bluuebunny/crossref_metadata_2025 huggingface dataset:
Use of a Blood Substitute to Determine Instantaneous Murine Right Ventricular Thickening With Optical Coherence Tomography
Authors: Villard Joseph W. , Feldman Marc D. , Kim Jeehyun , Milner Thomas E. , Freeman Gregory L.
Published: July 2002

Background
—

A satisfactory imaging technique to determine regional wall thickening of the murine myocardium is not available. Although cardiovascular imaging with light offers a novel solution, application is problematic because scattering by erythrocytes causes significant optical attenuation.

Methods and Results
—

Optical coherence tomography (OCT) is a technique for detailed resolution imaging of highly scattering biological tissues. To reduce the high level of blood scattering, a method was devised whereby murine blood was replaced with a hemoglobin-based blood substitute. The scattering and absorption properties of in vitro preparations of whole blood and dilutions of blood with a blood substitute were determined with a spectrophotometer and an inverse-adding doubling algorithm. OCT imaging of the same dilutions demonstrated a significant reduction in scattering at a hematocrit <5%. A fiber-optic OCT imaging system was used to image the murine right midventricular free wall before and after isovolumic replacement with blood substitute. Strong light attenuation prevented full thickness imaging before replacement, whereas visualization of the full ventricular thickness was possible after replacement. Baseline and imaging hematocrits were 52.4±3.8% and 3.7±1.2%, respectively. End-systolic and end-diastolic thickness values were 0.458±0.051 mm and 0.352±0.047 mm. Percent thickening fraction was 30.8± 7.5%.

Conclusion
—

Optical imaging of the intact beating murine right ventricle was substantially improved by isovolumic blood replacement with a hemoglobin-based blood substitute. Although the current study has been directed toward imaging the murine heart, a blood substitute may be applied to various optical diagnostic and therapeutic techniques under investigation in cardiovascular medicine.
Myocardial Fibrosis in Chronic Aortic Regurgitation
Authors: Borer Jeffrey S. , Truter Sharada , Herrold Edmund M. , Falcone Domenick J. , Pena Magda , Carter John N. , Dumlao Themy F. , Lee Jennifer A. , Supino Phyllis G.
Published: July 2002

Background
—

Myocardial fibrosis is common in patients with chronic aortic regurgitation (AR). Experimentally, fibrosis with disproportionate noncollagen extracellular matrix (ECM) elements precedes and contributes to heart failure in AR.

Method and Results
—

We assessed [
3
H]-glucosamine and [
3
H]-proline incorporation in ECM, variations in cardiac fibroblast (CF) gene expression, and synthesis of specific ECM proteins in CF cultured from rabbits with surgically induced chronic AR versus controls. To determine whether these variations are primary responses to AR, normal CF were exposed to mechanical strain that mimicked that of AR. Compared with normal CF, AR CF incorporated more glucosamine (1.8:1,
P
=0.001) into ECM, showed fibronectin gene upregulation (2.0:1,
P
=0.02), and synthesized more fibronectin (2:1 by Western blot,
P
<0.06; 1.5:1 by affinity chromatography,
P
=0.02). Proline incorporation was unchanged by AR (1.1:1, NS); collagen synthesis was unaffected (type I, 0.9:1; type III, 1.0:1, NS). Normal CF exposed to cyclical mechanical strain during culture showed parallel results: glucosamine incorporation increased with strain (2.1:1,
P
<0.001), proline incorporation was unaffected (1.1:1, NS), fibronectin gene expression (1.6:1,
P
=0.07) and fibronectin synthesis (Western analysis, 1.3:1,
P
<0.01; chromatography, 1.9:1, NS) were upregulated.

Conclusions
—

In AR, CF produce abnormal proportions of noncollagen ECM, specifically fibronectin, with relatively little change in collagen synthesis. At least in part, this is a primary response to strain imposed on CF by AR. Further study must relate these findings to the pathogenesis of heart failure in AR.
NADPH Oxidase Mediates Tissue Factor–Dependent Surface Procoagulant Activity by Thrombin in Human Vascular Smooth Muscle Cells
Authors: Herkert Olaf , Diebold Isabel , Brandes Ralf P. , Hess John , Busse Rudi , Görlach Agnes
Published: July 2002

Background

—

Tissue factor (TF) initiates the extrinsic coagulation cascade leading to thrombin formation. Thrombin induces TF mRNA in vascular smooth muscle cells (VSMCs), thereby contributing to the prolonged procoagulant activity and enhanced thrombogenicity at sites of vascular injury. However, the signaling mechanisms mediating this thrombogenic cycle are unclear. Characteristically, vascular injury promotes the generation of reactive oxygen species (ROS). Because ROS exert signaling functions, we investigated whether the NADPH oxidase, an important source of ROS in VSMCs, contributes to upregulation of TF by thrombin.

Methods and Results

—

Thrombin not only stimulated TF mRNA expression, but also TF-dependent surface procoagulant activity in cultured human VSMCs. This response was attenuated by antioxidants; the flavin inhibitor diphenylene-iodonium,
Clostridium difficile
toxin B, which inhibits Rho GTPases, p22phox antisense oligonucleotides, or the dominant-negative RacT17N mutant. Inhibitors of p38 MAP kinase and phosphatidylinositol (PI) 3-kinase also prevented thrombin-stimulated TF mRNA expression. Furthermore, thrombin stimulated the phosphorylation of the PI 3-kinase target protein kinase B/Akt in a redox-sensitive and NADPH oxidase–dependent manner.

