bluuebunny/crossref_metadata_2025 huggingface dataset:
Effects of Selective Cyclooxygenase-2 Inhibition on Vascular Responses and Thrombosis in Canine Coronary Arteries
Authors: Hennan James K. , Huang Jinbao , Barrett Terrance D. , Driscoll Edward M. , Willens David E. , Park Andrew M. , Crofford Leslie J. , Lucchesi Benedict R.
Published: September 2007

Background

Prostanoid synthesis via the action of cyclooxygenase-2 (COX-2) is a component of the inflammatory response. Prostacyclin, a product of COX-2 in vascular endothelium, has important physiological roles, such as increasing blood flow to injured tissues, reducing leukocyte adherence, and inhibiting platelet aggregation. We examined the possibility that selective COX-2 inhibition could suppress the protective effects of prostacyclin, resulting in an alteration of the hemostatic balance and vascular tone.

Methods and Results

Circumflex coronary artery thrombosis was induced in dogs by vascular electrolytic injury. Orally administered celecoxib (COX-2 inhibition) or high-dose aspirin (HDA) (COX-1 and COX-2 inhibition) did not alter time to occlusive thrombus formation compared with controls (celecoxib 77.7±7.2 minutes, HDA 72.0±18.5 minutes, control 93.0±21.8 minutes). Oral HDA with an endothelial recovery period (HDA-ER) (COX-1 inhibition) produced a significant increase in time to vessel occlusion (257.0±41.6 minutes). The observed increase in time to occlusion was abolished when celecoxib was administered to animals dosed with HDA-ER (80.7±20.6 minutes). The vasomotor effect of endothelium-derived prostacyclin was examined by monitoring coronary flow during intracoronary administration of arachidonic acid or acetylcholine. In celecoxib-treated animals, vasodilation in response to arachidonic acid was reduced significantly compared with controls.

Conclusions

The results indicate important physiological roles for COX-2–derived prostacyclin and raise concerns regarding an increased risk of acute vascular events in patients receiving COX-2 inhibitors. The risk may be increased in individuals with underlying inflammatory disorders, including coronary artery disease.
Plasminogen Activator Inhibitor-1 Deficiency Prevents Hypertension and Vascular Fibrosis in Response to Long-term Nitric Oxide Synthase Inhibition
Authors: Kaikita Koichi , Fogo Agnes B. , Ma Lijun , Schoenhard John A. , Brown Nancy J. , Vaughan Douglas E.
Published: September 2007

Background

Long-term inhibition of nitric oxide synthase (NOS) is known to induce hypertension and perivascular fibrosis. Recent evidence also suggests that long-term NOS inhibition induces expression of plasminogen activator inhibitor-1 (PAI-1) in vascular tissues and that PAI-1 may contribute to the development of fibrosis after chemical or ionizing injury. On the basis of these observations, we hypothesized that PAI-1 may influence the vascular response to long-term NOS inhibition by

N
ω

-nitro-
l
-arginine methyl ester (L-NAME).

Methods and Results

We compared the temporal changes in systolic blood pressure and coronary perivascular fibrosis in PAI-1–deficient (PAI-1
−/−
) and wild-type (WT) male mice (N=6 per group). At baseline, there were no significant differences in blood pressure between groups. After initiation of L-NAME, systolic blood pressure increased in both groups at 2 weeks. Over an 8-week study period, systolic blood pressure increased to 141±3 mm Hg in WT animals versus 112±4 mm Hg in PAI-1
−/−
mice (
P
<0.0001). The extent of coronary perivascular fibrosis increased significantly in L-NAME–treated WT mice (
P
<0.01 versus PAI-1
−/−
mice). Cardiac type I collagen mRNA expression was greater in control (
P
<0.01) and L-NAME–treated PAI-1
−/−
(
P
<0.05) groups than in control WT mice, indicating that PAI-1 deficiency prevents the increase of collagen deposition by promoting matrix degradation.

Conclusions

These findings suggest that PAI-1 deficiency alone is sufficient to protect against the structural vascular changes that accompany hypertension in the setting of long-term NOS inhibition. Direct inhibition of vascular PAI-1 activity may provide a new therapeutic strategy for the prevention of arteriosclerotic cardiovascular disease.
Platelet Glycoprotein Ibα HPA-2 Met/VNTR B Haplotype as a Genetic Predictor of Myocardial Infarction and Sudden Cardiac Death
Authors: Mikkelsson Jussi , Perola Markus , Penttilä Antti , Karhunen Pekka J.
Published: September 2007

Background

—

Sudden cardiac death (SCD) is one of the leading manifestations of coronary heart disease in early middle age. Platelet glycoprotein (GP) Ib-IX-V receptor complexes play a key role in the initial adhesion of platelets to collagen during the formation of a coronary thrombus. The HPA-2 (Thr145 Met) and VNTR polymorphisms of the gene for GP Ibα have been studied previously in hospitalized patients with acute coronary syndromes. The significance of these polymorphisms in victims of sudden cardiac death is not known.

Methods and Results

—

The association of these 2 polymorphisms with coronary atherosclerosis, coronary artery stenosis, coronary thrombosis, myocardial infarction (MI), and SCD was studied in the Helsinki Sudden Death Study, which comprised 2 large autopsy series, collected 10 years apart during 1981 to 1982 and 1991 to 1992, of 700 middle-aged white Finnish men who suffered sudden or violent out-of-hospital death. The 2 polymorphisms showed an almost complete linkage disequilibrium. Men with acute MI (n=80) and coronary thrombosis (n=65) were more likely to be carriers of the HPA-2 Met allele (OR 2.0 and 2.6, respectively,
P
<0.005 for both) than were control subjects who died of noncardiac causes (n=367). In men <55 years old, the Met allele was overrepresented (OR 2.2) among victims of SCD (n=98) compared with control subjects (n=249). In men <55 years old, 17 of 29 men with acute MI (58.6%) and 16 of 23 men with coronary thrombosis (69.6%) were carriers of the HPA-2 Met allele compared with the 49 of 249 (19.7%) who had died of noncardiac causes (ORs 5.6 and 9.2, respectively). Similar associations were observed in the separate analyses of both autopsy series.

