. However, little is known about prognostic implications of the reverse—a short QT interval. Several members of 2 different families were referred for syncope, palpitations, and resuscitated cardiac arrest in the presence of a positive family history for sudden cardiac death. Autopsy did not reveal any structural heart disease. All patients had a constantly and uniformly short QT interval at ECG.

Methods and Results—

Six patients from both families were submitted to extensive noninvasive and invasive work-up, including serial resting ECGs, echocardiogram, cardiac MRI, exercise testing, Holter ECG, and signal-averaged ECG. Four of 6 patients underwent electrophysiological evaluation including programmed ventricular stimulation. In all subjects, a structural heart disease was excluded. At baseline ECG, all patients exhibited a QT interval ≤280 ms (QTc ≤300 ms). During electrophysiological study, short atrial and ventricular refractory periods were documented in all and increased ventricular vulnerability to fibrillation in 3 of 4 patients.

Conclusions—

The short QT syndrome is characterized by familial sudden death, short refractory periods, and inducible ventricular fibrillation. It is important to recognize this ECG pattern because it is related to a high risk of sudden death in young, otherwise healthy subjects.
Reflex Cardiac Activity in Ischemia and Reperfusion
Authors: Bonnemeier Hendrik , Wiegand Uwe K.H. , Friedlbinder Julia , Schulenburg Simone , Hartmann Franz , Bode Frank , Katus Hugo A. , Richardt Gert
Published: August 2003

Background—

Abnormal heart rate turbulence (HRT) is associated with an increased risk of mortality in the chronic phase of myocardial infarction (MI) in the prethrombolytic and thrombolytic eras. However, the impact of direct percutaneous coronary intervention (PCI) on HRT in the acute phase of MI and its association to the epicardial infarct-related arterial flow has not been examined.

Methods and Results—

We investigated HRT in 126 patients undergoing direct PCI for a first MI. Turbulence onset and turbulence slope were determined before reperfusion, during the initial 2 hours after reperfusion, and during hours 6 to 24 after reperfusion. HRT significantly improved after PCI. There were no significant differences in baseline clinical characteristics between Thrombolysis in Myocardial Infarction Trial classification (TIMI) 2 (n=28) and TIMI 3 (n=98) flow. After PCI, turbulence slope increased (13.2±11 to 18.1±12 ms/beat,
P
<0.001) and turbulence onset decreased (−0.008±0.04% to −0.023±0.04%,
P
<0.01) in patients with TIMI 3 flow after PCI, whereas there were no significant alterations of turbulence slope (12.2±10 to 12.8±6.5 ms/beat) and turbulence onset (−0.009±0.05% to −0.003±0.03%) in patients with TIMI 2 flow.

Conclusions—

The improvement of HRT after successful reperfusion is a previously unreported effect of direct PCI for acute MI, reflecting rapid restoration of baroreceptor response. The persistent impairment of HRT after PCI in patients with TIMI 2 flow indicates a sustained blunted baroreflex response and may reflect a more severe microvascular dysfunction.
Parvovirus B19 Infection Mimicking Acute Myocardial Infarction
Authors: Kühl Uwe , Pauschinger Matthias , Bock Thomas , Klingel Karin , Schwimmbeck C. Peter Lothar , Seeberg Bettina , Krautwurm Lars , Poller Wolfgang , Schultheiss Heinz-Peter , Kandolf Reinhard
Published: August 2003

Background—

Enteroviruses (EVs) and adenoviruses (ADVs) have been considered common causes of myocarditis and dilated cardiomyopathy. In the present study, we report on the association of parvovirus B19 (PVB19) genomes in the clinical setting of acute myocarditis.

Methods and Results—

This study included 24 consecutive patients admitted to our hospital within 24 hours after onset of chest pain. Acute myocardial infarction had been excluded in all patients by coronary angiography. Endomyocardial biopsies were analyzed by nested polymerase chain reaction/reverse transcriptase-polymerase chain reaction for EV, ADV, PVB19, human cytomegalovirus, Epstein-Barr virus,
Chlamydia pneumoniae
, influenza virus A and B, and
Borrelia burgdorferi
genomes, respectively, followed by direct sequencing of the amplification products. All patients presented with acute onset of angina pectoris and ST-segment elevations or T-wave inversion mimicking acute myocardial infarction. Mean baseline peak creatinine kinase and creatine kinase-isoenzyme fraction were 342±241 U/L and 32±20 U/L, respectively. Mean troponin T was increased to 7.5±15.0 ng/mL and C-reactive protein to 91±98 mg/mL. Eighteen patients had global or regional wall motion abnormalities (ejection fraction 62.5±15.5%). Histological analysis excluded the presence of active or borderline myocarditis in all but one patient. PVB19, EV, and ADV genomes were detected in the myocardium of 12, 3, and 2 patients, respectively (71%). Follow-up biopsies of virus-positive patients (11 of 17) demonstrated persistence of PVB19 genomes in 6 of 6 patients, EV genomes in 2 of 3 patients, and ADV genomes in 1 of 2 patients, respectively.