Conclusion

—

These findings indicate that the NADPH oxidase is essentially involved in the redox-sensitive induction of TF mRNA expression and surface procoagulant activity by thrombin. This response is mediated by NADPH oxidase–dependent activation of p38 MAP kinase and the PI 3-kinase/protein kinase B/Akt pathway. Given that active TF promotes thrombin formation, the NADPH oxidase may play a crucial role in perpetuating the thrombogenic cycle in the injured vessel wall.
Quantification of Left Ventricular Systolic Function by Tissue Doppler Echocardiography
Authors: Edvardsen Thor , Urheim Stig , Skulstad Helge , Steine Kjetil , Ihlen Halfdan , Smiseth Otto A.
Published: July 2002

Background

—

Tissue Doppler imaging (TDI) is a potentially powerful method for diagnosing myocardial ischemia. This study was designed to investigate how velocity patterns in ischemic myocardium relates to regional function, and to determine whether timing of velocity measurements relative to ejection and isovolumic phases may increase the diagnostic power of TDI.

Methods and Results

—

In 17 open-chest anesthetized dogs we measured pressures by micromanometers, myocardial longitudinal segment lengths by sonomicrometry, and velocities by TDI. Myocardial longitudinal strain rate was calculated as velocity divided by distance to the left ventricle apex. Moderate ischemia (left anterior descending coronary artery stenosis) caused parallel reductions in regional systolic shortening by sonomicrometry (
P
<0.05) and in peak systolic velocities by TDI (
P
<0.05). Severe ischemia (left anterior descending coronary artery occlusion), however, induced systolic lengthening by sonomicrometry (
P
<0.001), whereas peak TDI velocity during ejection remained positive (
P
<0.05). When velocities during isovolumic contraction (IVC) and isovolumic relaxation (IVR) were included, TDI correlated well with sonomicrometry; ie, systolic lengthening occurred predominantly during IVC and was evident as negative velocities (
r
=0.70,
P
<0.001), and postsystolic shortening during IVR (
r
=0.72,
P
<0.001) as positive velocities. In nonischemic myocardium peak systolic strain rates were more uniform than velocities.

Conclusion

—

The present results indicate that peak ejection velocity is an inappropriate measure of function in severely ischemic myocardium. Dyskinetic myocardium deforms predominantly during the isovolumic phases, and therefore IVC and IVR velocities are better markers of function. When isovolumic as well as ejection velocities are measured, TDI has excellent ability to quantify regional myocardial dysfunction. Longitudinal strain rates are more uniform than velocities and may further improve the diagnostic power of TDI.
Angiotensinogen Genotype Affects Renal and Adrenal Responses to Angiotensin II in Essential Hypertension
Authors: Hopkins Paul N. , Hunt Steven C. , Jeunemaitre Xavier , Smith Barbara , Solorio Daniel , Fisher Naomi D.L. , Hollenberg Norman K. , Williams Gordon H.
Published: July 2002

Background

—

Renovascular and adrenal responses to infused angiotensin II (Ang II) are intermediate phenotypes that may indirectly reflect tissue renin-angiotensin system activity. We examine herein angiotensinogen (
AGT
) as a candidate gene to help elucidate potential mechanisms for previously reported
AGT
linkage and association studies.

Methods and Results

—

Renal plasma flow and plasma aldosterone were measured before and after a 45-minute infusion of Ang II (3 ng · kg
−1
· min
−1
) in 190 hypertensive patients who were on carefully controlled high- and low-salt diets. Reduced renal vascular (
P
=0.0002) and adrenal (
P
=0.002) responses to infused exogenous Ang II were associated with the
AGT
−6A allele. In multiple logistic regression, greater body mass index, lower basal renal plasma flow, and higher diastolic blood pressure together with
AGT
−6A genotype were associated with lower renal vascular response. In contrast, only male sex and
AGT
−6A genotype were associated with lower adrenal response. When both the renal and adrenal responses to Ang II were in the lowest tertile, the
AGT
−6AA genotype was present in 55.6%; in contrast, when both responses were in the upper 2 tertiles, the −6AA genotype was present in only 17.8% (
P
=0.001).

Conclusions

—

A clear association between
AGT
genotype and response to infused Ang II was demonstrated for both the renal vasculature and the adrenal, consistent with the hypothesis that the
AGT
−6A genotype results in increased tissue expression of angiotensinogen and Ang II.
Differential Influence of Diabetes Mellitus on Increased Jeopardized Myocardium After Initial Angioplasty or Bypass Surgery
Authors: Kip Kevin E. , Alderman Edwin L. , Bourassa Martial G. , Brooks Maria Mori , Schwartz Leonard , Holmes David R. , Califf Robert M. , Whitlow Patrick L. , Chaitman Bernard R. , Detre Katherine M.
Published: July 2002

Background

—

Data are absent that compare midterm angiographic outcome between patients with and without diabetes after initial percutaneous transluminal coronary angioplasty (PTCA) and coronary artery bypass graft surgery (CABG). Importantly, diabetes mellitus may differentially influence long-term survival after PTCA or CABG.

Methods and Results

—

Patients with multivessel coronary disease who were previously enrolled in the Bypass Angiopathy Revascularization Investigation to compare initial PTCA versus CABG (n=1829) and who had a reduction in jeopardized myocardium after initial revascularization and at least 1 angiogram during 5-year follow-up were analyzed (n=897). This included 369 CABG-treated patients (16% with diabetes) and 528 PTCA-treated patients (18% with diabetes). The influence of diabetes on angiographic increase in percentage of jeopardized myocardium after initial revascularization with either PTCA or CABG was investigated. Among PTCA patients, the mean percentage increase in total jeopardized myocardium was significantly greater in those with diabetes than in those without at 1-year protocol-directed angiography (42% versus 24%,
P
=0.05) and on the first clinically performed (unscheduled) angiogram within 30 months (63% versus 50%,
P
=0.01) but not at 5-year protocol-directed angiography (34% versus 26%,
P
=0.33). This excess midterm risk associated with diabetes persisted after statistical adjustment. In contrast, among CABG patients, diabetes was not associated with percentage increase in jeopardized myocardium at any angiographic follow-up interval.