Conclusions

—

Our results suggest that the HPA-2 Met/VNTR B haplotype of the platelet von Willebrand factor and thrombin receptor protein GP Ib-V-IX may be considered to be a major risk factor of coronary thrombosis, fatal MI, and SCD in early middle age.
Serial Intravascular Ultrasound Assessment of the Efficacy of Intracoronary γ-Radiation Therapy for Preventing Recurrence in Very Long, Diffuse, In-Stent Restenosis Lesions
Authors: Ahmed Javed M. , Mintz Gary S. , Waksman Ron , Mehran Roxana , Leiboff Borjanka , Pichard Augusto D. , Satler Lowell F. , Kent Kenneth M. , Weissman Neil J.
Published: September 2007

Background
—

The efficacy of coronary γ-irradiation in preventing recurrent in-stent restenosis (ISR) is well established. However, brachytherapy may be less effective in very long, diffuse ISR lesions.

Methods and Results
—

We used serial intravascular ultrasound (IVUS) to study patients with long, diffuse ISR lesions (length, 36 to 80 mm) who were enrolled in (1) Long WRIST (Washington Radiation In-Stent Restenosis Trial), a double-blind, placebo-controlled trial of intracoronary γ-irradiation (15 Gy at 2 mm from the source) and (2) high-dose (HD) Long WRIST, a registry that used a dose prescription of 18 Gy at 2 mm from the source. IVUS was performed using automated pullback (0.5 mm/s). Stent, lumen, and intimal hyperplasia were measured at 2-mm intervals. Complete postintervention and follow-up IVUS imaging was available in 30 irradiated and 34 placebo patients from Long WRIST and in 25 patients from HD Long WRIST. Stent length was longer in HD Long WRIST than in placebo or treated patients in Long WRIST (
P
=0.0064 and
P
=0.0125, respectively). Otherwise, baseline measurements were similar. At follow-up, the minimum lumen area was largest in the HD Long WRIST patients (4.0±1.4 mm
2
); areas were 2.9±1.0 mm
2
in irradiated patients in Long WRIST and 1.9±1.1 mm
2
in placebo patients in Long WRIST (
P
<0.005 for all comparisons).

Conclusions
—

Serial IVUS analysis shows that γ-irradiation reduces recurrent in-stent neointimal hyperplasia in long, diffuse ISR lesions; however, it is even more effective when given at a higher dose.
Circulating Matrix Metalloproteinases and Their Inhibitors in Patients with Kawasaki Disease
Authors: Senzaki Hideaki , Masutani Satoshi , Kobayashi Jun , Kobayashi Toshiki , Nakano Hirofumi , Nagasaka Hironori , Sasaki Nozomu , Asano Haruhiko , Kyo Shunei , Yokote Yuji
Published: September 2007

Background
—

Accelerated matrix breakdown caused by the increased activity of matrix metalloproteinases (MMPs) and/or the quantitative imbalance between MMP and tissue inhibitor of MMP (TIMP) have been implicated in several pathological conditions. MMP and TIMP may also be involved in the destruction of the coronary arterial wall and the resultant coronary arterial lesions in Kawasaki disease.

Methods and Results
—

Plasma levels of MMPs, neutrophil elastase, and TIMPs were measured by enzyme-linked immunoassay in 57 patients with Kawasaki disease and no coronary arterial lesions (group 1) and in 8 patients with Kawasaki disease and coronary arterial lesions (group 2). Blood samples were obtained before and after intravenous gamma globulin therapy and in the convalescent stage. Levels of MMPs, neutrophil elastase, and TIMPs were significantly higher in Kawasaki disease patients before gamma globulin therapy than in 18 age-matched afebrile control subjects and 17 age-matched febrile disease control subjects (
P
<0.01). More importantly, the pre-gamma globulin MMP9 level and MMP9/TIMP2 ratio and post-gamma globulin MMP3 level and MMP3/TIMP1 ratio were significantly higher in group 2 than in group 1 patients (
P
<0.05). Although MMP levels in febrile disease controls were significantly higher than those of afebrile controls, the MMP/TIMP ratios of febrile disease controls and afebrile controls were comparable.

Conclusions
—

These data suggest that patients with Kawasaki disease and high levels of MMP and/or MMP/TIMP are susceptible to coronary arterial lesions. Studies of the effects of MMP inhibitors on coronary outcome may provide evidence that MMP is a viable therapeutic target for the prevention of coronary arterial lesions due to Kawasaki disease.
Stent Coating With Titanium-Nitride-Oxide for Reduction of Neointimal Hyperplasia
Authors: Windecker Stephan , Mayer Isabella , De Pasquale Gabriella , Maier Willibald , Dirsch Olaf , De Groot Philip , Wu Ya-Ping , Noll Georg , Leskosek Boris , Meier Bernhard , Hess Otto M. ,   in collaboration with the Working Group on Novel Surface Coating of Biomedical Devices (SCOL)
Published: September 2007

Background

—

Coronary stents prevent constrictive arterial remodeling but stimulate neointimal hyperplasia. Stainless steel induces a metallic foreign body reaction, which is absent for titanium. The hypothesis of the present study was that titanium renders the stent surface biologically inert, with reduced platelet and fibrinogen binding.

