bluuebunny/crossref_metadata_2025 huggingface dataset:
Ischemic Preconditioning Attenuates Cardiac Sympathetic Nerve Injury via ATP-Sensitive Potassium Channels During Myocardial Ischemia
Authors: Miura Toshiro , Kawamura Shuji , Tatsuno Hironari , Ikeda Yasuhiro , Mikami Shunsuke , Iwamoto Hiroshi , Okamura Takayuki , Iwatate Mitsuo , Kimura Masayasu , Dairaku Yuka , Maekawa Tsuyoshi , Matsuzaki Masunori
Published: September 2007

Background

During myocardial ischemia, massive norepinephrine (NE) is released from the cardiac sympathetic nerve terminals, reflecting the sympathetic nerve injury. A brief preceding ischemia can reduce infarct size; this is known as ischemic preconditioning (PC). The effect of PC on sympathetic nerves, however, including its underlying mechanisms in dog hearts, has remained unclear. Thus, this study was designed to elucidate whether the activation of ATP-sensitive potassium (K
ATP
) channels is involved in the mechanism of cardiac sympathetic nerve protection conferred by PC.

Methods and Results

Interstitial NE concentration was measured by the in situ cardiac microdialysis method in 45 anesthetized dogs. Five minutes of ischemia followed by 5 minutes of reperfusion was performed as PC. In the controls, the dialysate NE concentration (dNE) increased 15-fold after the 40-minute ischemia. PC decreased dNE at 40-minute ischemia by 59% (
P
<0.01), which was reversed by glibenclamide. A K
ATP
channel opener, nicorandil (25 μg · kg
−1
· min
−1
IV), decreased dNE at 40 minutes of ischemia by 76% (
P
<0.01), which was also reversed by glibenclamide. During the PC procedure, no significant increase in dNE was detected, even with the uptake-1 inhibitor desipramine.

Conclusions

Cardiac sympathetic nerve injury during myocardial ischemia was attenuated by PC via the activation of K
ATP
channels, but the trigger of the PC effect is unlikely to be NE release in dog hearts.
Folic Acid Prevents Nitroglycerin-Induced Nitric Oxide Synthase Dysfunction and Nitrate Tolerance
Authors: Gori Tommaso , Burstein Jason M. , Ahmed Sofia , Miner Steve E.S. , Al-Hesayen Abdul , Kelly Susan , Parker John D.
Published: September 2007

Background—In healthy humans, continuous treatment with nitroglycerin (GTN) causes nitric oxide synthase dysfunction, probably through the reduced bioavailability of tetrahydrobiopterin. Recent studies proposed that folic acid is involved in the regeneration of tetrahydrobiopterin in different disease states. Therefore, we investigated whether folic acid administration would prevent this phenomenon. We also sought to determine if folic acid supplementation could prevent the development of tolerance to GTN.

Methods and Results—On the first visit, 18 healthy male volunteers (aged 19 to 32 years) were randomized to receive either oral folic acid (10 mg once a day) or placebo for 1 week in a double-blind designed study. All subjects also received continuous transdermal GTN (0.6 mg/h). On the second visit, forearm blood flow was measured with venous occlusion strain gauge plethysmography in response to incremental infusions of acetylcholine (7.5, 15, and 30 μg/min),N-monomethyl-l-arginine (1, 2, and 4 μmol/min), and GTN (11 and 22 nmol/min). Folic acid prevented GTN-induced endothelial dysfunction, as assessed by responses to intraarterial acetylcholine andN-monomethyl-l-arginine (P<0.01). Moreover, in the subjects treated with folic acid plus transdermal GTN, responses to intraarterial GTN were significantly greater than those observed after transdermal GTN plus placebo (P<0.05).

