bluuebunny/crossref_metadata_2025 huggingface dataset:
Stent Placement Compared With Balloon Angioplasty for Small Coronary Arteries
Authors: Koning René , Eltchaninoff Hélène , Commeau Philippe , Khalife Khalife , Gilard Martine , Lipiecki Janusz , Coste Pierre , Bedossa Marc , Lefèvre Thierry , Brunel Philippe , Morice Marie-Claude , Maillard Luc , Guyon Philippe , Puel Jacques , Cribier Alain ,   for the BESMART (BeStent in Small Arteries) Trial Investigators
Published: September 2007

Background

Stenting has been demonstrated to be superior to balloon angioplasty in de novo focal lesions located in large native vessels. However, in small vessels, the benefit of stenting remains questionable.

Methods and Results

A total of 381 symptomatic patients with de novo focal lesion located on a small coronary segment vessel (<3 mm) were randomly assigned to either stent implantation (192 patients; 197 lesions) or standard balloon angioplasty (189 patients; 198 lesions). The primary end point was the angiographic restenosis rate at 6 months, as determined by quantitative coronary angiography. On intention-to-treat analysis, angiographic success rate and major adverse cardiac events were comparable: 97.9% and 4.6% versus 93.9% and 5.8% in the stent group and the balloon group, respectively. After the procedure, a larger acute gain was achieved with stent placement (1.35±0.45 versus 0.94±0.47 mm,
P
=0.0001), resulting in a larger minimal lumen diameter (2.06±0.42 versus 1.70±0.46 mm,
P
=0.0001). At follow-up (obtained in 91% of patients), angiographic restenosis rate was 21% in the stent group versus 47% in the balloon group (
P
=0.0001), a risk reduction of 55%. Repeat target lesion revascularization was less frequent in the stent group (13% versus 25%,
P
=0.0006).

Conclusions

Elective stent placement in small coronary arteries with focal de novo lesions is safe and associated with a marked reduction in restenosis rate and subsequent target lesion revascularization rate at 6 months.
Expression of Interleukin-18 in Human Atherosclerotic Plaques and Relation to Plaque Instability
Authors: Mallat Ziad , Corbaz Anne , Scoazec Alexandra , Besnard Sandrine , Lesèche Guy , Chvatchko Yolande , Tedgui Alain
Published: September 2007

Background

Interleukin (IL)-18 is a potent proinflammatory cytokine with potential atherogenic properties. Its expression and role in atherosclerosis, however, are unknown.

Methods and Results

In the present study, we examined stable and unstable human carotid atherosclerotic plaques retrieved by endarterectomy for the presence of IL-18 using reverse transcription-polymerase chain reaction (PCR), Western blot, and immunohistochemical techniques. IL-18 was highly expressed in the atherosclerotic plaques compared with control normal arteries and was localized mainly in plaque macrophages. IL-18 receptor was also upregulated in plaque macrophages and endothelial cells, suggesting potential biological effects. To examine the role of IL-18 in atherosclerosis, we determined the relation between IL-18 mRNA expression and signs of plaque instability using real-time quantitative PCR. Interestingly, significantly higher levels of IL-18 mRNA were found in symptomatic (unstable) plaques than asymptomatic (stable) plaques (
P
<0.01).

Conclusions

These results suggest, for the first time, a major role for IL-18 in atherosclerotic plaque destabilization leading to acute ischemic syndromes.
Gender Influences [Ca2+]iDuring Metabolic Inhibition in Myocytes Overexpressing the Na+-Ca2+Exchanger
Authors: Sugishita Kazuro , Su Zhi , Li Fenghua , Philipson Kenneth D. , Barry William H.
Published: September 2007

BackgroundThe Na+-Ca2+exchanger (NCX) may contribute to Ca2+overload and injury in ischemic cardiomyocytes. Recently, NCX overexpression was reported to increase ischemia/reperfusion injury in male and oophorectomized female but not in female mice. We therefore measured the effects of gender and estrogen on [Ca2+]iand [Na+]iduring metabolic inhibition (MI) in myocytes from wild-type (WT) and transgenic (TG) mice overexpressing NCX.

Methods and ResultsFlow cytometry was used with fluo 3 for [Ca2+]iand sodium green for [Na+]imeasurements. Male TG mouse myocytes had higher [Ca2+]iafter 30 minutes of MI (1086±160 nmol/L, n=8) than male WT (688±104 nmol/L, n=9,P=0.01). The increase in [Ca2+]iduring MI induced by NCX overexpression in female myocytes was not significant, however (TG 552±62 nmol/L, n=9; WT 426±44 nmol/L, n=7). The magnitude of rise in [Ca2+]iduring MI was greater in male than female myocytes. KB-R7943, an NCX inhibitor, abolished the effect of NCX overexpression but did not totally eliminate the effect of gender on [Ca2+]iduring MI. NCX current density and basal Na+pump function were not influenced by gender. The rise in [Na+]iduring MI was greater in male than in female myocytes. Estrogen attenuated the increase in [Ca2+]iand [Na+]iin male myocytes during MI and abolished the gender difference in [Na+]iduring MI.

ConclusionsIncreased expression of NCX results in a more marked rise in [Ca2+]iduring MI in male than in female mouse myocytes. This gender difference appears to be mediated in part by an inhibitory effect of estrogen on the rise in [Na+]i, an NCX modifier, during MI.
Dysregulation of Peripheral and Central Chemoreflex Responses in Chagas’ Heart Disease Patients Without Heart Failure
Authors: Soares Barreto-Filho José Augusto , Consolim-Colombo Fernanda Marciano , Ferreira Lopes Heno , Martins Sobrinho Carlos Roberto , Guerra-Riccio Grazia M. , Krieger Eduardo Moacyr
Published: September 2007

Background

The peripheral and central chemoreflexes are important autonomic mechanisms for regulating breathing and cardiovascular function. Although pathological inflammatory infiltration of the peripheral chemoreceptors and central nervous system has been reported in Chagas’ disease, functional evaluation of chemoreflexes has not yet been performed.