Conclusions—

Virus genomes can be demonstrated in 71% of patients with normal coronary anatomy, clinically mimicking acute myocardial infarction. In addition to EVs and ADVs, PVB19 was the most frequent pathogen.
Complexity of Inducible Nitric Oxide Synthase
Authors: Poon Betty Y. , Raharjo Eko , Patel Kamala D. , Tavener Samantha , Kubes Paul
Published: August 2003

Background—

Inducible nitric oxide synthase (iNOS) has been shown to have both beneficial and detrimental effects in sepsis. We focused on a single organ, the heart, and used 2 distinct cell types that express iNOS—the cardiac myocyte and the infiltrating neutrophil—to study the distinct functional effects of iNOS derived from heterogeneous cellular sources.

Methods and Results—

In the first series of experiments, extravascular neutrophils were exposed to isolated single endotoxemic cardiac myocytes. Adhesion of wild-type neutrophils caused a rapid decrease in myocyte shortening and a concomitant increase in neutrophil-derived intracellular oxidative stress within the myocytes that was not observed with neutrophils from iNOS-deficient animals. We previously demonstrated that neutrophil-derived superoxide was essential for myocyte dysfunction; however, superoxide production was not compromised in the iNOS-deficient neutrophils. Because both superoxide and NO were essential for the neutrophil dysfunction, we probed for but could not detect any peroxynitrite assessed by detection of nitrotyrosine. There was a significant increase in length shortening in response to β-adrenergic stimulation of wild-type myocytes. Surprisingly, myocyte iNOS activity was essential rather than detrimental for the development of β-adrenergic receptor–mediated increases in shortening in endotoxemic iNOS-deficient myocytes.

Conclusions—

These results demonstrate that iNOS, when expressed in isolated cardiac myocytes, can regulate the response to β-adrenergic stimulation during sepsis. However, as the neutrophils migrate in proximity to myocytes, iNOS now becomes essential for the ability of neutrophils to damage myocytes. These findings demonstrate that cellular source strongly modulates the beneficial and detrimental effect of iNOS.
Therapy-Dependent Influence of Time-to-Treatment Interval on Myocardial Salvage in Patients With Acute Myocardial Infarction Treated With Coronary Artery Stenting or Thrombolysis
Authors: Schömig Albert , Ndrepepa Gjin , Mehilli Julinda , Schwaiger Markus , Schühlen Helmut , Nekolla Stephan , Pache Jürgen , Martinoff Stefan , Bollwein Hildegard , Kastrati Adnan
Published: August 2003

Background—

The relationship between myocardial salvage and time-to-treatment interval in patients with acute myocardial infarction (AMI) treated with coronary artery stenting or thrombolysis has not been studied.

Methods and Results—

This study analyzed 264 patients with AMI randomized to coronary stenting (133 patients) or thrombolysis (131 patients) in the setting of 2 randomized trials. Patients were divided into the following 3 groups defined by tertiles of the time-to-treatment interval: lower tertile (<165 minutes), middle tertile (165 to 280 minutes), and upper tertile (>280 minutes). Paired scintigraphic examinations were performed to obtain salvage index, which was the primary end point of the study. In the group with thrombolysis, the salvage index (median [25th; 75th] percentile) was 0.45 (0.16; 0.83) in the lower, 0.29 (0.17; 0.48) in the middle, and 0.20 (0.04; 0.46) in the upper tertile (
P
=0.03). In the group with stenting, the salvage index was 0.56 (0.49; 0.75) in the lower, 0.57 (0.36; 0.73) in the middle, and 0.57 (0.32; 0.75) in the upper tertile (
P
=0.59). In patients treated with stenting, the salvage index was greater than in patients treated with thrombolysis in the lower (0.56 versus 0.45,
P
=0.09), middle (0.57 versus 0.29,
P
=0.0003), and upper (0.57 versus 0.20,
P
=0.0005) tertiles of the time-to-treatment interval.