Methods and Results

—

Twelve pigs were instrumented with a stainless steel and 2 titanium-nitride-oxide–coated stents (TiNOX 1, ceramic; TiNOX 2, metallic). Animals were restudied after 6 weeks. Histological specimens of stented segments were analyzed by digital morphometry. Platelet adhesion and fibrinogen binding studies were performed in the perfusion chamber. Under in vitro conditions, TiNOX 1 showed reduced platelet adhesion (65±3%) compared with TiNOX 2 (72±5%;
P
<0.05) and stainless steel (71±4%;
P
<0.05). Platelet adhesion 48 hours after incubation with human plasma, however, was not different between TiNOX 1 (17±3%) and 2 (15±3%) but was significantly higher with stainless steel (23±2%;
P
<0.05). Fibrinogen binding was significantly reduced with TiNOX 2 (54±3%) compared with TiNOX 1 (82±4%,
P
<0.05) or stainless steel (100%,
P
<0.05). Histomorphometry revealed a significantly larger neointimal area in stainless steel (2.61±1.12 mm
2
) than in TiNOX 1–coated (1.47±0.84 mm
2
,
P
<0.02) or TiNOX 2–coated (1.39±0.93 mm
2
,
P
<0.02) stents. The reductions were 44% and 47%, respectively.

Conclusions

—

TiNOX coating significantly reduces neointimal hyperplasia in stainless steel stents. The antiproliferative effect was similar for both TiNOX coatings, suggesting that the electrochemical properties are more important for attenuation of neointimal proliferation than the observed differences in platelet adhesion and fibrinogen binding.
Overexpression of Functionally Coupled Cyclooxygenase-2 and Prostaglandin E Synthase in Symptomatic Atherosclerotic Plaques as a Basis of Prostaglandin E
2
-Dependent Plaque Instability
Authors: Cipollone Francesco , Prontera Cesaria , Pini Barbara , Marini Matteo , Fazia Maria , De Cesare Domenico , Iezzi Annalisa , Ucchino Sante , Boccoli Gianfranco , Saba Vittorio , Chiarelli Francesco , Cuccurullo Franco , Mezzetti Andrea
Published: September 2007

Background

—

Studies have implicated a role for prostaglandin (PG) E
2
-dependent matrix metalloproteinase (MMP) biosynthesis in the rupture of atherosclerotic plaque. Cyclooxygenase-2 (COX-2) and PGE synthase (PGES) are coregulated in nucleated cells by inflammatory stimuli. The aim of this study was to characterize the expression of COX-2 and PGES in carotid plaques and to correlate it with the extent of inflammatory infiltration and MMP activity and with clinical features of patients’ presentation.

Methods and Results

—

Plaques were obtained from 50 patients undergoing carotid endarterectomy and divided into 2 groups (symptomatic and asymptomatic) according to clinical evidence of recent transient ischemic attack or stroke. Plaques were analyzed for COX-2, PGES, MMP-2, and MMP-9 by immunocytochemistry and Western blot, whereas zymography was used to detect MMP activity. Immunocytochemistry was used to identify CD68+ macrophages, CD3+ T lymphocytes, and HLA-DR+ cells. The percentage of macrophage-rich areas was larger (
P
<0.0001) in symptomatic plaques. COX-2, PGES, and MMPs were detected in all specimens; enzyme concentration, however, was significantly higher in symptomatic plaques. COX-2, PGES, and MMPs were especially noted in shoulders of symptomatic plaques, colocalizing with HLA-DR+ macrophages. All symptomatic plaques contained activated forms of MMPs. Finally, inhibition of COX-2 by NS-398 was accompanied by decreased production of MMPs that was reversed by PGE
2
.

Conclusions

—

This study demonstrates the colocalization of COX-2 and PGES in symptomatic lesions and provides evidence that synthesis of COX-2 and PGES by activated macrophages is associated with acute ischemic syndromes, possibly through metalloproteinase-induced plaque rupture.
Patients With End-Stage Congestive Heart Failure Treated With β-Adrenergic Receptor Antagonists Have Improved Ventricular Myocyte Calcium Regulatory Protein Abundance
Authors: Kubo Hajime , Margulies Kenneth B. , Piacentino Valentino , Gaughan John P. , Houser Steven R.
Published: September 2007

Background

Alterations in Ca
2+
-handling proteins are thought to underlie the deranged Ca
2+
transients that contribute to deterioration of cardiac function in congestive heart failure (CHF). Clinical trials in CHF patients have shown that treatment with β-adrenergic receptor antagonists (βB) improves cardiac performance. The present study determined whether the abundance of Ca
2+
-handling proteins is different in failing hearts from patients treated or untreated with β B.

Methods and Results

Ca
2+
regulatory protein abundance was compared in LV myocardium of 10 nonfailing hearts (NF group) and 44 failing hearts (CHF group) removed at transplantation. Analysis was performed in βB-treated (βB-CHF) and non–βB treated (non-βB-CHF) patients and in 4 subgroups: ischemic cardiomyopathy (ICM, n=10), nonischemic dilated cardiomyopathy (DCM, n=10), ICM with βB therapy (βB-ICM, n=12), and DCM with βB therapy (βB-DCM, n=12). Sarcoplasmic reticulum Ca
2+
ATPase, phospholamban, and Na
+
-Ca
2+
exchanger protein abundance were determined by use of Western blot analysis. Ca
2+
transients were measured with fluo-3. Sarcoplasmic reticulum Ca
2+
ATPase was significantly less abundant whereas phospholamban and Na
+
-Ca
2+
exchanger were not significantly altered in non-βB-CHF versus NF. Sarcoplasmic reticulum Ca
2+
ATPase in the βB-ICM and βB-DCM was greater than in non-βB-CHF and were not different than in NF. Ca
2+
transients in non-βB-CHF myocytes had significantly smaller peaks and were prolonged versus NF myocytes. Ca
2+
transients from βB-CHF myocytes had shorter durations than in βB-CHF myocytes.

Conclusions

βB treatment in CHF patients can normalize the abundance of myocyte Ca
2+
regulatory proteins and improve Ca
2+
-handling.
Improvement of Left Ventricular Remodeling and Function by Hydroxymethylglutaryl Coenzyme A Reductase Inhibition With Cerivastatin in Rats With Heart Failure After Myocardial Infarction
Authors: Bauersachs Johann , Galuppo Paolo , Fraccarollo Daniela , Christ Michael , Ertl Georg
Published: September 2007

Background

Hydroxymethylglutaryl coenzyme A reductase inhibitors (statins) attenuate angiotensin II-induced cellular signaling. Because angiotensin II is involved in left ventricular (LV) remodeling after myocardial infarction (MI), we examined the effects of statin treatment in an experimental model of chronic heart failure after MI.