Conclusions

—

Presence of diabetes differentially influences worsening of jeopardized myocardium after initial PTCA compared with CABG. This differential effect occurs irrespective of whether follow-up angiography is undertaken for clinical or nonclinical purposes.
Accelerated Reendothelialization With Suppressed Thrombogenic Property and Neointimal Hyperplasia of Rabbit Jugular Vein Grafts by Adenovirus-Mediated Gene Transfer of C-Type Natriuretic Peptide
Authors: Ohno N. , Itoh H. , Ikeda T. , Ueyama K. , Yamahara K. , Doi K. , Yamashita J. , Inoue M. , Masatsugu K. , Sawada N. , Fukunaga Y. , Sakaguchi S. , Sone M. , Yurugi T. , Kook H. , Komeda M. , Nakao K.
Published: July 2002

Background

—

Vein graft disease limits the late results of coronary revascularization. C-type natriuretic peptide (CNP) inhibits the growth of vascular smooth muscle cells. Given the effects of CNP on cGMP cascade, we hypothesized that transfected
CNP
genes modulate endothelial repair and thrombogenicity in the vein graft.

Methods and Results

—

Autologous rabbit jugular vein grafts were incubated ex vivo in a solution of adenovirus vectors containing
CNP
gene (
Ad.CNP
) or
Escherichia coli lac Z
gene (
Ad.LacZ
) and then interposed in the carotid artery. Reendothelialization, mural thrombi formation, and intima/media ratio were evaluated on the 14th and 28th postoperative days. More reendothelialization was seen in
Ad.CNP
-infected grafts than in
Ad.LacZ
-infected grafts both at 14 days (0.81±0.05 versus 0.30±0.14,
P
<0.01) and at 28 days (0.96±0.01 versus 0.45±0.08,
P
<0.001). The mural thrombus area was smaller in
Ad.CNP
-infected grafts than in
Ad.LacZ
-infected grafts. Neointimal thickening was significantly suppressed in the
Ad.CNP
group. The in vitro wound assay with human coronary artery endothelial cells revealed significant potentiation of the wound repair process by CNP and atrial natriuretic peptide administration.

Conclusions

—

Infected
Ad.CNP
accelerated reendothelialization and suppressed thrombosis and neointimal hyperplasia. The method may potentially prevent vein graft disease in patients undergoing coronary artery revascularization.
Cardiovascular Aging Is Associated With Vitamin E Increase
Authors: van der Loo Bernd , Labugger Ralf , Aebischer Claude P. , Skepper Jeremy N. , Bachschmid Markus , Spitzer Volker , Kilo Juliane , Altwegg Lukas , Ullrich Volker , Lüscher Thomas F.
Published: July 2002

Background

—

Aging is an independent risk factor for the development of cardiovascular disease. Therefore, therapies to delay vascular aging may have enormous medical consequences. In this context, vitamin E is of particular interest, mainly because of its antioxidative properties.

Methods and Results

—

In 3-year-old rats, which are not susceptible to atherosclerosis, vitamin E levels, as measured by reversed-phase high-performance liquid chromatography, were markedly increased both in plasma and in major organs (
P
<0.01 to
P
<0.0001). The highest increase (at least 70-fold) was found in the aortic wall.

Conclusions

—

This unexpected accumulation of vitamin E appears to be a compensatory mechanism that attempts to counterbalance age-associated oxidative stress and that may represent a self-regulatory protective adaptation.
Characterization of Reentrant Circuits in Left Atrial Macroreentrant Tachycardia
Authors: Ouyang Feifan , Ernst Sabine , Vogtmann Thomas , Goya Masahiko , Volkmer Marius , Schaumann Anselm , Bänsch Dietmar , Antz Matthias , Kuck Karl-Heinz
Published: July 2002

Background

—

Left atrial macroreentrant tachycardia (LAMRT) has not been characterized in detail.

Methods and Results

—

Twenty-eight patients with LAMRT, including 4 patients with ablated typical atrial flutter (AFL), underwent electroanatomic mapping of the left atrium (LA) between February 1999 and October 2001. LA maps were performed during LAMRT in 26 patients and during sinus rhythm in 2 patients. Electrically silent areas or continuous lines of double potentials were identified as acquired anatomic barriers in all patients. In 23 of 26 patients with LAMRT mapping, 42 reentry circuits with a protected isthmus were identified. The isthmus was 11.8±5.9 mm wide, with the maximal amplitude of 0.07 to 3.61 mV. Radiofrequency pulses terminated all LAMRTs in 23 patients and resulted in conduction block across the isthmus in 20 patients. In 2 patients with sinus mapping, all identified isthmuses were ablated. Additionally, AFL was induced and ablated in 6 patients. Atrial tachycardia recurred in 4 patients: 3 patients without validated block across the isthmus presented with recurrence of the same LAMRT, and 1 patient without ablated cavotricuspid isthmus presented with AFL. All tachycardias were abolished during a second procedure. Of 25 patients with identified isthmuses, 20 patients were without atrial arrhythmia and 5 had only atrial fibrillation during a median follow-up of 14 months.

Conclusion

—

The reentry circuit with a protected isthmus can be identified in 89% patients with LAMRT by electroanatomic mapping. The isthmuses were amenable to radiofrequency applications in most patients. No atrial tachycardia recurred in any patients with isthmus block.
Multimarker Approach to Risk Stratification in Non-ST Elevation Acute Coronary Syndromes
Authors: Sabatine Marc S. , Morrow David A. , de Lemos James A. , Gibson C. Michael , Murphy Sabina A. , Rifai Nader , McCabe Carolyn , Antman Elliott M. , Cannon Christopher P. , Braunwald Eugene
Published: July 2002

Background
—

In patients with acute coronary syndromes (ACS), troponin I (TnI), C-reactive protein (CRP), and B-type natriuretic peptide (BNP) each predict adverse cardiac events. Little is known, however, about the utility of these biomarkers in combination.