Conclusions—

The influence of the time-to-treatment interval on the myocardial salvage in patients with AMI depends on the type of reperfusion therapy. Coronary artery stenting was superior to thrombolysis independent of the time-to-treatment intervals, and the difference in benefit increased with more prolonged time from symptom onset.
Safety of an Aspirin-Alone Regimen After Intracoronary Stenting With a Heparin-Coated Stent
Authors: Mehran Roxana , Aymong Eve D. , Ashby Dale T. , Fischell Tim , Whitworth Hall , Siegel Robert , Thomas William , Wong S. Chiu , Narasimaiah Raj , Lansky Alexandra J. , Leon Martin B.
Published: August 2003

Background—

Stent thrombosis is an infrequent complication of intracoronary stenting that often has devastating clinical consequences. This study assesses the additional benefit of heparin coating with the BX VELOCITY Balloon-Expandable Stent with HEPACOAT, Carmeda end-point attached heparin (HEPACOAT) in patients with de novo or restenotic native coronary artery lesions treated with aspirin monotherapy after optimal stenting.

Methods and Results—

This was a multicenter, prospective, nonrandomized, pilot study. Two hundred patients (69% men; mean age, 64.1±11.2 years) meeting the eligibility criteria were treated with the HEPACOAT stent and aspirin alone after stenting. Any other antiplatelet or anticoagulation therapy was not permitted. Procedural success was achieved in all patients. There were 3 postprocedural non–Q-wave myocardial infarctions. The primary end point of stent thrombosis at 30 days occurred in 2 of 200 patients (1%): in one after blunt chest trauma and in the other in the setting of essential thrombocytosis. Major adverse cardiac events (death, myocardial infarction, target lesion revascularization, and coronary artery bypass grafting) were observed at 30 days in 5 of 200 (2.5%) patients.

Conclusions—

The BX VELOCITY stent with HEPACOAT and aspirin alone after the procedure was safe in select patients with de novo or restenotic lesions in native coronary arteries. Heparin coating provides additional protection against stent thrombosis.
Consequences of Pressure Overload on Sarcomere Protein Mutation-Induced Hypertrophic Cardiomyopathy
Authors: Schmitt Joachim P. , Semsarian Christopher , Arad Michael , Gannon Joseph , Ahmad Ferhaan , Duffy Catherine , Lee Richard T. , Seidman Christine E. , Seidman J.G.
Published: August 2003

Background—

Whether ventricular remodeling from hypertrophic cardiomyopathy (HCM), systemic hypertension, or other pathologies arises through a common signaling pathway or through independent molecular mechanisms is unknown. To study this, we assessed cardiac hypertrophy in a mouse model of HCM subjected to increased left ventricular (LV) load.

Methods and Results—

Transverse aortic banding of mice with or without an Arg403Gln cardiac myosin heavy chain mutation (αMHC
403/+
) produced similarly elevated LV pressures (120±30 versus 112±14 mm Hg;
P
=NS). No mice developed heart failure, and mortality (26% αMHC
403/+
, 35% wild-type) was comparable. Load-induced hypertrophy was identical in banded 129SvEv αMHC
403/+
mice (LV anterior wall [LVAW]=1.28±0.11) and 129SvEv wild-type mice (LVAW=1.29±0.11 mm;
P
=NS). Genetically outbred Black Swiss (BS) αMHC
403/+
mice showed only mildly exaggerated hypertrophy in response to aortic banding (BS αMHC
403/+
LVAW=1.30±0.13 mm; BS wild-type LVAW=1.17±0.15 mm;
P
=0.03), suggesting some effect from a BS genetic locus that modifies hypertrophy induced by the cardiac MHC Arg403Gln mutation. Histopathology and molecular markers of hypertrophy were comparable in all banded 129SvEv or BS mice. Banded αMHC
403/+
mice had potential for greater hypertrophy, because cyclosporin A treatment markedly augmented hypertrophy.

Conclusions—

The uniform hypertrophic response to increased ventricular load in wild-type and αMHC
403/+
mice indicates independent cardiac remodeling pathways and predicts that coexistent hypertension and HCM should not profoundly exacerbate cardiac hypertrophy. In contrast, sarcomere mutation and cyclosporin A-mediated calcineurin inhibition stimulate a shared hypertrophic signaling pathway. Defining distinct signaling pathways that trigger myocyte growth should help to tailor therapies for cardiac hypertrophy.
Effect of Pexelizumab, an Anti-C5 Complement Antibody, as Adjunctive Therapy to Fibrinolysis in Acute Myocardial Infarction
Authors: Mahaffey Kenneth W. , Granger Christopher B. , Nicolau Jose C. , Ruzyllo Witold , Weaver W. Douglas , Theroux Pierre , Hochman Judith S. , Filloon Thomas G. , Mojcik Christopher F. , Todaro Thomas G. , Armstrong Paul W.
Published: August 2003