Methods and Results

The hypothesis that chemoreflex function is altered in patients with Chagas’ heart disease (CH) but normal left ventricle function was tested in 12 CH patients and 13 matched control subjects. The ventilatory rate, minute ventilation, heart rate, mean arterial pressure, forearm blood flow, forearm vascular resistance, and venous norepi-nephrine responses to hypoxia and hypercapnia were determined. During hypoxia, the decrease in oxygen saturation was smaller in CH patients, despite a similar ventilatory response between groups. Both groups showed an increase in heart rate during hypoxia, but this response was blunted in CH patients. Although the mean arterial pressure response to hypoxia was similar in both groups, forearm vascular resistance significantly decreased in control subjects while remaining unchanged in CH patients. Moreover, a significant increase in plasma norepinephrine levels elicited by stimulation of peripheral chemoreceptors was observed only in the CH group. During hypercapnia, the increase in minute ventilation was smaller in CH patients, who did not exhibit the increase in norepinephrine observed in control subjects.

Conclusions

These data suggest that CH potentiates respiratory, cardiovascular, and autonomic responses to peripheral chemoreceptor activation by hypoxia in patients with normal left ventricular function. The ventilatory and sympathetic responses to central chemoreceptor activation by hypercapnia, however, are significantly blunted.
Parasympathetic Neural Activity Accounts for the Lowering of Exercise Heart Rate at High Altitude
Authors: Boushel Robert , Calbet Jose-Antonio L. , Rådegran Goran , Sondergaard Hans , Wagner Peter D. , Saltin Bengt
Published: September 2007

Background

In chronic hypoxia, both heart rate (HR) and cardiac output (Q) are reduced during exercise. The role of parasympathetic neural activity in lowering HR is unresolved, and its influence on Q and oxygen transport at high altitude has never been studied.

Methods and Results

HR, Q, oxygen uptake, mean arterial pressure, and leg blood flow were determined at rest and during cycle exercise with and without vagal blockade with glycopyrrolate in 7 healthy lowlanders after 9 weeks’ residence at ≥5260 m (ALT). At ALT, glycopyrrolate increased resting HR by 80 bpm (73±4 to 153±4 bpm) compared with 53 bpm (61±3 to 114±6 bpm) at sea level (SL). During exercise at ALT, glycopyrrolate increased HR by ≈40 bpm both at submaximal (127±4 to 170±3 bpm; 118 W) and maximal (141±6 to 180±2 bpm) exercise, whereas at SL, the increase was only by 16 bpm (137±6 to 153±4 bpm) at 118 W, with no effect at maximal exercise (181±2 bpm). Despite restoration of maximal HR to SL values, glycopyrrolate had no influence on Q, which was reduced at ALT. Breathing F
io
2
=0.55 at peak exercise restored Q and power output to SL values.

Conclusions

Enhanced parasympathetic neural activity accounts for the lowering of HR during exercise at ALT without influencing Q. The abrupt restoration of peak exercise Q in chronic hypoxia to maximal SL values when arterial P
o
2
and S
o
2
are similarly increased suggests hypoxia-mediated attenuation of Q.
Vasoconstrictor Effect of the Angiotensin-Converting Enzyme–Resistant, Chymase-Specific Substrate [Pro
11
D
-Ala
12
] Angiotensin I in Human Dorsal Hand Veins
Authors: McDonald John E. , Padmanabhan Neal , Petrie Mark C. , Hillier Chris , Connell John M.C. , McMurray John J.V.
Published: September 2007

Background

[Pro
11
D
-Ala
12
] angiotensin I is an ACE-resistant substrate specific for chymase. We used this peptide to determine whether a functionally significant non-ACE angiotensin (Ang) II–generating pathway exists in human dorsal hand veins.

Methods and Results

Using a modified Aellig technique, we studied the response to Ang I and [Pro
11
D
-Ala
12
] Ang I in dorsal hand veins in vivo in patients with coronary heart disease. We measured the venoconstrictor effect of each peptide given before and after a 6.25-mg oral dose of the ACE inhibitor captopril or matching placebo. Placebo or captopril was given in a double-blind, randomized fashion. Ang I induced a mean±SEM venoconstrictor response of 45±11%, 40±10%, 55±8%, and 4±4% before placebo, after placebo, before captopril, and after captopril, respectively. Hence, the response to Ang I was reproducible and was reduced significantly only after treatment with captopril (
P
=0.002). [Pro
11
D
-Ala
12
] Ang I induced a mean venoconstrictor response of 42±9%, 49±9%, 48±10%, and 54±11% before placebo, after placebo, before captopril, and after captopril, respectively. Hence, captopril had no significant effect on the response to [Pro
11
D
-Ala
12
] Ang I.

Conclusions

We have demonstrated that [Pro
11
D
-Ala
12
] Ang I is able to induce venoconstriction in humans in vivo. With this specific pharmacological probe, we have shown that a non-ACE pathway capable of generating Ang II exists in human veins in vivo and is potentially functionally important. This pathway is likely to involve the enzyme chymase.
In Vivo Blockade of Tumor Necrosis Factor-α Accelerates Functional Endothelial Recovery After Balloon Angioplasty
Authors: Krasinski Kevin , Spyridopoulos Ioakim , Kearney Marianne , Losordo Douglas W.
Published: September 2007

Background

Tumor necrosis factor-α (TNF) is expressed locally in arteries at sites of balloon injury. In vitro studies have shown that TNF inhibits cell cycle progression and induces apoptosis in endothelial cells. Accordingly, we performed a series of experiments to test the hypothesis that inhibiting TNF could accelerate endothelial recovery after angioplasty.