Methods and Results

Rats with extensive MI were treated with placebo or cerivastatin (0.3 mg/kg per day) as a dietary supplement or via gavage for 11 weeks starting on the 7th postoperative day. Infarct size and cholesterol levels were similar among all groups. LV cavity area, an index of LV dilatation, was reduced in MI rats on cerivastatin compared with placebo. LV end-diastolic pressure was increased in MI rats on placebo (24.1±4.1 mm Hg versus sham: 5.1±0.3 mm Hg;
P
<0.01), and it was significantly reduced by cerivastatin treatment (13.7±2.7 mm Hg;
P
<0.05 versus placebo). Cerivastatin partially normalized LV dP/dt
max
and dP/dt
min
, indices of LV systolic and diastolic function, which were significantly reduced in MI rats on placebo. Improvement of LV function by cerivastatin was accompanied by a reduced expression of collagen type I and β-myosin heavy chain. LV endothelial nitric oxide synthase was increased, whereas the nitrotyrosine protein level was decreased in MI rats by cerivastatin treatment.

Conclusions

Cerivastatin improved LV remodeling and function in rats with heart failure. This effect was associated with an attenuated LV expression of fetal myosin heavy chain isoenzymes and collagen I. Statin treatment may retard the progression of chronic heart failure.
Implantation of Bone Marrow Mononuclear Cells Into Ischemic Myocardium Enhances Collateral Perfusion and Regional Function via Side Supply of Angioblasts, Angiogenic Ligands, and Cytokines
Authors: Kamihata Hiroshi , Matsubara Hiroaki , Nishiue Takashi , Fujiyama Soichiro , Tsutsumi Yoshiaki , Ozono Ryozo , Masaki Hiroya , Mori Yasukiyo , Iba Osamu , Tateishi Eriko , Kosaki Atsushi , Shintani Satoshi , Murohara Toyoaki , Imaizumi Tsutomu , Iwasaka Toshiji
Published: September 2007

Background

Bone marrow implantation (BMI) was shown to enhance angiogenesis in a rat ischemic heart model. This preclinical study using a swine model was designed to test the safety and therapeutic effectiveness of BMI.

Methods and Results

BM-derived mononuclear cells (BM-MNCs) were injected into a zone made ischemic by coronary artery ligation. Three weeks after BMI, regional blood flow and capillary densities were significantly higher (4.6- and 2.8-fold, respectively), and cardiac function was improved. Angiography revealed that there was a marked increase (5.7-fold) in number of visible collateral vessels. Implantation of porcine coronary microvascular endothelial cells (CMECs) did not cause any significant increase in capillary densities. Labeled BM-MNCs were incorporated into ≈31% of neocapillaries and corresponded to ≈8.7% of macrophages but did not actively survive as myoblasts or fibroblasts. There was no bone formation by osteoblasts or malignant ventricular arrhythmia. Time-dependent changes in plasma levels for cardiac enzymes (troponin I and creatine kinase-MB) did not differ between the BMI, CMEC, and medium-alone implantation groups. BM-MNCs contained 16% of endothelial-lineage cells and expressed basic fibroblast growth factor≫vascular endothelial growth factor>angiopoietin 1 mRNAs, and their cardiac levels were significantly upregulated by BMI. Cardiac interleukin-1β and tumor necrosis factor-α mRNA expression were also induced by BMI but not by CMEC implantation. BM-MNCs were actively differentiated to endothelial cells in vitro and formed network structure with human umbilical vein endothelial cells.

Conclusions

BMI may constitute a novel safety strategy for achieving optimal therapeutic angiogenesis by the natural ability of the BM cells to secrete potent angiogenic ligands and cytokines as well as to be incorporated into foci of neovascularization.
Decreased Coagulability Has No Clinically Relevant Effect on Atherogenesis
Authors: Šrámek A. , Reiber J.H.C. , Gerrits W.B.J. , Rosendaal F.R.
Published: September 2007

Background

Hemostasis affects ischemic cardiovascular disease through its role in formation of occluding arterial thrombi. Several studies suggest that hemostasis also might play a role in atherogenesis. We investigated whether individuals with an inherited bleeding tendency are protected against development of atherosclerosis.

Methods and Results

A total of 76 individuals with an inherited bleeding tendency (hemophilia and von Willebrand disease) and 142 healthy controls were included in the present study. Early atherosclerotic vessel-wall changes were quantified by measurement of intima-media thickness in the carotid and femoral arteries by B-mode ultrasonography. To validate intima-media thickness measurements, measurements also were performed in 77 individuals with clinically proven atherosclerosis and in 34 healthy, age-matched controls. A large difference in intima-media thickness was found between individuals with proven atherosclerosis and healthy controls, in particular for the femoral artery (difference for carotid artery, 0.16 mm; femoral artery, 0.53 mm). Comparison between patients with a bleeding tendency and healthy controls showed only minimally reduced intima-media in femoral artery in individuals with a bleeding tendency (adjusted difference, −0.078 mm; 95% CI, −0.17 to 0.018 mm). Subgroup analysis revealed that in subjects with moderate to severe hemophilia, vessel walls were thinnest (adjusted difference, −0.10 mm; 95% CI, −0.27 to 0.061 mm).

Conclusions

Hypocoagulability caused by hemophilia or von Willebrand disease has at most a limited effect on atherogenesis.
Coronary Heart Disease Prediction From Lipoprotein Cholesterol Levels, Triglycerides, Lipoprotein(a), Apolipoproteins A-I and B, and HDL Density Subfractions
Authors: Sharrett A.R. , Ballantyne C.M. , Coady S.A. , Heiss G. , Sorlie P.D. , Catellier D. , Patsch W.
Published: September 2007

Background

—

Despite consensus on the need for blood cholesterol reductions to prevent coronary heart disease (CHD), available evidence on optimal cholesterol levels or the added predictive value of additional lipids is sparse.