Background—

Complement activation mediates myocardial damage that occurs during ischemia and reperfusion through multiple pathways. We performed 2 separate, parallel, double-blind, placebo-controlled trials to determine the effects of pexelizumab (a novel C5 complement monoclonal antibody fragment) on infarct size in patients receiving reperfusion therapy: COMPlement inhibition in myocardial infarction treated with thromboLYtics (COMPLY) and COMplement inhibition in Myocardial infarction treated with Angioplasty (COMMA). The COMPLY trial is reported here.

Methods and Results—

Overall, 943 patients with acute ST-segment elevation myocardial infarction (MI) (20% with isolated inferior MI) receiving fibrinolysis were randomly assigned <6 hours after symptom onset to placebo, pexelizumab 2.0-mg/kg bolus, or pexelizumab 2.0-mg/kg bolus plus 0.05 mg/kg per h for 20 hours. Infarct size determined by creatine kinase–MB area under the curve was the primary analysis, which included patients who received at least some study drug and fibrinolysis (n=920). The median infarct size did not differ by treatment (placebo, 5230; bolus, 4952; bolus plus infusion, 5557 [ng/mL] · h; bolus versus placebo,
P
=0.85; bolus plus infusion versus placebo,
P
=0.81), nor did the 90-day composite incidence of death, new or worsening congestive heart failure, shock, or stroke (placebo, 18.6%; bolus, 18.4%; bolus plus infusion, 19.7%). Pexelizumab inhibited complement for 4 hours with bolus-only dosing and for 20 to 24 hours with bolus-plus-infusion dosing, with no increase in infections.

Conclusions—

When used adjunctively with fibrinolysis, pexelizumab blocked complement activity but reduced neither infarct size by creatine kinase–MB assessment nor adverse clinical outcomes.
Pexelizumab, an Anti-C5 Complement Antibody, as Adjunctive Therapy to Primary Percutaneous Coronary Intervention in Acute Myocardial Infarction
Authors: Granger Christopher B. , Mahaffey Kenneth W. , Weaver W. Douglas , Theroux Pierre , Hochman Judith S. , Filloon Thomas G. , Rollins Scott , Todaro Thomas G. , Nicolau Jose C. , Ruzyllo Witold , Armstrong Paul W.
Published: August 2003

Background—

Complement, activated during myocardial ischemia and reperfusion, causes myocardial damage through multiple processes. The COMplement inhibition in Myocardial infarction treated with Angioplasty (COMMA) trial was performed to determine the effect of pexelizumab, a C5 complement inhibitor, on infarct size in patients with ST-segment–elevation myocardial infarction (MI) undergoing primary percutaneous coronary intervention.

Methods and Results—

In COMMA, 960 patients with MI (20% isolated inferior MI) were randomized to placebo, pexelizumab 2.0-mg/kg bolus, or pexelizumab 2.0-mg/kg bolus and 0.05-mg/kg per h infusion for 20 hours. Infarct size by creatine kinase–MB area under the curve, the primary outcome, did not differ significantly between groups (placebo median, 4393; bolus pexelizumab, 4526; bolus plus infusion pexelizumab, 4713 [ng/mL] · h;
P
=0.89 for bolus versus placebo;
P
=0.76 for bolus plus infusion versus placebo), nor did the composite of 90-day death, new or worsening heart failure, shock, or stroke (placebo, 11.1%; bolus, 10.7%; bolus plus infusion, 8.5%). The ninety-day mortality rate was significantly lower with pexelizumab bolus plus infusion (1.8% versus 5.9% with placebo; nominal
P
=0.014); the bolus-only group had an intermediate mortality rate (4.2%).

Conclusions—

In patients with ST-elevation MI undergoing percutaneous coronary intervention, pexelizumab had no measurable effect on infarct size. However, the significant reduction in mortality suggests that pexelizumab may benefit patients through alternative novel mechanisms and provides impetus for additional investigation.
Lack of Adverse Clopidogrel–Atorvastatin Clinical Interaction From Secondary Analysis of a Randomized, Placebo-Controlled Clopidogrel Trial
Authors: Saw Jacqueline , Steinhubl Steven R. , Berger Peter B. , Kereiakes Dean J. , Serebruany Victor L. , Brennan Danielle , Topol Eric J.
Published: August 2003

Background—

Statins primarily metabolized by cytochrome P450 3A4 (CYP3A4) reportedly reduce clopidogrel’s metabolism to active metabolite, thus attenuating its inhibition of platelet aggregation ex vivo. However, the clinical impact of this interaction has not been evaluated.