Methods and Results

TNF soluble receptor (TNFsr) has been shown to neutralize the actions of TNF in vitro and in vivo. Sprague-Dawley rats received TNFsr versus control IgG through an intraperitoneal injection. De-endothelializing balloon injury was then performed, and animals were killed after 1 week to evaluate re-endothelialization (Evans blue dye staining) and after 2 weeks to evaluate re-endothelialization and endothelial function. At both time points, blockade of TNF using TNFsr resulted in an increase in re-endothelialization, as measured as absolute area and percent area re-endothelialized. TNFsr also accelerated functional endothelial recovery, which manifest as an increase in nitric oxide production. Neointimal thickening was also shown inhibited.

Conclusions

In vivo blockade of TNF accelerates functional endothelial recovery after barotraumatic de-endothelializing injury. These findings suggest that locally expressed TNF acts to inhibit functional endothelial recovery after angioplasty and that transient blockade of TNF may improve the long-term success of angioplasty.
Plasminogen Activator Inhibitor Type 1 Increases Neointima Formation in Balloon-Injured Rat Carotid Arteries
Authors: DeYoung Mary Beth , Tom Clifford , Dichek David A.
Published: September 2007

Background

Elevated plasma levels of plasminogen activator inhibitor type 1 (PAI-1) are associated with myocardial infarction, atherosclerosis, and restenosis. PAI-1 is increased in atherosclerotic arteries and failed vein grafts. No experimental data, however, support a causal relationship between elevated PAI-1 expression and vascular lesions. Paradoxically, data generated in PAI-1 knockout mice suggest that PAI-1 might decrease lesion formation after arterial injury and that PAI-1 gene transfer might prevent restenosis.

Methods and Results

Using the rat carotid balloon injury model and a PAI-1-expressing adenoviral vector, we tested whether elevated arterial PAI-1 expression would alter neointima formation. Compared with control-transduced arteries, neointima formation in PAI-1-transduced arteries was initially retarded. By 14 days, however, the intimas of PAI-1-transduced arteries were significantly larger than intimas of control-transduced arteries (1.6±0.1×10
5
versus 1.2±0.1×10
5
μm
2
, n=18 to 19,
P
<0.03). PAI-1 expression in individual arteries correlated with increased cell proliferation at 4 and 8 days after injury (
R
=0.6,
P
<0.02 and
P
<0.006). PAI-1 expression also correlated with fibrin(ogen) accumulation (
R
=0.77,
P
<0.001), and fibrin(ogen) accumulation correlated strongly with proliferation (
R
=0.86,
P
<0.00001).

Conclusions

Increased expression of PAI-1 in the artery wall promotes neointima growth after balloon injury. Therefore, despite encouraging data generated in other animal models, PAI-1 is not a promising agent for gene therapy to prevent restenosis. Moreover, our data associate elevated PAI-1 expression with fibrin(ogen) accumulation and increased cell proliferation. These data suggest a mechanism to explain the association between elevated PAI-1 expression and the progression of arterial disease.
Vascular Abnormalities and Elevated Blood Pressure in Mice Lacking Adrenomedullin Gene
Authors: Shindo Takayuki , Kurihara Yukiko , Nishimatsu Hiroaki , Moriyama Nobuo , Kakoki Masao , Wang Yuhui , Imai Yasushi , Ebihara Aya , Kuwaki Tomoyuki , Ju Ki-Hwan , Minamino Naoto , Kangawa Kenji , Ishikawa Takatoshi , Fukuda Minoru , Akimoto Yoshihiro , Kawakami Hayato , Imai Tomihiko , Morita Hiroyuki , Yazaki Yoshio , Nagai Ryozo , Hirata Yasunobu , Kurihara Hiroki
Published: September 2007

Background

Adrenomedullin (AM) is a vasodilating peptide involved in the regulation of circulatory homeostasis and in the pathophysiology of certain cardiovascular diseases. Levels of AM are markedly increased in the fetoplacental circulation during pregnancy, although its function there remains unknown. To clarify the physiological functions of AM, we chose a gene-targeting strategy in mice.

Methods and Results

Targeted null mutation of the
AM
gene is lethal in utero: the mortality rate among
AM
−/−
embryos was >80% at E13.5. The most apparent abnormality in surviving
AM
−/−
embryos at E13.5 to E14.0 was severe hemorrhage, readily observable under the skin and in visceral organs. Hemorrhage was not detectable at E12.5 to E13.0, although the yolk sac lacked well-developed vessels. Electron microscopic examination showed endothelial cells to be partially detached from the basement structure at E12.5 in vitelline vessels and hepatic capillaries, which allowed efflux of protoerythrocytes through the disrupted barrier. The basement membrane was not clearly recognizable in the aorta and cervical artery, and the endothelial cells stood out from the wall of the lumen, only partially adhering to the basement structure.
AM
+/−
mice survived to adulthood but exhibited elevated blood pressures with diminished nitric oxide production.

Conclusions

AM is indispensable for the vascular morphogenesis during embryonic development and for postnatal regulation of blood pressure by stimulating nitric oxide production.
Lipid Peroxidation and Platelet Activation in Murine Atherosclerosis
Authors: Cyrus Tillmann , Tang Lina X. , Rokach Joshua , FitzGerald Garret A. , Praticò Domenico
Published: September 2007

Background

Lipid peroxidation and platelet activation are thought to be important contributors to the pathogenesis of atherosclerosis. The relevance of their interaction in vivo, however, is unknown.