Conclusion—Our data demonstrate that supplemental folic acid prevents both nitric oxide synthase dysfunction induced by continuous GTN and nitrate tolerance in the arterial circulation of healthy volunteers. We hypothesize that the reduced bioavailability of tetrahydrobiopterin is involved in the pathogenesis of both phenomena. Our results confirm the view that oxidative stress contributes to nitrate tolerance.
De Novo Mutation in the

SCN5A

Gene Associated With Early Onset of Sudden Infant Death
Authors: Wedekind Horst , Smits Jeroen P.P. , Schulze-Bahr Eric , Arnold Raoul , Veldkamp Marieke W. , Bajanowski Thomas , Borggrefe Martin , Brinkmann Bernd , Warnecke Irene , Funke Harald , Bhuiyan Zahurul A. , Wilde Arthur A.M. , Breithardt Günter , Haverkamp Wilhelm
Published: September 2007

Background

—

Congenital long QT syndrome (LQTS), a cardiac ion channel disease, is an important cause of sudden cardiac death. Prolongation of the QT interval has recently been associated with sudden infant death syndrome, which is the leading cause of death among infants between 1 week and 1 year of age. Available data suggest that early onset of congenital LQTS may contribute to premature sudden cardiac death in otherwise healthy infants.

Methods and Results

—

In an infant who died suddenly at the age of 9 weeks, we performed mutation screening in all known LQTS genes. In the surface ECG soon after birth, a prolonged QTc interval (600 ms
1/2
) and polymorphic ventricular tachyarrhythmias were documented. Mutational analysis identified a missense mutation (Ala1330Pro) in the cardiac sodium channel gene
SCN5A
, which was absent in both parents. Subsequent genetic testing confirmed paternity, thus suggesting a de novo origin. Voltage-clamp recordings of recombinant A1330P mutant channel expressed in HEK-293 cells showed a positive shift in voltage dependence of inactivation, a slowing of the time course of inactivation, and a faster recovery from inactivation.

Conclusions

—

In this study, we report a de novo mutation in the sodium channel gene
SCN5A
, which is associated with sudden infant death. The altered functional characteristics of the mutant channel was different from previously reported LQTS3 mutants and caused a delay in final repolarization. Even in families without a history of LQTS, de novo mutations in cardiac ion channel genes may lead to sudden cardiac death in very young infants.
Role of Endothelin-1 in the Active Constriction of Human Atherosclerotic Coronary Arteries
Authors: Kinlay Scott , Behrendt Dominik , Wainstein Marco , Beltrame John , Fang James C. , Creager Mark A. , Selwyn Andrew P. , Ganz Peter
Published: September 2007

Background—Atherosclerotic coronary arteries are prone to constriction but the underlying causes are incompletely understood. We tested the hypothesis that endothelin-1 (ET-1), a potent vasoconstrictor, contributes to the heightened tone of atherosclerotic human coronary arteries.

Methods and Results—In 8 patients with coronary artery disease (CAD) and 8 patients with angiographically smooth coronary arteries (normal), we infused BQ-123, an antagonist of the ETAreceptor, into a major coronary artery (infused artery) at 40 nmol/min for 60 minutes. The infused artery in the CAD patients contained a >50% stenosis. Using quantitative angiography, we compared the dilation of the infused artery with another, noninfused coronary artery. To estimate the magnitude of the contribution of ET-1 to coronary tone, we compared the dilation to BQ-123 with that elicited by intracoronary nitroglycerin (200 μg). BQ-123 induced significant dilation in the normal arteries (7.3% at 60 minutes,P<0.001 versus noninfused arteries) and a greater dilation in the CAD arteries (16.3% at 60 minutes,P<0.001 versus infused normal arteries). The dilation at stenoses was particularly pronounced (21.6% at 60 minutes,P<0.001 versus infused CAD arteries). Compared with the dilation from nitroglycerin, ET-1 contributed to 39% of the coronary tone in normal arteries, 74% of tone in CAD arteries, and 106% of tone at stenoses (P<0.01).