Methods and Results—

Clopidogrel for the Reduction of Events During Observation (CREDO) was a double-blind, placebo-controlled, randomized trial comparing pretreatment (300 mg) and 1-year (75 mg/d) clopidogrel therapy (clopidogrel) with no pretreatment and 1-month clopidogrel therapy (75 mg/d) (control) after a planned percutaneous coronary intervention. All patients received aspirin. The 1-year primary end point was a composite of death, myocardial infarction, and stroke. We performed a post hoc analysis to evaluate the clinical efficacy of concomitant clopidogrel and statin administration, categorizing baseline statin use to those predominantly CYP3A4-metabolized (atorvastatin, lovastatin, simvastatin, and cerivastatin) (CYP3A4-MET) or others (pravastatin and fluvastatin) (non-CYP3A4-MET). Of the 2116 patients enrolled, 1001 received a CYP3A4-MET and 158 a non-CYP3A4-MET statin. For the overall study population, the primary end point was significantly reduced in the clopidogrel group (8.5% versus 11.5%, RRR 26.9%;
P
=0.025). This clopidogrel benefit was similar with statin use, irrespective of treatment with a CYP3A4-MET (7.6% clopidogrel, 11.8% control, RRR 36.4%, 95% CI 3.9 to 57.9;
P
=0.03) or non-CYP3A4-MET statin (5.4% clopidogrel, 13.6% control, RRR 60.6%, 95% CI −23.9 to 87.4;
P
=0.11). Patients given atorvastatin or pravastatin had similar 1-year event rates. Additionally, concomitant therapy with statins had no impact on major or minor bleeding rates.

Conclusions—

Although ex vivo testing has suggested a potential negative interaction when coadministering a CYP3A4-metabolized statin with clopidogrel, this was not clinically observed statistically in a post hoc analysis of a placebo-controlled study.
Mapping and Ablation of Ventricular Fibrillation Associated With Long-QT and Brugada Syndromes
Authors: Haïssaguerre Michel , Extramiana Fabrice , Hocini Mélèze , Cauchemez Bruno , Jaïs Pierre , Cabrera Jose Angel , Farre Geronimo , Leenhardt Antoine , Sanders Prashanthan , Scavée Christophe , Hsu Li-Fern , Weerasooriya Rukshen , Shah Dipen C. , Frank Robert , Maury Philippe , Delay Marc , Garrigue Stéphane , Clémenty Jacques
Published: August 2003

Background—

The long-QT and Brugada syndromes are important substrates of malignant ventricular arrhythmia. The feasibility of mapping and ablation of ventricular arrhythmias in these conditions has not been reported.

Methods and Results—

Seven patients (4 men; age, 38±7 years; 4 with long-QT and 3 with Brugada syndrome) with episodes of ventricular fibrillation or polymorphic ventricular tachycardia and frequent isolated or repetitive premature beats were studied. These premature beats were observed to trigger ventricular arrhythmias and were localized by mapping the earliest endocardial activity. In 4 patients, premature beats originated from the peripheral right (1 Brugada) or left (3 long-QT) Purkinje conducting system and were associated with variable Purkinje-to-muscle conduction times (30 to 110 ms). In the remaining 3 patients, premature beats originated from the right ventricular outflow tract, being 25 to 40 ms ahead of the QRS. The accuracy of mapping was confirmed by acute elimination of premature beats after 12±6 minutes of radiofrequency applications. During a follow-up of 17±17 months using ambulatory monitoring and defibrillator memory interrogation, no patients had recurrence of symptomatic ventricular arrhythmia but 1 had persistent premature beats.

Conclusion—

Triggers from the Purkinje arborization or the right ventricular outflow tract have a crucial role in initiating ventricular fibrillation associated with the long-QT and Brugada syndromes. These can be eliminated by focal radiofrequency ablation.
Regional Alterations in Protein Expression in the Dyssynchronous Failing Heart
Authors: Spragg David D. , Leclercq Christophe , Loghmani Morteza , Faris Owen P. , Tunin Richard S. , DiSilvestre Deborah , McVeigh Elliot R. , Tomaselli Gordon F. , Kass David A.
Published: August 2003

Background—

Left ventricular (LV) mechanical dyssynchrony induces regional heterogeneity of mechanical load and is an independent predictor of mortality and sudden death in heart failure (HF) patients. We tested whether dyssynchrony also induces localized disparities in the expression of proteins involved with mechanical stress, function, and arrhythmia susceptibility.