Methods and Results

LDL receptor–deficient (LDLR
−/−
) mice on a high-fat diet developed extensive atherosclerosis and had increased urinary levels of 8,12-
iso
-isoprostane (iP) F
2α
-VI and 2,3-dinor-thromboxane (Tx) B
2
, markers of in vivo lipid peroxidation and platelet activation, respectively. Vitamin E supplementation suppressed 8,12-
iso
-iPF
2α
-VI biosynthesis and reduced atherosclerosis (65%) without having a significant effect on lipid levels or TxB
2
biosynthesis. Addition of the platelet inhibitor indomethacin to vitamin E simultaneously suppressed 8,12-
iso
-iPF
2α
-VI and TxB
2
, significantly reduced soluble intercellular adhesion molecule-1 and monocyte chemoattractant protein-1, and remarkably, further reduced atherosclerosis (80%).

Conclusions

These results indicate that in vivo lipid peroxidation and platelet activation coexist in murine atherosclerosis and that lipid peroxidation does not contribute to platelet activation and reflects the oxidant component of the inflammatory response. Our findings suggest that oxidant stress and platelet activation represent 2 distinct therapeutic targets in atherogenesis. We propose that a combination of antioxidants and platelet inhibitors might be rationally evaluated in the prevention of progression of human atherosclerosis.
Differential Characteristics of Neural Circulatory Control
Authors: van de Borne Philippe , Neubauer Jolanta , Rahnama Mohsen , Jansens Jean-Luc , Montano Nicola , Porta Alberto , Somers Virend K. , Degaute Jean Paul
Published: September 2007

Background

Reappearance of low-frequency (LF) (±0.10 Hz) oscillations in RR interval (RR) after cardiac transplantation is indicative of sympathetic efferent reinnervation. We hypothesized that restored LF oscillations in RR in heart transplant recipients (HTRs) are linked to oscillations in muscle sympathetic nerve traffic (MSNA).

Methods and Results

RR, RR variability, and MSNA were recorded 5±2 months (n=7, short-term HTRs) and 138±8 months (n=7, long-term HTRs) after heart transplantation and compared with matched hypertensive patients (n=7). A coherence function determined the coupling between LF oscillations in MSNA and RR. RR variance did not differ between short-term and long-term HTRs. However, LF variability was only 1±0.5 ms
2
in the short-term HTRs but was 15±8 ms
2
in the long-term HTRs (
P
<0.05). Normalized LF variability was also higher in the long-term HTRs (40±14 normalized unites) versus the short-term HTRs (6±3 normalized united,
P
<0.05) but did not differ from the LF variability of the hypertensive patients. Long-term HTRs were taking less cyclosporine (
P
<0.01) but had higher MSNA than the short-term HTRs (62±7 versus 31±7 burst/min, respectively,
P
<0.05). Coherence between LF oscillations in MSNA and RR was similar in the long-term HTRs (0.59±0.11) and the hypertensive patients (0.60±0.07) and was 3-fold greater than in the short-term HTRs (0.20±0.06,
P
<0.05).

Conclusions

Cardiac reinnervation after long-term heart transplantation is characterized by a restoration of the coherence between LF oscillations in RR and MSNA. Higher MSNA in long-term than in short-term HTRs suggests that time elapsed after cardiac transplantation may be a major determinant of sympathetic excitation in heart transplant recipients.
Expression of Neutrophil Collagenase (Matrix Metalloproteinase-8) in Human Atheroma
Authors: Herman Michael P. , Sukhova Galina K. , Libby Peter , Gerdes Norbert , Tang Nga , Horton Daniel B. , Kilbride Meagan , Breitbart Roger E. , Chun Miyoung , Schönbeck Uwe
Published: September 2007

Background

Loss of interstitial collagen, particularly type I collagen, the major load-bearing molecule of atherosclerotic plaques, renders atheroma prone to rupture. Initiation of collagen breakdown requires interstitial collagenases, a matrix metalloproteinase (MMP) subfamily consisting of MMP-1, MMP-8, and MMP-13. Previous work demonstrated the overexpression of MMP-1 and MMP-13 in human atheroma. However, no study has yet evaluated the expression of MMP-8, known as “neutrophil collagenase,” the enzyme that preferentially degrades type I collagen, because granulocytes do not localize in plaques.

Methods and Results

Transcriptional profiling and reverse transcription–polymerase chain reaction analysis revealed inducible expression of MMP-8 transcripts in CD40 ligand–stimulated mononuclear phagocytes. Western blot analysis demonstrated that 3 atheroma-associated cell types, namely, endothelial cells, smooth muscle cells, and mononuclear phagocytes, expressed MMP-8 in vitro upon stimulation with proinflammatory cytokines such as interleukin-1β, tumor necrosis factor-α, or CD40 ligand. MMP-8 protein elaborated from these atheroma-associated cell types migrated as 2 immunoreactive bands, corresponding to the molecular weights of the zymogen and the active molecule. Extracts from atherosclerotic, but not nondiseased arterial tissue, contained similar immunoreactive bands. Moreover, all 3 cell types expressed MMP-8 mRNA and protein in human atheroma in situ. Notably, MMP-8 colocalized with cleaved but not intact type I collagen within the shoulder region of the plaque, a frequent site of rupture.

Conclusions

These data point to MMP-8 as a previously unsuspected participant in collagen breakdown, an important determinant of the vulnerability of human atheroma.
Treatment of Isolated Systolic Hypertension Is Most Effective in Older Patients With High-Risk Profile
Authors: Ferrucci Luigi , Furberg Curt D. , Penninx Brenda W.J.H. , DiBari Mauro , Williamson Jeff D. , Guralnik Jack M. , Chen John G. , Applegate William B. , Pahor Marco
Published: September 2007

Background

Although present guidelines suggest that treatment of hypertension is more effective in patients with multiple risk factors and higher risk of cardiovascular events, this hypothesis was never verified in older patients with systolic hypertension.