Methods and Results
—

Baseline measurements of TnI, CRP, and BNP were performed in 450 patients in OPUS-TIMI 16. Elevations in TnI, CRP, and BNP each were independent predictors of the composite of death, myocardial infarction (MI), or congestive heart failure (CHF). When patients were categorized on the basis of the number of elevated biomarkers at presentation, there was a near doubling of the mortality risk for each additional biomarker that was elevated (
P
=0.01). Similar relationships existed for the endpoints of MI, CHF, and the composite, both at 30 days and through 10 months. In a validation cohort of 1635 patients in TACTICS-TIMI 18, the number of elevated biomarkers remained a significant predictor of the composite endpoint after adjustment for known clinical predictors: patients with one, two, and three elevated biomarkers had a 2.1- (
P
=0.006), 3.1- (
P
<0.001), and 3.7- (
P
=0.001) fold increase in the risk of death, MI, or CHF by 6 months.

Conclusions
—

Troponin, CRP, and BNP each provide unique prognostic information in patients with ACS. A simple multimarker strategy that categorizes patients based on the number of elevated biomarkers at presentation allows risk stratification over a broad range of short- and long-term major cardiac events.
Statin Prevents Tissue Factor Expression in Human Endothelial Cells
Authors: Eto Masato , Kozai Toshiyuki , Cosentino Francesco , Joch Hana , Lüscher Thomas F.
Published: July 2002

Background
—

Tissue factor plays a pivotal role in thrombus formation in acute coronary syndromes. However, the regulatory mechanisms underlying tissue factor expression are poorly understood. Statins are effective in patients with acute coronary syndromes. Hence, the aim of this study was to clarify in human endothelial cells the signaling pathways of thrombin-induced tissue factor expression and potential inhibitory effects of statins.

Methods and Results
—

In human aortic endothelial cells, simvastatin prevented tissue factor induction by thrombin (4 U/mL) in a concentration-dependent manner. The increase in tissue factor activity on the cell surface was also blocked by simvastatin. Simvastatin also prevented the upregulation of tissue factor expression and activity in human aortic smooth muscle cells. Mevalonate (100 μmol/L) reversed the inhibitory effect of simvastatin on tissue factor expression. Thrombin induced rapid activation of Rho A and p38 MAP kinase. The Rho-kinase inhibitor Y-27632 and the p38 MAP kinase inhibitor SB203580 prevented tissue factor induction. Akt was dephosphorylated by thrombin; the phosphoinositol 3-kinase inhibitor wortmannin enhanced its dephosphorylation as well as thrombin-induced tissue factor expression. Simvastatin prevented thrombin-induced Rho A activation but not p38 MAP kinase activation. Akt dephosphorylation by thrombin was blocked by both simvastatin and Y-27632.

Conclusions
—

Endothelial tissue factor induction by thrombin is regulated by Rho/Rho-kinase, Akt, and p38 MAP kinase. Simvastatin prevents its induction through inhibition of Rho/Rho-kinase and activation of Akt. These findings provide new insights into the action of statins in acute coronary syndromes.
Noninvasive Imaging of Myocardial Reperfusion Injury Using Leukocyte-Targeted Contrast Echocardiography
Authors: Christiansen Jonathan P. , Leong-Poi Howard , Klibanov Alexander L. , Kaul Sanjiv , Lindner Jonathan R.
Published: July 2002

Background
—

We hypothesized that myocardial contrast echocardiography (MCE) with leukocyte-targeted microbubbles could temporally and spatially characterize the severity of postischemic myocardial inflammation.

Methods and Results
—

In 9 open-chest dogs, either the left anterior descending or left circumflex coronary artery was occluded for 90 minutes (n=6), while the remaining dogs served as non-ischemic controls. During occlusion, MCE was performed to determine the risk area (RA) and regions supplied by collateral flow. Myocardial inflammation was assessed 5, 60, and 120 minutes after reflow by MCE imaging of leukocyte-targeted (phosphatidylserine-containing) lipid microbubbles. The spatial extent and severity of inflammation were also assessed by radionuclide imaging of the neutrophil-avid tracer
99m
TcRP517 and tissue myeloperoxidase activity. Early after reflow, MCE detected inflammation throughout the entire risk area, the extent of which decreased over time due to reduced signal in collateral-supplied regions. The spatial extent of inflammation late after reflow was similar for MCE and radionuclide imaging. The severity of inflammation in the infarct zone, the noninfarcted risk area, and collateral-supplied territories determined by quantitative MCE correlated well with myeloperoxidase activity (
r
=0.81).

Conclusions
—

MCE with leukocyte-targeted microbubbles can temporally assess the severity and extent of postischemic myocardial inflammation and could be used to evaluate new treatment strategies designed to limit inflammation in acute coronary syndromes.
Cost-Effectiveness of the Implantable Cardioverter-Defibrillator Versus Antiarrhythmic Drugs in Survivors of Serious Ventricular Tachyarrhythmias
Authors: Larsen Greg , Hallstrom Alfred , McAnulty John , Pinski Sergio , Olarte Anna , Sullivan Sean , Brodsky Michael , Powell Judy , Marchant Christy , Jennings Cheryl , Akiyama Toshio ,   the AVID Investigators
Published: July 2002

Background

—

The implantable cardioverter-defibrillator (ICD) is an effective but expensive device. We used prospectively collected data from a large randomized clinical trial of secondary prevention of life-threatening ventricular arrhythmias to determine the cost-effectiveness of the ICD compared with antiarrhythmic drug (AAD) therapy, largely with amiodarone.