Methods and Results—

Eleven dogs underwent tachycardia-induced HF pacing, either from the right atrium or high right ventricular free wall. Whereas global LV dysfunction was similar between groups, LV contractile coordination assessed by tagged MRI was markedly dyssynchronous with right ventricular pacing but synchronous with right atrial pacing. In dyssynchronous failing hearts, the lateral LV endocardium displayed a 2-fold increase in phosphorylated
erk
mitogen-activated protein kinase expression (with no change in phospho-
p38
or phospho-
jnk
), a 30% decline in sarcoplasmic reticulum Ca
2+
-ATPase, an 80% reduction in phospholamban, and a 60% reduction in the gap junction protein connexin43, relative to neighboring myocardial segments. In contrast, hearts from both right atrial–paced HF dogs and an additional 4 noninstrumented control animals showed minimal regional variability in protein expression.

Conclusions—

LV dyssynchrony in failing hearts generates myocardial protein dysregulation concentrated in the late-activated, high-stress lateral endocardium. Such molecular polarization within the LV creates transmural and transchamber expression gradients of calcium handling and gap junction proteins that may worsen chamber function and arrhythmia susceptibility.
Gene Transfer of Human Guanosine 5′-Triphosphate Cyclohydrolase I Restores Vascular Tetrahydrobiopterin Level and Endothelial Function in Low Renin Hypertension
Authors: Zheng Jie-Sheng , Yang Xiang-Qun , Lookingland Keith J. , Fink Gregory D. , Hesslinger Christian , Kapatos Gregory , Kovesdi Imre , Chen Alex F.
Published: August 2003

Background—

We recently reported that arterial superoxide (O
2
−
) is augmented by increased endothelin-1 (ET-1) in deoxycorticosterone acetate (DOCA)-salt hypertension, a model of low renin hypertension. Tetrahydrobiopterin (BH
4
), a potent reducing molecule with antioxidant properties and an essential cofactor for endothelial nitric oxide synthase, protects against O
2
−
–induced vascular dysfunction. However, the interaction between O
2
−
and BH
4
on endothelial function and the underlying mechanisms are unknown.

Methods and Results—

The present study tested the hypothesis that BH
4
deficiency due to ET-1–induced O
2
−
leads to impaired endothelium-dependent relaxation and that gene transfer of human guanosine 5′-triphosphate (GTP) cyclohydrolase I (GTPCH I), the first and rate-limiting enzyme for BH
4
biosynthesis, reverses such deficiency and endothelial dysfunction in carotid arteries of DOCA-salt rats. There were significantly increased arterial O
2
−
levels and decreased GTPCH I activity and BH
4
levels in DOCA-salt compared with sham rats. Treatment of arteries of DOCA-salt rats with the selective ET
A
receptor antagonist ABT-627, NADPH oxidase inhibitor apocynin, or superoxide dismutase (SOD) mimetic tempol abolished O
2
−
and restored BH
4
levels. Basal arterial NO release and endothelium-dependent relaxations were impaired in DOCA-salt rats, conditions that were improved by apocynin or tempol treatment. Gene transfer of GTPCH I restored arterial GTPCH I activity and BH
4
levels, resulting in reduced O
2
−
and improved endothelium-dependent relaxation and basal NO release in DOCA-salt rats.

Conclusions—

These results indicate that a BH
4
deficiency resulting from ET-1–induced O
2
−
via an ET
A
/NADPH oxidase pathway leads to endothelial dysfunction, and gene transfer of GTPCH I reverses the BH
4
deficiency and endothelial dysfunction by reducing O
2
−
in low renin mineralocorticoid hypertension.
A Genome-Wide Scan for Urinary Albumin Excretion in Hypertensive Families
Authors: Freedman Barry I. , Beck Stephanie R. , Rich Stephen S. , Heiss Gerardo , Lewis Cora E. , Turner Stephen , Province Michael A. , Schwander Karen L. , Arnett Donna K. , Mellen Beverly G.
Published: August 2003