Methods and Results

—

After 10 years follow-up of 12 339 middle-aged participants free of CHD in the Atherosclerosis Risk in Communities Study (ARIC), 725 CHD events occurred. The lowest incidence was observed in those at the lowest LDL cholesterol (LDL-C) quintile, with medians of 88 mg/dL in women and 95 mg/dL in men, and risk accelerated at higher levels, with relative risks (RRs) for the highest quintile of 2.7 in women and 2.5 in men. LDL-C, HDL-C, lipoprotein(a) [Lp(a)], and in women but not men, triglycerides (TG) were all independent CHD predictors, providing an RR, together with blood pressure, smoking, and diabetes, of 13.5 in women and 4.9 in men. Lp(a) was less significant in blacks than whites. Prediction was not enhanced by HDL-C density subfractions or apolipoproteins (apo) A-I or B. Despite strong univariate associations, apoB did not contribute to risk prediction in subgroups with elevated TG, with lower LDL-C, or with high apoB relative to LDL-C.

Conclusions

—

Optimal LDL-C values are <100 mg/dL in both women and men. LDL-C, HDL-C, TG, and Lp(a), without additional apolipoproteins or lipid subfractions, provide substantial CHD prediction, with much higher RR in women than men.
Downregulation of Matrix Metalloproteinases and Reduction in Collagen Damage in the Failing Human Heart After Support With Left Ventricular Assist Devices
Authors: Li Yun You , Feng Yiqin , McTiernan Charles F. , Pei Wei , Moravec Christine S. , Wang Ping , Rosenblum Warren , Kormos Robert L. , Feldman Arthur M.
Published: September 2007

Background

—

Left ventricular assist device (LVAD) support of the failing heart induces salutary changes in myocardial structure and function. Matrix metalloproteinases (MMPs) are increased in the failing heart and are induced by stretch in cardiac cells in vitro. We hypothesized that mechanical unloading may affect LV plasticity by regulating MMPs and their substrates.

Methods and Results

—

LV samples were collected from patients with dilated cardiomyopathy (DCM, n=14) or ischemic cardiomyopathy (ICM, n=16) at the time of implantation of the LVAD and again during cardiac transplantation. MMP-1, -3, and -9 were measured by ELISA, MMP-2 and -9 gelatinolytic activity by gelatin zymography, and tissue inhibitors of metalloproteinases (TIMPs) by Western blot. Total soluble and insoluble collagens were separated by pepsin solubilization, and the contents were determined by quantification of hydroxyproline. The undenatured soluble collagen was measured by Sircol collagen assay. The results showed that MMP-1 and -9 were decreased, whereas TIMP-1 and -3 were increased, but there was no change in MMP-2 and -3 and TIMP-2 and -4 after LVAD support. The undenatured collagen was increased, with the ratio of undenatured to total soluble collagens increased in ICM and that of insoluble to total soluble collagens increased in DCM after LVAD support.

Conclusions

—

The reduced MMPs and increased TIMPs and ratios of undenatured to total soluble collagens and insoluble to total soluble collagens after LVAD support suggest that reduced MMP activity diminished damage to the matrix. These changes may contribute to the functional recovery and LV plasticity after LVAD support.
Oxidative Stress and Platelet Activation in Homozygous Homocystinuria
Authors: Davì G. , Di Minno G. , Coppola A. , Andria G. , Cerbone A.M. , Madonna P. , Tufano A. , Falco A. , Marchesani P. , Ciabattoni G. , Patrono C.
Published: September 2007

Background

—

Severe hyperhomocysteinemia due to cystathionine β-synthase deficiency (CβSD) is associated with early atherothrombotic vascular disease. Homocysteine may exert its effects by promoting oxidative damage. In the present study, we investigated whether in vivo formation of 8-iso-prostaglandin (PG) F
2α
, a platelet-active product of arachidonic acid peroxidation, is enhanced in CβSD and whether it correlates with in vivo platelet activation, as reflected by thromboxane (TX) metabolite excretion.

Methods and Results

—

Urine and blood samples were obtained from patients with homozygous CβSD (n=13) and age-matched healthy subjects. Urinary 8-iso-PGF
2α
excretion was significantly higher in CβSD patients than in control subjects (640±384 versus 213±43 pg/mg creatinine;
P
=0.0015) and correlated with plasma homocysteine (ρ=0.398,
P
=0.0076). Similarly, urinary 11-dehydro-TXB
2
excretion was enhanced in CβSD (1166±415 versus 324±72 pg/mg creatinine;
P
=0.0015) and correlated with urinary 8-iso-PGF
2α
(ρ=0.362,
P
=0.0153). Vitamin E supplementation (600 mg/d for 2 weeks) was associated with a statistically significant increase in its plasma levels (from 16.6±4.6 to 40.4±8.7 μmol/L,
P
=0.0002) and with reductions in 8-iso-PGF
2α
(from 790±159 to 559±111 pg/mg creatinine,
P
=0.018) and 11-dehydro-TXB
2
(from 1273±383 to 913±336 pg/mg creatinine,
P
=0.028). A statistically significant inverse correlation was found between urinary 8-iso-PGF
2α
and plasma vitamin E levels (ρ=−0.745,
P
=0.0135).