Methods and Results

—

Charges for initial and repeat hospitalizations, emergency room, and day surgery stays and the costs of antiarrhythmic drugs were collected on 1008 patients. Detailed records of all other medical encounters and expenses were collected on a subgroup of 237 patients. Regression models were then created to attribute these expenses to the rest of the patients. Charges were converted to 1997 costs using standard methods. Costs and life years were discounted at 3% per year. Three-year survival data from the Antiarrhythmics Versus Implantable Defibrillators trail were used to calculate the base-case cost-effectiveness (C/E) ratio. Six-year, twenty-year, and lifetime C/E ratios were also estimated. At 3 years, total costs were $71 421 for a patient taking AADs and $85 522 for a patient using an ICD, and the ICD provided a 0.21-year survival benefit over AAD treatment. The base-case C/E ratio was thus $66 677 per year of life saved by the ICD compared with AAD therapy (95% CI, $30 761 to $154 768). Six- and 20-year C/E ratios remained stable between $68 000 and $80 000 per year of life saved.

Conclusions

—

The ICD is moderately cost-effective for secondary prevention of life-threatening ventricular arrhythmias, as judged from prospectively collected data in a randomized clinical trial.
Anisotropic Conduction Properties in Canine Atria Analyzed by High-Resolution Optical Mapping
Authors: Koura Takahiro , Hara Motoki , Takeuchi Susumu , Ota Kenichi , Okada Yasumasa , Miyoshi Shunichiro , Watanabe Atsushi , Shiraiwa Kazumi , Mitamura Hideo , Kodama Itsuo , Ogawa Satoshi
Published: July 2002

Background

—

Anisotropic conduction properties may provide a substrate for reentrant arrhythmias. We investigated the age-dependent changes of structural and functional anisotropy in isolated right atria from infant (1 to 2 months), young (6 to 12 months), and old (6 to 10 years) dogs.

Methods and Results

—

The histology of the mapped atrial tissues (a small subepicardial area, 2.8×4.2 mm) was characterized by an age-dependent increase of myofiber width and fat cell infiltration between myofibers. Cx43 was distributed homogeneously over the entire cell surface in infant dogs, whereas it progressively polarized to the cell termini with increasing age. The activation sequences were analyzed by high-resolution optical mapping using a voltage-sensitive dye. Activation fronts from the pacing site proceeded more rapidly along fiber orientation (longitudinal) than across it (transverse). Infant dogs showed “elliptical” isochrones with a smooth transition between longitudinal and transverse propagation, whereas old dogs had a “square” pattern with a sharp transition. Conduction block occurred predominantly during longitudinal propagation in infant dogs but during transverse propagation in old dogs. The shape of the wave front and the degree of lateral uncoupling seemed to decide the preferential direction of block. A zigzag activation causing an extremely slow transverse conduction was observed only in old dogs.

Conclusions

—

Along with the age-dependent structural anisotropy, the preferential direction of block changed from longitudinal to transverse in association with a change in the wave front configuration. A zigzag propagation based on lateral uncoupling would predispose the elderly to multiple reentry and a higher incidence of atrial fibrillation.
Cardiac Membrane Fatty Acid Composition Modulates Myocardial Oxygen Consumption and Postischemic Recovery of Contractile Function
Authors: Pepe Salvatore , McLennan Peter L.
Published: July 2002

Background

—

Regular fish consumption is associated with low cardiovascular disease morbidity and mortality. Fish oils modify cardiac membrane phospholipid fatty acid composition with potent antiarrhythmic effects. We tested the effects of dietary fish oil on ventricular hemodynamics and myocardial oxygen consumption (MVO
2
).

Methods and Results

—

Male Wistar rats were fed for 16 weeks on a reference diet rich in
n
-6 polyunsaturated fatty acids (PUFA), a diet rich in saturated animal fat (SAT), or a diet rich in
n
-3 PUFA from fish oil. Isolated working hearts were perfused with porcine erythrocytes (40% hematocrit) at 75 mm Hg afterload with variable preload (5 to 20 mm Hg) or with low coronary flow ischemia with maintained afterload, preload, and heart rate, then reperfused. MVO
2
was low and coronary perfusion reserve high in
n
-3 PUFA hearts, and cardiac output increased with workload. The
n
-3 PUFA reduced ischemic markers—acidosis, K
+
, lactate, and creatine kinase—and increased contractile recovery during reperfusion. SAT hearts had high MVO
2
, low coronary perfusion reserve, and poor contractile function and recovery. Dietary differences in MVO
2
were abolished by KCl arrest (basal metabolism) or ruthenium red (3.4 μmol/L) but not by ryanodine (1 nmol/L). Fish oil or ryanodine, but not ruthenium red, prevented ventricular fibrillation in reperfusion.

Conclusions

—

Dietary fish oil directly influenced heart function and improved cardiac responses to ischemia and reperfusion. The
n
-3 PUFA reduced oxygen consumption at any given work output and increased postischemic recovery. Thus, direct effects on myocardial function may contribute to the altered cardiovascular disease profile associated with fish consumption.
Importance of NAD(P)H Oxidase–Mediated Oxidative Stress and Contractile Type Smooth Muscle Myosin Heavy Chain SM2 at the Early Stage of Atherosclerosis
Authors: Itoh Shinichi , Umemoto Seiji , Hiromoto Mitsuyuki , Toma Yoichi , Tomochika Yasuaki , Aoyagi Shumpei , Tanaka Masakazu , Fujii Takashi , Matsuzaki Masunori
Published: July 2002

Background

—

Increased vascular oxidative stress induced by hyperlipidemia may alter the phenotype of vascular smooth muscle (SM) cells and play a crucial role in the progression of atherosclerosis. To clarify the mechanisms underlying vascular dysfunction and oxidative stress in hypercholesterolemia, we compared the effects of antioxidant probucol with those of pravastatin on aortic stiffness, phenotypic modulation, oxidative stress, and NAD(P)H oxidase essential subunit p22
phox
expression in aortic medial SM cells of cholesterol-fed rabbits by using color image analysis of immunostained sections.