Methods and Results

Using data from the Systolic Hypertension in the Elderly Program, we calculated the global cardiovascular risk score according to the American Heart Association Multiple Risk Factor Assessment Equation in 4,189 participants free of cardiovascular disease (CVD) and in 264 participants with CVD at baseline. In the placebo group, rates of cardiovascular events over 4.5 years were progressively higher according to higher quartiles of CVD risk. The protection conferred by treatment was similar across quartiles of risk. However, the numbers needed to treat (NNTs) to prevent one cardiovascular event were progressively smaller according to higher cardiovascular risk quartiles. In participants with baseline CVD, the NNTs to prevent one cardiovascular event were similar to those estimated for CVD-free participants in the highest-risk quartile.

Conclusions

Treatment of systolic hypertension is most effective in older patients who, because of additional risk factors or prevalent CVD, are at higher risk of developing a cardiovascular event. These patients are prime candidates for antihypertensive treatment.
Ionic Remodeling of Cardiac Purkinje Cells by Congestive Heart Failure
Authors: Han Wei , Chartier Denis , Li Danshi , Nattel Stanley
Published: September 2007

Background

Cardiac Purkinje cells (PCs) are important for the generation of triggered arrhythmias, particularly in association with abnormal repolarization. The effects of congestive heart failure (CHF) on the ionic properties of PCs are unknown.

Methods and Results

PCs were isolated from false tendons of control dogs and dogs with ventricular tachypacing-induced CHF. CHF PCs were hypertrophied (capacitance, mean±SEM, 149±4 pF, n=130; versus 128±3 pF, n=150, control;
P
<0.001). Transient outward current density was reduced in CHF PCs without change in voltage dependence or kinetics. CHF also reduced inward-rectifier current density, with no change in form of the current-voltage relationship. Densities of L- and T-type calcium, rapid and slow delayed rectifier, and Na
+
-Ca
2+
exchange currents were unaltered by CHF, but L-type calcium current inactivation was slowed at positive potentials. Purkinje fiber action potentials from CHF dogs showed decreased phase 1 amplitudes and elevated plateau voltages and demonstrated twice as much prolongation on exposure to the rapid delayed rectifier blocker E-4031 as control Purkinje fibers.

Conclusions

CHF causes remodeling of important K
+
and Ca
2+
currents in cardiac PCs, decreasing repolarization reserve and causing an exaggerated repolarization delay in response to a class III drug. These results have important potential implications regarding ventricular arrhythmogenesis, particularly related to triggered activity in PCs, in patients with CHF.
In Vivo Accuracy of Multispectral Magnetic Resonance Imaging for Identifying Lipid-Rich Necrotic Cores and Intraplaque Hemorrhage in Advanced Human Carotid Plaques
Authors: Yuan Chun , Mitsumori Lee M. , Ferguson Marina S. , Polissar Nayak L. , Echelard Denise , Ortiz Geraldo , Small Randy , Davies Joseph W. , Kerwin William S. , Hatsukami Thomas S.
Published: September 2007

Background

High-resolution MRI has been shown to be capable of identifying plaque constituents, such as the necrotic core and intraplaque hemorrhage, in human carotid atherosclerosis. The purpose of this study was to evaluate differential contrast-weighted images, specifically a multispectral MR technique, to improve the accuracy of identifying the lipid-rich necrotic core and acute intraplaque hemorrhage in vivo.

Methods and Results

Eighteen patients scheduled for carotid endarterectomy underwent a preoperative carotid MRI examination in a 1.5-T GE Signa scanner using a protocol that generated 4 contrast weightings (T1, T2, proton density, and 3D time of flight). MR images of the vessel wall were examined for the presence of a lipid-rich necrotic core and/or intraplaque hemorrhage. Ninety cross sections were compared with matched histological sections of the excised specimen in a double-blinded fashion. Overall accuracy (95% CI) of multispectral MRI was 87% (80% to 94%), sensitivity was 85% (78% to 92%), and specificity was 92% (86% to 98%). There was good agreement between MRI and histological findings, with a value of κ=0.69 (0.53 to 0.85).

Conclusions

Multispectral MRI can identify the lipid-rich necrotic core in human carotid atherosclerosis in vivo with high sensitivity and specificity. This MRI technique provides a noninvasive tool to study the pathogenesis and natural history of carotid atherosclerosis. Furthermore, it will permit a direct assessment of the effect of pharmacological therapy, such as aggressive lipid lowering, on plaque lipid composition.
Reducing Emotional Distress Improves Prognosis in Coronary Heart Disease
Authors: Denollet Johan , Brutsaert Dirk L.
Published: September 2007

Background

The impact of treating emotional distress on prognosis in coronary heart disease (CHD) has not been documented convincingly. We tested the hypothesis that treatment-related changes in emotional distress may explain the beneficial effect of rehabilitation on prognosis.

Methods and Results

In this nonrandomized clinical trial, 150 men with CHD participated in rehabilitation (n=78) or received standard medical care (n=72). There were no differences between rehabilitation and control patients with regard to left ventricular ejection fraction (LVEF) or standard care. End points were reduction in distress after 3 months and mortality after 9 years. At the end of the 3-month trial, 64 patients (43%) reported improvement and 22 (15%) reported deterioration in negative affect. Rehabilitation patients improved more (
P
=0.004) and deteriorated less (
P
=0.001) than control patients; rehabilitation was effective in reducing distress. After 9 years of follow-up, 15 patients had died (13 cardiac and 2 cancer deaths). Mortality was associated with LVEF ≤50% (
P
=0.038) and deterioration in negative affect (
P
=0.007). Rate of death was 17% (12/72) for control patients versus 4% (3/78) for rehabilitation patients (
P
=0.009); rehabilitation was effective in reducing mortality. LVEF ≤50% (OR 3.2; 95% CI 1.1 to 9.8;
P
=0.041) and rehabilitation (OR 0.2; 95% CI 0.1 to 0.7;
P
=0.016) were independent predictors of mortality. Rehabilitation warded off the deleterious effect of deterioration in negative affect on prognosis.