Conclusions

—

The results of the present study suggest that enhanced peroxidation of arachidonic acid to form bioactive F
2
-isoprostanes may represent an important mechanism linking hyperhomocysteinemia and platelet activation in CβSD patients. Moreover, they provide a rationale for dose-finding studies of vitamin E supplementation in this setting.
Taurine Prevents the Decrease in Expression and Secretion of Extracellular Superoxide Dismutase Induced by Homocysteine
Authors: Nonaka Hidemi , Tsujino Takeshi , Watari Yasuhiro , Emoto Noriaki , Yokoyama Mitsuhiro
Published: September 2007

Background

—

Hyperhomocysteinemia is an independent risk factor for atherosclerosis. Homocysteine has been shown to induce endoplasmic reticulum (ER) stress in vascular endothelial cells. ER stress is a condition in which glycoprotein trafficking is disrupted and unfolded proteins accumulate in the ER. ER molecular chaperons, such as GRP78, are induced and an ER resident kinase, PERK, is activated when cells are subjected to ER stress. Conversely, taurine is reported to have antiatherogenic effects by unknown mechanisms. To elucidate the mechanisms by which homocysteine induces atherosclerosis and taurine prevents it, we examined whether homocysteine and taurine affect the expression and secretion of extracellular superoxide dismutase (EC-SOD), a glycoprotein secreted from vascular smooth muscle cells (VSMCs) that protects the vascular wall from oxidative stress.

Methods and Results

—

We assessed the expression of EC-SOD and GRP78 mRNA in cultured rat VSMCs by Northern blot analysis. The EC-SOD protein secreted into the culture medium was examined by Western blot analysis. Homocysteine (5 mmol/L) and other ER stress inducers, including A23187, were found to decrease EC-SOD mRNA expression and protein secretion. Furthermore, they upregulated GRP78 mRNA expression and activated PERK. Taurine (0.5 to 10 mmol/L), conversely, prevented these actions induced by homocysteine.

Conclusions

—

Homocysteine induces ER stress and reduces the secretion and expression of EC-SOD in VSMCs, leading to increased oxidative stress in the vascular wall. Taurine restores the secretion and expression of EC-SOD by ameliorating ER stress induced by homocysteine.
Imaging Dispersion of Myocardial Repolarization, I
Authors: Burnes John E. , Ghanem Raja N. , Waldo Albert L. , Rudy Yoram
Published: September 2007

Background

Body-surface ECG measures (QT dispersion [QTd], QRST integrals) have been used as indices of myocardial repolarization abnormalities with the goal of identifying patients at risk of fatal arrhythmias. The clinical utility of these measures has been questioned. We investigate the complex relationship between epicardial and body-surface potentials in the context of regionally abnormal myocardial repolarization.

Methods and Results

Epicardial potentials were recorded with a 224-electrode sock from an open-chest dog during control, regional epicardial warming, cooling, and adjacent warming and cooling to induce localized alterations in myocardial repolarization and regions of increased repolarization dispersion. Body-surface potentials were generated from these epicardial potentials in a human torso model. Epicardial estimates of repolarization (activation recovery intervals [ARIs] and QRST integrals) were evaluated for their ability to identify regions with increased repolarization dispersion. Body-surface QRST integrals and QTd in 12-lead ECG and 64-lead body-surface potential maps were evaluated for their ability to detect increased dispersion of myocardial repolarization. Epicardial ARI and QRST integral maps successfully located epicardial regions with increased dispersion of repolarization. The increased dispersion was not consistently reflected in the 12-lead or 64-lead ECG QTd or in the body-surface QRST integral maps.

Conclusions

This study demonstrates the inadequacy of body-surface measures that are thought to reflect myocardial dispersion of repolarization. In contrast, measures based on epicardial electrograms (ARI or epicardial QRST integral maps) provide physiologically relevant information about myocardial repolarization and can locate regions of increased dispersion.
Endothelial Nitric Oxide Synthase Limits Left Ventricular Remodeling After Myocardial Infarction in Mice
Authors: Scherrer-Crosbie Marielle , Ullrich Roman , Bloch Kenneth D. , Nakajima Hiroshi , Nasseri Boris , Aretz H. Thomas , Lindsey Merry L. , Vançon Anne-Claire , Huang Paul L. , Lee Richard T. , Zapol Warren M. , Picard Michael H.
Published: September 2007

Background

To investigate the role of endothelial nitric oxide synthase (NOS3) in left ventricular (LV) remodeling after myocardial infarction (MI), the impact of left anterior descending coronary artery ligation on LV size and function was compared in 2- to 4-month-old wild-type (WT) and NOS3-deficient mice (NOS3
−/−
).

Methods and Results

Two days after MI, both strains of mice had a similar LV size, fractional shortening, and ejection fraction by echocardiography. Twenty-eight days after MI, both strains had dilated LVs with decreased fractional shortening and lower ejection fractions. Although the infarcted fraction of the LV was similar in both strains, LV end-diastolic internal diameter, end-diastolic volume, and mass were greater, but fractional shortening, ejection fraction, and the maximum rate of developed LV pressure (dP/dt
max
) were lower in NOS3
−/−
than in WT mice. Impairment of diastolic function, as measured by the time constant of isovolumic relaxation (τ) and the maximum rate of LV pressure decay (dP/dt
min
), was more marked in NOS3
−/−
than in WT mice. Mortality after MI was greater in NOS3
−/−
than in WT mice. Long-term administration of hydralazine normalized blood pressure in NOS3
−/−
mice, but it did not prevent the LV dilatation, impaired systolic and diastolic function, and increased LV mass that followed MI. In WT mice, capillary density and myocyte width in the nonischemic portion of the LV did not differ before and 28 days after MI, whereas in NOS3
−/−
mice, capillary density decreased and myocyte width increased after MI, whether or not hydralazine was administered.

Conclusions

These results suggest that the presence of NOS3 limits LV dysfunction and remodeling in a murine model of MI by an afterload-independent mechanism, in part by decreasing myocyte hypertrophy in the remote myocardium.
Apolipoprotein J/Clusterin Is Induced in Vascular Smooth Muscle Cells After Vascular Injury
Authors: Miyata Masaaki , Biro Sadatoshi , Kaieda Hiroshi , Eto Hideyuki , Orihara Koji , Kihara Takashi , Obata Hachiro , Matsushita Noriko , Matsuyama Takami , Tei Chuwa
Published: September 2007

Background
—

Understanding the precise molecular mechanisms underlying the phenomenon of restenosis after PTCA may help us to develop a new strategy for the treatment of restenosis after PTCA. The purpose of this study was to identify the genes involved in vascular restenosis.