Methods and Results

—

Japanese white male rabbits were fed either normal chow or 1% cholesterol diet for 14 weeks. After the first 7 weeks, cholesterol-fed rabbits were further divided into 3 groups: those fed with cholesterol feed only and those additionally given pravastatin (10 mg/d) or probucol (1.3 g/d) for the last 7 weeks. Within 7 weeks of treatment, probucol improved aortic stiffness more effectively than did pravastatin, inhibiting phenotypic modulation by selectively upregulating contractile-type SM myosin heavy chain isoform SM2 and by reducing both p22
phox
and superoxide content in medial SM cells of cholesterol-fed rabbit aorta. No significant differences in cholesterol levels, superoxide content, and endothelial NO synthase levels in the intima, aortic morphology and fibrosis, and synthetic-type myosin heavy chain in medial SM cells were observed between the 2 drug-treated groups.

Conclusions

—

These results suggest that oxidative stress and SM2 in medial SM cells might be important factors for vascular dysfunction, and strategies aimed at blocking NAD(P)H oxidase and upregulating SM2 may have therapeutic potential against the progression of atherosclerosis in hypercholesterolemia.
Increased Platelet Binding to Circulating Monocytes in Acute Coronary Syndromes
Authors: Sarma Jaydeep , Laan Caterina A. , Alam Shirjel , Jha Ashwani , Fox Keith A.A. , Dransfield Ian
Published: July 2002

Background

—

Present therapies for acute coronary syndromes aim toward limiting platelet–platelet adhesion and aggregation processes. However, platelet–leukocyte interactions may contribute importantly to disease progression in the arterial wall. Recent studies suggest that prevention of platelet–leukocyte binding via P-selectin glycoprotein ligand-1 (PSGL-1) may be beneficial in animal models of vascular injury.

Methods and Results

—

P-selectin–PSGL-1 interactions were found to account for most platelet–monocyte binding observed in peripheral blood samples from healthy donors. However, a significant component of observed adhesion was calcium independent, involving neither PSGL-1 nor P-selectin. Platelet–monocyte interactions were examined in 52 patients admitted within 14 hours of symptom onset, with acute coronary syndromes defined as unstable angina (n=12) and acute myocardial infarction (n=13) or noncardiac chest pain (n=27). When compared with patients with noncardiac chest pain, significantly elevated levels of platelet–monocyte binding were found in patients with acute myocardial infarction (70.1±15.4% versus 45.4±23.3%;
P
<0.01) and unstable angina (67.4±12.9% versus 45.4±23.3%;
P
>0.01). Calcium-independent platelet–monocyte binding was significantly elevated in myocardial infarction patients alone (14.7±7.7% versus 6.1±5.96%;
P
<0.001).

Conclusions

—

There is evidence for a significant P-selectin–independent molecular component to the platelet–monocyte conjugation observed in peripheral blood. Patients with myocardial infarction and unstable angina demonstrate increased total binding of platelets to monocytes. Additionally, calcium-independent adhesion was significantly elevated in patients with evidence of myocardial infarction. These findings demonstrate that novel cation-independent adhesion mechanisms may mediate platelet–monocyte binding, representing a new therapeutic target after vascular injury associated with myocardial infarction.
Characteristics of Wavefront Propagation in Reentrant Circuits Causing Human Ventricular Tachycardia
Authors: Chow Anthony W.C. , Schilling Richard J. , Davies D. Wyn , Peters Nicholas S.
Published: July 2002

Background

—

We investigated the relationship between wavefront curvature and slowing of conduction both within and outside the diastolic pathway of circuits causing ventricular tachycardia (VT) in the infarcted human heart.

Methods and Results

—

Propagation was determined around the reentrant circuits of 11 VT (cycle length, 348±75 ms) in 8 patients undergoing high-resolution noncontact mapping. The diastolic pathway had a mean wavefront velocity of 0.82±0.49 m/s and occupied 68±7% of VT cycle length. Significant changes (>5 degrees/mm) in trajectory of propagation occurred in 8 diastolic pathway segments (10.1±3 degrees/mm) in which wavefront propagation slowed to 0.41±0.11 m/s compared with the segments immediately preceding (0.91±0.16 m/s,
P
< 0.05) and following (1.07±0.33,
P
<0.05) the change in trajectory. At the turning points of entry (9.3±3.9 degrees/mm) and exit (9.0±4.8 degrees/mm) of the diastolic pathway propagation, velocity slowed at entry from 1.23±0.4 to 0.6±0.26 ms (
P
<0.001) and was more rapid at exit turning points (0.8±0.25 m/s) (
P
<0.05). There was an inverse relationship between wavefront curvature and velocity, both within and outside the diastolic pathway (
r
=0.46,
P
=0.0001), and VT cycle length correlated with total curvature multiplied by length of the diastolic pathway (
P
< 0.01).

Conclusions

—

Slowing of propagation in circuits causing VT in the infarcted human heart occurs over regions of wavefront turning, with an inverse relationship between wavefront curvature and velocity, both within and outside the diastolic pathway. Conduction is slower at entry than exit turning points of the diastolic pathway but is slowest during turns within the diastolic pathway.
Calcineurin in Human Heart Hypertrophy
Authors: Ritter Oliver , Hack Susanne , Schuh Kai , Röthlein Nicola , Perrot Andreas , Osterziel Karl J. , Schulte Hagen D. , Neyses Ludwig
Published: July 2002

Background

—

In animal models, increased signaling through the calcineurin pathway has been shown to be sufficient for the development of cardiac hypertrophy. Calcineurin activity has been reported to be elevated in the myocardium of patients with congestive heart failure. In contrast, few data are available about calcineurin activity in patients with pressure overload or cardiomyopathic hypertrophy who are not in cardiac failure.