Albuminuria increases the risk of cardiovascular events in patients with essential hypertension and diabetic subjects. The heritability (h
2
) of albuminuria in multiplex hypertensive families is unknown. We calculated the familial aggregation of urine albumin:creatinine ratio (ACR) and performed a genome-wide scan to assess for loci contributing to ACR in participants enrolled in the
Hyper
tension
G
enetic
E
pidemiology
N
etwork (HyperGEN). To perform the genome scan, we analyzed genotype results from 2589 individuals from 805 families in the Family Blood Pressure Program. ACR and covariates were available in 1727 individuals (mean age, 57.1 years). Estimates of h
2
were obtained by using variance component methodology as implemented in the SOLAR software package. Linkage was tested between 387 markers spanning the genome at an average interval of 9.32 cM, using SOLAR multipoint analysis. The h
2
of log urine ACR was 0.49 (
P
<1×10
−7
) after controlling for significant main and interactive effects of age, gender, race, body mass index, blood pressure, and use of ACE inhibitors or angiotensin-2 receptor blockers. The genome-wide scan revealed a maximum LOD score of 2.73 on chromosome 19 (robust corrected LOD, 2.40;
P
=0.0009) at marker D19S591 and a LOD score of 2.0 on chromosome 12 (robust corrected LOD, 1.75;
P
=0.005) at marker PAH. These analyses demonstrate the marked heritability of urine ACR in families enriched for the presence of members with essential hypertension. They suggest that a gene(s) associated with urinary ACR may be present on human chromosomes 19 and 12.
Deoxycorticosterone Upregulates
PDS
(
Slc26a4
) in Mouse Kidney
Authors: Verlander Jill W. , Hassell Kathryn A. , Royaux Ines E. , Glapion Dawn M. , Wang Mou-Er , Everett Lorraine A. , Green Eric D. , Wall Susan M.
Published: August 2003

Pendrin is an anion exchanger expressed along the apical plasma membrane and apical cytoplasmic vesicles of type B and of non-A, non-B intercalated cells of the distal convoluted tubule, connecting tubule, and cortical collecting duct. Thus,
Pds
(
Slc26a4
) is a candidate gene for the putative apical anion-exchange process of the type B intercalated cell. Because apical anion exchange–mediated transport is upregulated with deoxycorticosterone pivalate (DOCP), we tested whether
Pds
mRNA and protein expression in mouse kidney were upregulated after administration of this aldosterone analogue by using quantitative real-time polymerase chain reaction as well as light and electron microscopic immunolocalization. In kidneys from DOCP-treated mice,
Pds
mRNA increased 60%, whereas pendrin protein expression in the apical plasma membrane increased 2-fold in non-A, non-B intercalated cells and increased 6-fold in type B cells. Because pendrin transports HCO
3
−
and Cl
−
, we tested whether DOCP treatment unmasks abnormalities in acid-base or NaCl balance in
Pds (-/-
) mice. In the absence of DOCP, arterial pH, systolic blood pressure, and body weight were similar in
Pds (+/+
) and
Pds (-/-
) mice. After DOCP treatment, weight gain and hypertension were observed in
Pds (+/+
) but not in
Pds (-/-
) mice. Moreover, after DOCP administration, metabolic alkalosis was more severe in
Pds (-/-
) than
Pds (+/+
) mice. We conclude that pendrin is upregulated with aldosterone analogues and is critical in the pathogenesis of mineralocorticoid-induced hypertension and metabolic alkalosis.
The ACE Gene
I/D
Polymorphism Is Not Associated With the Blood Pressure and Cardiovascular Benefits of ACE Inhibition
Authors: Harrap Stephen B. , Tzourio Christophe , Cambien François , Poirier Odette , Raoux Segolene , Chalmers John , Chapman Neil , Colman Samuel , Leguennec Solenn , MacMahon Stephen , Neal Bruce , Ohkubo Takayoshi , Woodward Mark
Published: August 2003

The insertion/deletion (
I/D
) polymorphism of the angiotensin-converting enzyme (ACE) gene might have consequences for the risks of vascular diseases. We examined the ACE genotype and the effects of a perindopril-based blood pressure-lowering regimen on macrovascular events, dementia, and cognitive decline among hypertensive and nonhypertensive patients with a history of cerebrovascular disease. ACE
I/D
genotypes were measured in 5688 of 6105 individuals with previous stroke or transient ischemic attack who participated in the PROGRESS trial. The
DD
genotype was significantly (
P
<0.0001) less frequent in Asian subjects (Chinese and Japanese, 14.7%) than in non-Asian subjects (32.0%). Controlling for racial background, there were no associations between ACE genotypes and cerebrovascular disease history or cardiovascular risk factors, including baseline blood pressure. The ACE genotype was not associated with the long-term risks of stroke, cardiac events, mortality, dementia, or cognitive decline; neither did the ACE genotype predict the blood pressure reduction associated with the use of the ACE inhibitor perindopril. Similarly, there was no evidence that the ACE genotype modified the relative benefits of ACE inhibitor-based therapy over placebo. This study provides no evidence that in patients with cerebrovascular disease, knowledge of ACE genotype is useful for predicting either the risk of disease or the benefits of perindopril-based blood pressure-lowering treatment.
Endothelin-A Receptors Mediate Renal Hemodynamic Effects of Exogenous Angiotensin II in Humans
Authors: Montanari Alberto , Biggi Almerina , Carra Nicoletta , Ziliotti Maurizio , Fasoli Elena , Musiari Luisa , Perinotto Patrizia , Novarini Almerico
Published: August 2003