Methods and Results
—

Applying a differential hybridization method to a model of the balloon-injured rabbit aorta, we identified 6 cDNA clones that were upregulated after injury. Northern blot showed that 5 genes, but not apolipoprotein J (apoJ)/clusterin, were constitutively expressed in noninjured aorta and upregulated after balloon injury. ApoJ mRNA was not detectable in noninjured aorta (control), began to be expressed at 6 hours after injury, showed a peak level at 24 hours (a 48-fold increase), gradually declined, and returned to the control level at 24 weeks. Western blot and immunohistochemistry demonstrated no expression of apoJ protein in noninjured aorta, an expression of apoJ at 2 days after balloon injury, and a peak level (a 55-fold increase) at 2 to 8 weeks. The expression of apoJ protein continued until 24 weeks after injury. In situ hybridization revealed that apoJ mRNA was expressed in smooth muscle cells (SMCs) of media at 2 days after injury and in SMCs of media and neointima at 2 weeks. To analyze the function of apoJ, stably transfected rabbit SMCs were created. The expression of apoJ stimulated proliferation and migration of SMCs.

Conclusions
—

ApoJ is dramatically induced in media and neointima after vascular injury, suggesting that apoJ contributes to restenosis after angioplasty.
Reduced Functional Expression and Molecular Synthesis of Inducible Nitric Oxide Synthase in Rostral Ventrolateral Medulla of Spontaneously Hypertensive Rats
Authors: Chan Julie Y.H. , Wang Ling-Lin , Wu Kay L.H. , Chan Samuel H.H.
Published: September 2007

Background

We demonstrated recently that the prevalence of neuronal (nNOS) over inducible (iNOS) nitric oxide synthase activity at the rostral ventrolateral medulla (RVLM), the medullary origin of sympathetic neurogenic vasomotor tone, and the associated dominance of sympathoexcitation over sympathoinhibition underlie the maintenance of sympathetic vasomotor outflow by the endogenous NO. Here, we evaluated the hypothesis that a significant downregulation of iNOS at the RVLM may play a crucial role in the genesis of augmented sympathetic vasomotor tone during hypertension.

Methods and Results

Spontaneously hypertensive rats (SHR) and normotensive Wistar-Kyoto (WKY) rats anesthetized with propofol were used. Compared with SHR, the hypotension, bradycardia, or depression in sympathetic vasomotor tone induced by bilateral microinjection of lipopolysaccharide (5 or 10 ng) into the RVLM of WKY rats exhibited significantly shorter-onset latency, appreciably steeper slope, and a greater incidence of mortality. All these effects of lipopolysaccharide (10 ng) were significantly blunted by coadministration of the selective iNOS inhibitor
S
-methylisothiourea (250 pmol). Reverse transcription-polymerase chain reaction and Western blot analyses further revealed significantly lower iNOS mRNA and protein levels at the ventrolateral medulla in SHR under basal conditions or on activation by lipopolysaccharide (10 ng). Conversely, nNOS mRNA and protein levels remained constant in the RVLM and were comparable in both strains of rats.

Conclusions

We conclude that a significant downregulation in both functional expression and molecular synthesis of iNOS at the RVLM may underlie the augmented sympathetic vasomotor tone during hypertension.
Heme Oxygenase-1 Inhibits Atherogenesis in Watanabe Heritable Hyperlipidemic Rabbits
Authors: Ishikawa Kazunobu , Sugawara Daisuke , Goto Jun , Watanabe Yasuyuki , Kawamura Keiichi , Shiomi Masashi , Itabe Hiroyuki , Maruyama Yukio
Published: September 2007

Background

Heme oxygenase-1 (HO-1) is proposed to have a variety of adaptive responses against oxidative stress. To examine the function of HO-1 against atherogenesis in vivo, we observed the effects of HO-1 inhibition on atherosclerotic lesion formation in Watanabe heritable hyperlipidemic rabbits (WHHL).

Methods and Results

During 4 weeks of a 1% cholesterol diet, intravenous injections of Sn-protoporphyrin IX to inhibit HO-1 (S group, n=10) and saline as a control (C group, n=10) were given to 3-month-old WHHL rabbits. The percentages of en face atherosclerotic lesion areas in total descending aorta by Sudan IV staining (EFA) and the ratio of intima to media in microscopic atherosclerotic lesions in the ascending aortas (I/M) were calculated. Two different quantitative methods revealed significantly greater atherosclerotic lesions in the S group than the C group (EFA,
P
<0.001; I/M,
P
<0.005). HO-1 expression in atherosclerotic lesions was confirmed by Northern blot and immunohistochemical analyses. The dominant cell types expressing HO-1 were macrophages and foam cells, in which oxidized phospholipids were also accumulated. HO inhibition increased plasma and tissue lipid peroxide levels without affecting plasma lipid co osition.

Conclusions

These results suggest the possibilities that HO-1 has antiatherogenic properties in vivo and that the antiatherogenic properties of HO-1 are conducted through the prevention of lipid peroxidation.
Length Dependence of Tension Generation in Rat Skinned Cardiac Muscle
Authors: Fukuda Norio , Sasaki Daisuke , Ishiwata Shin’ichi , Kurihara Satoshi
Published: September 2007

Background

At the basis of the Frank-Starling mechanism is the intrinsic ability of cardiac muscle to produce active tension in response to stretch. Titin, a giant filamentous molecule involved in passive tension development, is intimately associated with the thick filament in the sarcomere. Titin may therefore contribute to active tension development by modulating the thick filament structure when the muscle is elongated.