Methods and Results

—

We investigated calcineurin activity and protein expression in 2 different forms of cardiac hypertrophy: hypertrophic obstructive cardiomyopathy (HOCM) and aortic stenosis (AS). We found that the C-terminus of calcineurin A protein containing the autoinhibitory domain was less abundant in myocardial hypertrophy than in normal heart, which suggests the possibility of proteolysis. No new splice variants could be detected by reverse-transcription polymerase chain reaction. This resulted in a significant elevation of calcineurin enzymatic activity in HOCM and AS compared with 6 normal hearts. Increased calcineurin phosphatase activity caused increased migration of NF-AT2 (nuclear factor of activated T cells 2) in SDS-PAGE compatible with pronounced NF-AT dephosphorylation in hypertrophied myocardial tissue.

Conclusions

—

Hypertrophy in HOCM and AS without heart failure is characterized by a significant increase in calcineurin activity. This might occur by (partial) proteolysis of the calcineurin A C-terminus containing the autoinhibitory domain. Increased calcineurin activity has functional relevance, as shown by altered NF-AT phosphorylation state. Although hypertrophy in AS and HOCM may be initiated by different upstream triggers (internal versus external fiber overload), in both cases, there is activation of calcineurin, which suggests an involvement of this pathway in the pathogenesis of human cardiac hypertrophy.
Structure, Endothelial Function, Cell Growth, and Inflammation in Blood Vessels of Angiotensin II–Infused Rats
Authors: Diep Quy N. , El Mabrouk Mohammed , Cohn Jeffrey S. , Endemann Dierk , Amiri Farhad , Virdis Agostino , Neves Mario Fritsch , Schiffrin Ernesto L.
Published: July 2002

Background

—

Pioglitazone and rosiglitazone, thiazolidinedione peroxisome proliferator–activated receptor-γ (PPARγ) activators, reduce blood pressure (BP) in some hypertensive models by unclear mechanisms. We tested the hypothesis that pioglitazone or rosiglitazone would prevent BP elevation and vascular dysfunction in angiotensin (Ang) II–infused rats by direct vascular effects.

Methods and Results

—

Sprague-Dawley rats received Ang II (120 ng · kg
−1
· min
−1
SC) with or without pioglitazone (10 mg · kg
−1
· d
−1
) or rosiglitazone (5 mg · kg
−1
· d
−1
) for 7 days. Systolic BP, elevated in Ang II–infused rats (176±5 mm Hg) versus controls (109±2 mm Hg,
P
<0.01), was reduced by pioglitazone (134±2 mm Hg) or rosiglitazone (123±2 mm Hg). In mesenteric small arteries studied in a pressurized myograph, media/lumen ratio was increased (
P
<0.05) and acetylcholine-induced relaxation impaired in Ang II–infused rats (
P
<0.05); both were normalized by the thiazolidinediones. In Ang II–infused rats, vascular DNA synthesis (by
3
H-thymidine incorporation); expression of cell cycle proteins cyclin D1 and cdk4, angiotensin II type 1 receptors, vascular cell adhesion molecule-1, and platelet and endothelial cell adhesion molecule; and nuclear factor-κB activity were increased. These changes were abrogated by pioglitazone or rosiglitazone.

Conclusions

—

Thiazolidinedione PPAR-γ activators attenuated the development of hypertension, corrected structural abnormalities, normalized cell growth, and improved endothelial dysfunction induced by Ang II and prevented upregulation of angiotensin II type 1 receptors, cell cycle proteins, and proinflammatory mediators. Thiazolidinediones may be useful in the prevention and/or treatment of hypertension, particularly when it is associated with insulin resistance or diabetes mellitus.
Electrical Conduction in Canine Pulmonary Veins
Authors: Hocini Mélèze , Ho Siew Y. , Kawara Tokuhiro , Linnenbank André C. , Potse Mark , Shah Dipen , Jaïs Pierre , Janse Michiel J. , Haïssaguerre Michel , de Bakker Jacques M.T.
Published: July 2002

Background

—

Paroxysmal atrial fibrillation in patients is often initiated by foci in the pulmonary veins. The mechanism of these initiating arrhythmias is unknown. The aim of this study was to determine electrophysiological characteristics of canine pulmonary veins that may predispose to initiating arrhythmias.

Methods and Results

—

Extracellular recordings were obtained from the luminal side of 9 pulmonary veins in 6 Langendorff-perfused dog hearts after the veins were incised from the severed end to the ostium. Pulmonary veins were paced at the distal end, the ostium, and an intermediate site. During basic and premature stimulation, extracellular electrical activity was recorded with a grid electrode that harbored 247 electrode terminals. In 4 hearts, intracellular electrograms were recorded with microelectrodes. Myocyte arrangement immediately beneath the venous walls was determined by histological analysis in 3 hearts. Extracellular mapping revealed slow and complex conduction in all pulmonary veins. Activation delay after premature stimulation could be as long as 96 ms over a distance of 3 mm. Action potential duration was shorter at the distal end of the veins than at the orifice. No evidence for automaticity or triggered activity was found. Histological investigation revealed complex arrangements of myocardial fibers that often showed abrupt changes in fiber direction and short fibers arranged in mixed direction.

Conclusions

—

Zones of activation delay were observed in canine pulmonary veins and correlated with abrupt changes in fascicle orientation. This architecture of muscular sleeves in the pulmonary veins may facilitate reentry and arrhythmias associated with ectopic activity.
Physical Activity and Coronary Event Incidence in Northern Ireland and France
Authors: Wagner Aline , Simon Chantal , Evans Alun , Ferrières Jean , Montaye Michèle , Ducimetière Pierre , Arveiler Dominique
Published: July 2002

Background

—

The influence of physical activity on the incidence of angina pectoris and hard coronary events (myocardial infarction and coronary deaths) was examined in Northern Ireland and France at contrasting risk for coronary heart disease (CHD) and with different physical activity patterns.