Conclusions

Deterioration in negative affect is associated with a high long-term mortality risk. Warding off deterioration in negative affect is a mechanism that may explain the beneficial effect of comprehensive rehabilitation on prognosis in patients with CHD.
Inhibition of Collagen Synthesis With Prolyl 4-Hydroxylase Inhibitor Improves Left Ventricular Function and Alters the Pattern of Left Ventricular Dilatation After Myocardial Infarction
Authors: Nwogu John I. , Geenen David , Bean Maurice , Brenner Mitchell C. , Huang Xinfan , Buttrick Peter M.
Published: September 2007

Background

Left ventricular (LV) remodeling after myocardial infarction (MI) is associated with fibrosis, dilatation, and dysfunction. We postulated that prevention of fibrosis after MI with a prolyl 4-hydroxylase inhibitor (P4HI) would preserve LV function and attenuate LV enlargement.

Methods and Results

Adult female rats (200 to 250 g) had experimental MI and were then randomized to treatment with P4HI (MI-FG041, n=29) or vehicle (MI-control, n=29) 48 hours after MI for 4 weeks in 2 phases. Echocardiograms were performed weekly with a 15-MHz linear transducer, and at 4 weeks, collagen isoform determinations and in vivo hemodynamics were performed. At randomization, the infarct size and LV function and size were similar in MI-FG041 and MI-control but significantly different from shams (n=9). At week 4, the LV function in MI-FG041 was significantly better than in MI-controls (fractional shortening 21% versus 16%,
P
=0.01; fractional area change 30% versus 19%,
P
=0.002; ejection fraction 35% versus 23%,
P
=0.001). In the FG041 group, LV area in systole was less (
P
<0.05), the dP/dt
max
after isoproterenol was higher (
P
<0.05), and types I and III collagen in noninfarcted LV were less than in MI-control. The hydroxyproline/proline ratio was increased by 64% in MI-control and reduced to the sham value in MI-FG041 rats. In the scar tissue, it was reduced by 24% in MI-FG041.

Conclusions

This study demonstrates that prevention of interstitial fibrosis with a P4H inhibitor alters the pattern of LV enlargement and produces partial recovery of LV function after MI.
Upregulation of Phosphodiesterase 1A1 Expression Is Associated With the Development of Nitrate Tolerance
Authors: Kim Dongsoo , Rybalkin Sergei D. , Pi Xinchun , Wang Yining , Zhang Changxi , Munzel Thomas , Beavo Joseph A. , Berk Bradford C. , Yan Chen
Published: September 2007

Background

The efficacy of nitroglycerin (NTG) as a vasodilator is limited by tolerance, which develops shortly after treatment begins. In vascular smooth muscle cells (VSMCs), NTG is denitrated to form nitric oxide (NO), which activates guanylyl cyclase and generates cGMP. cGMP plays a key role in nitrate-induced vasodilation by reducing intracellular Ca
2+
concentration. Therefore, one possible mechanism for development of nitrate tolerance would be increased activity of the cGMP phosphodiesterase (PDE), which decreases cGMP levels.

Methods and Results

To test this hypothesis, rats were made tolerant by continuous infusion of NTG for 3 days (10 μg · kg
−1
· min
−1
SC) with an osmotic pump. Analysis of PDE activities showed an increased function of Ca
2+
/calmodulin (CaM)–stimulated PDE (PDE1A1), which preferentially hydrolyzes cGMP after NTG treatment. Western blot analysis for the Ca
2+
/CaM-stimulated PDE revealed that PDE1A1 was increased 2.3-fold in NTG-tolerant rat aortas. Increased PDE1A1 was due to mRNA upregulation as measured by relative quantitative reverse transcription–polymerase chain reaction. The PDE1-specific inhibitor vinpocetine partially restored the sensitivity of the tolerant vasculature to subsequent NTG exposure. In cultured rat aortic VSMCs, angiotensin II (Ang II) increased PDE1A1 activity, and vinpocetine blocked the effect of Ang II on decrease in cGMP accumulation.

Conclusions

Induction of PDE1A1 in nitrate-tolerant vessels may be one mechanism by which NO/cGMP-mediated vasodilation is desensitized and Ca
2+
-mediated vasoconstriction is supersensitized. Inhibiting PDE1A1 expression and/or activity could be a novel therapeutic approach to limit nitrate tolerance.
Platelet Inhibition Reduces Cyclic Flow Variations and Neointimal Proliferation in Normal and Hypercholesterolemic-Atherosclerotic Canine Coronary Arteries
Authors: Anderson H. Vernon , McNatt Janice , Clubb Fred J. , Herman Michael , Maffrand Jean-Pierre , DeClerck Fred , Ahn Chul , Buja L. Maximilian , Willerson James T.
Published: September 2007

Background

Platelet-derived growth factors help stimulate the neointimal proliferation of restenosis after coronary interventions. Reducing platelet accumulation at treated sites may attenuate restenosis. We tested this hypothesis by inducing repetitive platelet aggregation at coronary angioplasty sites in dogs and measuring subsequent neointima formation.

Methods and Results

Cholesterol-sensitive dogs (n=74) received either 4% cholesterol-enriched diets for >8 months (n=29), creating visible atheromas, or normal canine diets (n=45). A coronary balloon angioplasty cyclic flow variation (CFV) model was used. One group of control dogs (group 1, n=8) had angioplasty with no arterial constriction applied and no drug treatment. Three other groups had arterial constrictors applied to provoke CFVs: group 2 (n=28) received no drug therapy, group 3 (n=18) received oral aspirin alone, and group 4 (n=20) received 3 oral antiplatelet agents: ridogrel, ketanserin, and clopidogrel (R+K+C) to simultaneously inhibit the thromboxane A
2
, serotonin, and ADP pathways of platelet aggregation, respectively. Bleeding times were moderately prolonged in the aspirin-treated group (124±9 seconds after 3 weeks versus 76±6 seconds at baseline,
P
<0.01) and greatly prolonged on R+K+C (>600 versus 104±5 seconds,
P
<0.001). The frequency and severity of CFVs were inversely related to the degree of platelet inhibition and prolongation of bleeding times, as was sudden death due to acute thrombotic coronary occlusion. Quantitative histology at 8 weeks revealed increased intima-to-media ratio with CFVs: 0.89±0.14 in the untreated group 2 versus 0.11±0.04 in the control group (
P
<0.001). Intima-to-media ratio was significantly reduced with antiplatelet treatment (0.27±0.05 with aspirin treatment and 0.20±0.05 with R+K+C treatment, respectively,
P
<0.001). Cholesterol feeding did not appear to influence results.