Methods and Results

Rat skinned right ventricular trabeculae were used. Passive tension at a sarcomere length (SL) of 2.0 to 2.4 μm was decreased after treatment of the preparation with trypsin (0.25 μg/mL) for 13 minutes in the relaxed state at 20°C. This mild trypsin treatment degraded titin without affecting other major contractile proteins. The sarcomere structure was little affected by brief contractions in the trypsin-treated preparations. When SL was adjusted to the slack SL (1.9 μm), active tension was unaffected by trypsin under partial (pCa 5.55) and maximal (pCa 4.8) activation. At longer SLs, however, active tension was significantly (
P
<0.01) decreased after trypsin treatment at either pCa. The increase in active tension on reduction of interfilament lattice spacing, produced by dextran T-500 (molecular weight ≈500 000), was not influenced by trypsin (SL 1.9 μm). In trypsin-treated preparations, the increase in active tension as a function of muscle diameter was nearly the same for lengthening and osmotic compression at the slack SL.

Conclusions

The length-dependent activation in cardiac muscle, an underlying mechanism of the Frank-Starling law of the heart, is at the myofilament level, predominantly modulated by titin and interfilament lattice spacing changes.
Volume-Outcome Relation for Physicians and Hospitals Performing Angioplasty for Acute Myocardial Infarction in New York State
Authors: Vakili Babak A. , Kaplan Robert , Brown David L.
Published: September 2007

Background

An inverse relation exists between the number of coronary angioplasty procedures performed by physicians or hospitals and short-term mortality. It is not known, however, whether a similar relation holds for physicians and hospitals that perform primary angioplasty for acute myocardial infarction.

Methods and Results

We analyzed data from the 1995 New York State Coronary Angioplasty Reporting System Registry to determine the relation between the number of primary angioplasty procedures performed by physicians and hospitals and in-hospital mortality. Patients who underwent angioplasty procedures within 23 hours of onset of acute myocardial infarction without preceding thrombolytic therapy were included (n=1342). In-hospital mortality was reduced 57% among patients who underwent primary angioplasty by high-volume as opposed to low-volume physicians (adjusted relative risk 0.43; 95% CI 0.21 to 0.83). When patients with acute myocardial infarction were treated with primary angioplasty in high-volume hospitals rather than low-volume institutions, the relative risk reduction for in-hospital mortality was 44% (adjusted relative risk 0.56; 95% CI 0.29 to 1.1). Compared with patients treated at low-volume hospitals by low-volume physicians, patients treated at high-volume hospitals by high-volume physicians had a 49% reduction in the risk of in-hospital mortality (adjusted relative risk 0.51; 95% CI 0.26 to 0.99).

Conclusions

Among hospitals in New York State, a higher volume of primary angioplasty procedures performed by physicians and/or hospitals was associated with a lower mortality rate.
Dietary Protein and Weight Reduction
Authors: St. Jeor Sachiko T. , Howard Barbara V. , Prewitt T. Elaine , Bovee Vicki , Bazzarre Terry , Eckel Robert H. ,   for the AHA Nutrition Committee
Published: September 2007

High-protein diets have recently been proposed as a “new” strategy for successful weight loss. However, variations of these diets have been popular since the 1960s. High-protein diets typically offer wide latitude in protein food choices, are restrictive in other food choices (mainly carbohydrates), and provide structured eating plans. They also often promote misconceptions about carbohydrates, insulin resistance, ketosis, and fat burning as mechanisms of action for weight loss. Although these diets may not be harmful for most healthy people for a short period of time, there are no long-term scientific studies to support their overall efficacy and safety. These diets are generally associated with higher intakes of total fat, saturated fat, and cholesterol because the protein is provided mainly by animal sources. In high-protein diets, weight loss is initially high due to fluid loss related to reduced carbohydrate intake, overall caloric restriction, and ketosis-induced appetite suppression. Beneficial effects on blood lipids and insulin resistance are due to the weight loss, not to the change in caloric composition. Promoters of high-protein diets promise successful results by encouraging high-protein food choices that are usually restricted in other diets, thus providing initial palatability, an attractive alternative to other weight-reduction diets that have not worked for a variety of reasons for most individuals. High-protein diets are not recommended because they restrict healthful foods that provide essential nutrients and do not provide the variety of foods needed to adequately meet nutritional needs. Individuals who follow these diets are therefore at risk for compromised vitamin and mineral intake, as well as potential cardiac, renal, bone, and liver abnormalities overall.
Activation of Barium-Sensitive Inward Rectifier Potassium Channels Mediates Remote Dilation of Coronary Arterioles
Authors: Rivers Richard J. , Hein Travis W. , Zhang Cuihua , Kuo Lih
Published: September 2007

Background

Conducted vasodilation seems to be critical for the functional distribution of blood flow in the skeletal muscle microcirculation. However, this vasoregulatory phenomenon has not been documented in the coronary microcirculation, and its underlying mechanism remains elusive. Because potassium ions are potent metabolic vasodilators in the heart, by activating vascular inward rectifier K
+
(K
ir
) channels, we tested the hypothesis that coronary arterioles exhibit remote vasodilation through activation of this type of channel.

Methods and Results

Porcine coronary arterioles were isolated, cannulated, and pressurized for in vitro study. Vessels dilated concentration-dependently to extraluminal KCl (5 to 20 mmol/L), bradykinin, adenosine, pinacidil, and sodium nitroprusside. A K
ir
channel blocker, BaCl
2
(30 μmol/L), inhibited vasodilatory responses to KCl and bradykinin but not to adenosine, pinacidil, or nitroprusside. In a flow chamber, localized administration of bradykinin, adenosine, and KCl to the downstream end of the arterioles caused ≈80% dilation at the site of drug application (local site) and also produced 30% to 60% dilation at the upstream end of arterioles (remote site). Nitroprusside produced a similar dilation at the local site but failed to initiate remote vasodilation. In the presence of Ba
2+
, adenosine still dilated the local site, but the local dilations to bradykinin and KCl and the remote dilations to adenosine, bradykinin, and KCl were inhibited.

Conclusions

We demonstrated that some modes of local vasodilation can be conducted to remote sites in coronary arterioles and that local and remote dilations can occur through different vasodilatory mechanisms. Activation of K
ir
channels seems critical for some agonist-induced local vasodilations and also for the initiation and/or transmission of signals causing remote vasodilation.