To investigate whether endothelin-A receptors mediate hemodynamic changes caused by exogenous Angiotensin II in humans, 7 healthy volunteers on a 250-mmol sodium diet underwent 3 separate
p
-aminohippurate and inulin-based renal hemodynamic studies. In 2 studies, Angiotensin II (increasing rates of 0.625, 1.25, and 2.5 ng/kg per minute, each for 30 minutes) was infused either alone or combined with endothelin-A blocker, BQ123, 0.4 nmol/kg per minute. A third infusion of BQ123 alone was not followed by any change. Angiotensin II infusion alone produced a progressive decrease in renal blood flow (1080±94 mL/min×1.73 m
2
to 801±52,
P
<0.001, versus baseline) and glomerular filtration rate (115±7 mL/min×1.73 m
2
to 97±7,
P
<0.001) with increase in filtration fraction (0.188±.017 to 0.220±.030,
P
<0.01). Mean arterial pressure and renal vascular resistance increased markedly (86.8±3.1 to 97.5±4.4 mm Hg,
P
<0.001 and 83±7 to 133±20 mm Hg/min per liter,
P
<0.001, respectively). With Angiotensin II+BQ 123, mean arterial pressure still rose (86.2±3.1 to 91.1±4.3,
P
<0.05 versus both baseline and BQ123 alone) but significantly less than with Angiotensin II alone (
P
<0.05). Renal blood flow (1077±76 to 993±79,
P
<0.001) and glomerular filtration rate (115±7 to 105±7,
P
<0.05) also changed to a significantly lesser extent than with Angiotensin II alone (
P
<0.05 for both), whereas filtration fraction remained unchanged (0.185±.015 to 0.186±.016). Renal vascular resistance rose only by 17% (82±5 to 95±9,
P
<0.001 versus baseline as well as versus BQ123 or Angiotensin II alone). The results show that endothelin through Endothelin-A receptors contributes substantially to the systemic and renal vasoconstriction of low-dose exogenous Angiotensin II in healthy humans.
Aged Spontaneously Hypertensive Rats Exhibit a Selective Loss of EDHF-Mediated Relaxation in the Renal Artery
Authors: Büssemaker Eckhart , Popp Rüdiger , Fisslthaler Beate , Larson Christiana M. , Fleming Ingrid , Busse Rudi , Brandes Ralf P.
Published: August 2003

Endothelium-dependent relaxation is frequently attenuated in hypertension. We hypothesized that the contribution of the endothelium-derived hyperpolarizing factor (EDHF) to the acetylcholine (ACh)-induced, endothelium-dependent relaxation is attenuated with aging in the renal artery of spontaneously hypertensive rats (SHR) compared with age-matched Wistar-Kyoto (WKY) rats. ACh-induced, NO-mediated relaxation was identical in young (8-week-old) WKY and SHR, whereas EDHF-mediated relaxations (assessed in the presence of

N
ω

-nitro-
l
-arginine and diclofenac) were much more pronounced in SHR than WKY. KCl-induced relaxations were more pronounced in vessels from young WKY rats than from young SHR. The cytochrome P450 inhibitor sulfaphenazole significantly inhibited EDHF-mediated relaxation in vessels from young SHR but not WKY. Vessels from old (22 months) SHR exhibited a slightly reduced NO-mediated relaxation but a complete loss of EDHF-mediated responses. In contrast, aging did not affect EDHF-mediated responses in WKY. Moreover, ACh-induced hyperpolarization and resting membrane potential were decreased in old SHR but not in WKY. KCl-induced relaxation increased with age in WKY, whereas no response to KCl was recorded in arteries from aged SHR. In vessels from old WKY but not old SHR, mRNA expression of the Na-K-ATPase subunit α
2
was increased by 2-fold compared with young animals. These data indicate that the increase in EDHF responses in renal arteries from aged WKY can be attributed to the release of K
+
ions from the endothelium, whereas increased EDHF responses in renal arteries from young SHR can be attributed to a sulfaphenazole-sensitive cytochrome P450-dependent EDHF.