Methods and Results

—

Participants of the Prospective Epidemiological Study of Myocardial Infarction (PRIME) (n=9758; age, 50 to 59 years), free of CHD at baseline, were followed up for 5 years: 167 hard CHD and 154 angina events were recorded. Net energy expenditure (EE) as the result of physical activity was assessed by means of the MONICA Optional Study of Physical Activity Questionnaire (MOSPA-Q). Leisure-time physical activity EE was calculated; subjects were also categorized as to whether they performed high-intensity leisure-time activities or walked or cycled to work. After multivariate adjustment, leisure-time physical activity EE was associated with a lower risk of hard CHD events (
P
<0.04), whereas walking or cycling to work was not independently related to hard CHD events. No interaction by country was found. The beneficial effect of leisure-time physical activity was also present among subjects who did not report high-intensity activities (
P
<0.04), with similar results in France and Northern Ireland. In contrast, an increasing level of leisure-time physical activity was associated with a higher risk of angina in both countries.

Conclusions

—

These data indicate a beneficial effect of leisure-time physical activity EE on hard CHD incidence in middle-aged men, which could partly explain the unfavorable rate of CHD in Northern Ireland. The higher level of leisure-time activities in France could, in part, explain its lower rate of CHD.
Benefits and Safety of Tirofiban Among Acute Coronary Syndrome Patients With Mild to Moderate Renal Insufficiency
Authors: Januzzi James L. , Snapinn Steven M. , DiBattiste Peter M. , Jang Ik-Kyung , Theroux Pierre
Published: July 2002

Background

—

The role of glycoprotein IIb/IIIa receptor antagonists for the treatment of patients with acute coronary syndrome and renal insufficiency remains undefined.

Methods and Results

—

Patients from the Platelet Receptor Inhibition in Ischemic Syndrome Management in Patients Limited by Unstable Signs and Symptoms (PRISM-PLUS) trial were stratified by creatinine clearance (CrCl) and assessed with respect to treatment assignment to tirofiban/heparin versus heparin alone for the risk of adverse outcomes and bleeding. Patients with severe renal insufficiency (defined as a serum creatinine ≥2.5 mg/dL) were excluded from PRISM-PLUS as a whole. Patients with the lowest CrCl (<30 mL/min) were more likely to present with high-risk clinical features. Decreasing renal function was strongly associated with adverse outcome, increasing the risk for ischemic complications at all time points examined (all
P
<0.002). Irrespective of CrCl, therapy with tirofiban reduced the odds of the composite end point of death, myocardial infarction, or refractory ischemia at 48 hours (odds ratio [OR], 0.68; 95% confidence interval [CI], 0.46 to 1.0;
P
=0.05), 7 days (OR, 0.68; 95% CI, 0.52 to 0.88;
P
= 0.003), 30 days (OR, 0.78; 95% CI, 0.63 to 0.98;
P
=0.03), and 6 months (OR, 0.81; 95% CI, 0.68 to 0.98;
P
=0.03). The risk of myocardial infarction/death was also significantly decreased to a similar magnitude at all time points examined. There was no evidence of treatment-by-CrCl interaction. The presence of declining renal function independently increased the risk for bleeding (OR, 1.57;
P
<0.001 for trend across categories), as did therapy with tirofiban, but no unexpected incremental risk of bleeding due to tirofiban was observed among lowest CrCl categories.

Conclusions

—

Among patients with mild-to-moderate renal insufficiency in PRISM-PLUS, tirofiban was well tolerated and effective in reducing ischemic acute coronary syndrome complications.
Bypass Surgery Versus Stenting for the Treatment of Multivessel Disease in Patients With Unstable Angina Compared With Stable Angina
Authors: de Feyter P.J. , Serruys P.W. , Unger F. , Beyar R. , de Valk V. , Milo S. , Simon R. , Regensburger D. , Crean P.A. , McGovern E. , van den Heuvel P. , van Cauwelaert C. , Penn I. , Tyers G.F.O. , Lindeboom W.
Published: July 2002

Background

—

Earlier reports have shown that the outcome of balloon angioplasty or bypass surgery in unstable angina is less favorable than in stable angina. Recent improvements in percutaneous treatment (stent implantation) and bypass surgery (arterial grafts) warrant reevaluation of the relative merits of either technique in treatment of unstable angina.

Methods and Results

—

Seven hundred fifty-five patients with stable angina were randomly assigned to coronary stenting (374) or bypass surgery (381), and 450 patients with unstable angina were randomly assigned to coronary stenting (226) or bypass surgery (224). All patients had multivessel disease considered to be equally treatable by either technique. Freedom from major adverse events, including death, myocardial infarction, and cerebrovascular events, at 1 year was not different in unstable patients (91.2% versus 88.9%) and stable patients (90.4% versus 92.6%) treated, respectively, with coronary stenting or bypass surgery. Freedom from repeat revascularization at 1 year was similar in unstable and stable angina treated with stenting (79.2% versus 78.9%) or bypass surgery (96.3% versus 96%) but was significantly higher in both unstable and stable patients treated with stenting (16.8% versus 16.9%) compared with bypass surgery (3.6% versus 3.5%). Neither the difference in costs between stented or bypassed stable or unstable angina ($2594 versus $3627) nor the cost-effectiveness was significantly different at 1 year.

Conclusions

—

There was no difference in rates of death, myocardial infarction, and cerebrovascular event at 1 year in patients with unstable angina and multivessel disease treated with either stented angioplasty or bypass surgery compared with patients with stable angina. The rate of repeat revascularization of both unstable and stable angina was significantly higher in patients with stents.