Conclusions

Repetitive platelet accumulation at coronary angioplasty sites caused enhanced neointimal proliferation by 8 weeks. Oral inhibitors of platelet aggregation attenuated platelet function, prolonged bleeding times, reduced or prevented cyclic flows and abrupt thrombotic occlusions, and thereby inhibited neointimal proliferation. Platelet inhibition should continue to receive attention in efforts to reduce restenosis after coronary interventions.
Inducible Nitric Oxide Synthase Inhibition of Weibel-Palade Body Release in Cardiac Transplant Rejection
Authors: Qian Zhiping , Gelzer-Bell Ramona , Yang Shui-xiang , Cao Wangsen , Ohnishi Tomokazu , Wasowska Barbara A. , Hruban Ralph H. , Rodriguez E. Rene , Baldwin William M. , Lowenstein Charles J.
Published: September 2007

Background

Inducible nitric oxide synthase (iNOS, or NOS2) reduces the severity of accelerated graft arteriosclerosis (AGA) in transplanted organs, although the precise mechanism is unclear.

Methods and Results

We transplanted wild-type murine hearts into either wild-type or NOS2-null recipient mice; we then measured cardiac allograft survival and analyzed tissue sections by immunohistochemistry. We have confirmed that NOS2 increases cardiac allograft survival. We now show that there is less inflammation of cardiac allografts in wild-type hosts than in NOS2-null hosts. Furthermore, staining for von Willebrand factor reveals that the presence of NOS2 is correlated with the presence of Weibel-Palade bodies inside endothelial cells, whereas the absence of NOS2 is correlated with the release of Weibel-Palade bodies.

Conclusions

Weibel-Palade bodies contain mediators that promote thrombosis and inflammation. Therefore, nitric oxide (NO) may stabilize the vessel wall and prevent endothelial activation in part by inhibiting the release of the contents of Weibel-Palade bodies. Prevention of Weibel-Palade body release might be a mechanism by which NO protects the vessel wall from inflammatory disorders such as atherosclerosis or graft arteriosclerosis.
n-3 Polyunsaturated Fatty Acids, Fish, and Nonfatal Acute Myocardial Infarction
Authors: Tavani Alessandra , Pelucchi Claudio , Negri Eva , Bertuzzi Michaela , La Vecchia Carlo
Published: September 2007

Background

The relation between n-3 polyunsaturated fatty acids (PUFAs), fish intake, and risk of coronary heart disease is controversial.

Methods and Results

An Italian case-control study including 507 patients with nonfatal acute myocardial infarction (AMI) and 478 hospital controls found a multivariate odds ratio (OR) of 0.67 (95% CI, 0.47 to 0.95) for the highest n-3 PUFA intake and 0.68 (95% CI, 0.47 to 0.98) for an intake of >1 portion of fish per week compared with ≥2 portions per week.

Conclusions

Small amounts of n-3 PUFAs may be inversely related to AMI risk in this low-risk population.
Low Plasma Levels of Vitamin B
6
Are Independently Associated With a Heightened Risk of Deep-Vein Thrombosis
Authors: Cattaneo M. , Lombardi R. , Lecchi A. , Bucciarelli P. , Mannucci P.M.
Published: September 2007

Background

Elevated plasma levels of total homocysteine (tHcy) before and after an oral methionine load (PML) are associated with an elevated risk of deep-vein thrombosis (DVT). We investigated whether plasma levels of B vitamins that are involved in Hcy metabolism are associated with an elevated risk of DVT.

Methods and Results

We compared 397 cases with previous DVT with 585 matched healthy controls. The plasma levels of folate, vitamin B
12
, vitamin B
6,
, and fasting and PML tHcy were measured. The ORs for DVT associated with high (>95th percentile) fasting levels and PML increases of tHcy were 2.1 (95% CI, 1.2 to 3.4) and 2.4 (95% CI, 1.5 to 3.9) after adjustment for established risk factors for DVT. Fasting plasma levels and PML increases in tHcy correlated negatively with vitamin levels. The crude OR for folate levels in the lowest quartile compared with the highest was 1.5 (95% CI, 1.1 to 2.1), and that for B
6
levels in the lowest and second quartiles compared with the highest was 1.5 (95% CI, 1.0 to 2.1). However, after adjustment for established risk factors and fasting and PML tHcy, the ORs for B
6
levels in the lowest and second quartiles only remained statistically significant (lowest quartile: OR, 1.8; 95% CI, 1.2 to 2.8; second quartile, OR, 1.9; 95% CI, 1.3 to 2.9).

Conclusions

High fasting and PML tHcy and low vitamin B
6
plasma levels are associated with an elevated risk for DVT independently of established risk factors for DVT. The association of low vitamin B
6
levels with the risk for DVT is independent of fasting and PML tHcy levels.
Augmentation of Cardiac Contractility Mediated by the Human β
3
-Adrenergic Receptor Overexpressed in the Hearts of Transgenic Mice
Authors: Kohout Trudy A. , Takaoka Hideyuki , McDonald Patricia H. , Perry Stephen J. , Mao Lan , Lefkowitz Robert J. , Rockman Howard A.
Published: September 2007

Background

Stimulation of β
1
- and β
2
-adrenergic receptors (ARs) in the heart results in positive inotropy. In contrast, it has been reported that the β
3
AR is also expressed in the human heart and that its stimulation leads to negative inotropic effects.

Methods and Results

To better understand the role of β
3
ARs in cardiac function, we generated transgenic mice with cardiac-specific overexpression of 330 fmol/mg protein of the human β
3
AR (TGβ
3
mice). Hemodynamic characterization was performed by cardiac catheterization in closed-chest anesthetized mice, by pressure-volume-loop analysis, and by echocardiography in conscious mice. After propranolol blockade of endogenous β
1
- and β
2
ARs, isoproterenol resulted in an increase in contractility in the TGβ
3
mice (30%), with no effect in wild-type mice. Similarly, stimulation with the selective human β
3
AR agonist L-755,507 significantly increased contractility in the TGβ
3
mice (160%), with no effect in wild-type mice, as determined by hemodynamic measurements and by end-systolic pressure-volume relations. The underlying mechanism of the positive inotropy incurred with L-755,507 in the TGβ
3
mice was investigated in terms of β
3
AR–G-protein coupling and adenylyl cyclase activation. Stimulation of cardiac membranes from TGβ
3
mice with L-755,507 resulted in a pertussis toxin–insensitive 1.33-fold increase in [
35
S]GTPγS loading and a 1.6-fold increase in adenylyl cyclase activity.

Conclusions

Cardiac overexpression of human β
3
ARs results in positive inotropy only on stimulation with a β
3
AR agonist. Overexpressed β
3
ARs couple to G
s
and activate adenylyl cyclase on agonist stimulation.
Elevating High-Density Lipoprotein Cholesterol in Apolipoprotein E-Deficient Mice Remodels Advanced Atherosclerotic Lesions by Decreasing Macrophage and Increasing Smooth Muscle Cell Content
Authors: Rong James X. , Li Jie , Reis Ernane D. , Choudhury Robin P. , Dansky Hayes M. , Elmalem Valerie I. , Fallon John T. , Breslow Jan L. , Fisher Edward A.
Published: September 2007

Background

HDL cholesterol levels are inversely correlated with coronary heart disease risk in humans, and in animal studies, HDL elevation decreases formation and progression of foam-cell lesions. The potential for HDL to affect preexisting advanced atherosclerotic lesions is not known. To approach this issue, we used a novel mouse aortic transplantation model.

Methods and Results

ApoE-deficient (EKO) mice were fed a Western-type diet for 6 months, and thoracic aortic segments containing advanced lesions replaced segments of the abdominal aorta of 4-month-old EKO syngeneic mice not expressing (plasma HDL cholesterol ≈26 mg/dL) or expressing (HDL ≈64 mg/dL) a human apoAI (hAI) transgene. Both types of recipients had comparable non-HDL cholesterol levels. Five months after transplantation, mice were killed and grafts analyzed. Compared with lesion area in pretransplant mice (0.14±0.04 mm
2
, mean±SEM), there was progression in the EKO recipients (0.39±0.06 mm
2
,
P
<0.01). Compared with EKO recipients, hAI/EKO recipients had retarded progression (0.24±0.04 mm
2
,
P
<0.05). Immunostaining for CD68 and other macrophage-associated proteins, monocyte chemoattractant protein-1, acyl coenzyme A:cholesterol acyltransferase, and tissue factor, in lesions of pretransplant and EKO recipient mice showed abundant macrophages. In contrast, compared with any other group, lesional macrophage area in hAI/EKO mice decreased >80% (
P
<0.003), and smooth muscle cell content (α-actin staining) increased >300% (
P
<0.006). The decrease in macrophages and increase in smooth muscle cells was primarily in the superficial subendothelial layer.

Conclusions

Increasing HDL cholesterol levels in EKO mice retards progression of advanced atherosclerotic lesions and remodels them to a more stable-appearing phenotype.
Limits of Detection of Regional Differences in Vasodilated Flow in Viable Myocardium by First-Pass Magnetic Resonance Perfusion Imaging
Authors: Klocke Francis J. , Simonetti Orlando P. , Judd Robert M. , Kim Raymond J. , Harris Kathleen R. , Hedjbeli Sascha , Fieno David S. , Miller Stephan , Chen Vicky , Parker Michele A.
Published: September 2007

Background

Perfusion imaging techniques intended to identify regional limitations in coronary flow reserve in viable myocardium need to identify 2-fold differences in regional flow during coronary vasodilation consistently. This study evaluated the suitability of current first-pass magnetic resonance approaches for evaluating such differences, which are 1 to 2 orders of magnitude less than in myocardial infarction.

Methods and Results

Graded regional differences in vasodilated flow were produced in chronically instrumented dogs with either left circumflex (LCx) infusion of adenosine or partial LCx occlusion during global coronary vasodilation. First-pass myocardial signal intensity-time curves were obtained after right atrial injection of gadoteridol (0.025 mmol/kg) with an MRI inversion recovery true-FISP sequence. The area under the initial portion of the LCx curve was compared with that of a curve from a remote area of the ventricle. Relative LCx and remote flows were assessed simultaneously with microspheres. The ratio of LCx and remote MRI curve areas and the ratio of LCx and remote microsphere concentrations were highly correlated and linearly related over a 5-fold range of flow differences (
y
=0.96
x
±0.07,
P
<0.0001,
r
2
=0.87). The 95% confidence limits for individual MRI measurements were ±35%. Regional differences of ≥2-fold were consistently apparent in unprocessed MR images.

Conclusions

Clinically relevant regional reductions in vasodilated flow in viable myocardium can be detected with 95% confidence over the range of 1 to 5 times resting flow. This suggests that MRI can identify and quantify limitations in perfusion reserve that are expected to be produced by stenoses of ≥70%.