Conclusions—ET-1 accounts for nearly all the resting tone in atherosclerotic coronary arteries, especially at stenoses. Inhibitors of ET-1, by relieving constriction, may significantly lessen the hemodynamic significance of coronary stenoses and thereby reduce myocardial ischemia.
Anti–Tumor Necrosis Factor-α Antibody Limits Heart Failure in a Transgenic Model
Authors: Kadokami Toshiaki , Frye Carole , Lemster Bonnie , Wagner Carrie L. , Feldman Arthur M. , McTiernan Charles F.
Published: September 2007

Background
—

Tumor necrosis factor (TNF)-α has been implicated in the pathophysiology of congestive heart failure. A strain of transgenic mice (TNF1.6) with cardiac-specific overexpression of TNF-α develop congestive heart failure.

Methods and Results
—

To determine the effect of anti-TNF-α therapy in this model, we studied 3 groups: TNF1.6 mice treated with saline, wild-type mice treated with saline, and TNF1.6 mice treated with TNF-α neutralizing antibody (cV1q) from 6 to 12 weeks of age. We used echocardiography to compare cardiac hypertrophy, function, and catecholamine response at 12 weeks of age versus baseline (6 weeks). cV1q treatment did not limit cardiac hypertrophy, but it significantly improved basal fractional shortening and responsiveness to β-adrenergic stimulation, and it limited development of cardiac dilation.

Conclusions
—

Blockade of TNF-α bioactivity by antibody therapy may both preserve cardiac function and partially reverse pathological changes in congestive heart failure.
Pharmacological Stress Myocardial Perfusion Imaging With the Potent and Selective A2AAdenosine Receptor Agonists ATL193 and ATL146e Administered by Either Intravenous Infusion or Bolus Injection
Authors: Glover David K. , Ruiz Mirta , Takehana Kazuya , Petruzella Frank D. , Riou Laurent M. , Rieger Jayson M. , Macdonald Timothy L. , Watson Denny D. , Linden Joel , Beller George A.
Published: September 2007

Background—Adenosine (Ado) and dipyridamole are alternatives to exercise stress for myocardial perfusion imaging. Though generally safe, side effects frequently occur that cause patient discomfort and sometimes lead to premature termination of the study or require aminophylline administration. Recently, a new class of A2AAdo receptor agonists was synthesized. ATL193 and ATL146e are 2-propynylcyclohexyl-5′-N-ethylcarboxamido derivatives of Ado. The study goals were to evaluate the potency and selectivity of these new compounds on recombinant canine Ado receptors and to evaluate their hemodynamic properties in dogs to assess their usefulness as vasodilators for myocardial perfusion imaging.

Methods and Results—In assays of recombinant canine Ado receptors, ATL-193 and ATL-146e were highly selective for the A2Aover the A1and A3receptors and were more potent than MRE-0470 and CGS-21680. In 16 anesthetized dogs, the agonists were administered by infusion (ATL-193; n=7 normal) or bolus injection (ATL-146e; n=9 critical left anterior descending coronary artery stenosis), and hemodynamic responses were compared with those of Ado. Both agonists produced dose-dependent coronary flow (CF) elevation without provoking the hypotension observed with Ado. After an ATL-146e bolus, the CF increase was sustained for several minutes, providing ample time for injection and myocardial uptake of99mTc-sestamibi, and CF returned to baseline within 20 minutes. The CF increase was completely blocked by the selective A2Aantagonist ZM241385 (3 μg · kg−1· min−1).

Conclusions—ATL-193 and ATL-146e are highly potent and selective Ado A2Areceptor agonists with excellent potential for use as vasodilators for myocardial perfusion imaging. An important advantage of ATL-146e is the ability to administer it by bolus injection.
Hypertensive End-Organ Damage and Premature Mortality Are p38 Mitogen-Activated Protein Kinase–Dependent in a Rat Model of Cardiac Hypertrophy and Dysfunction
Authors: Behr Thomas M. , Nerurkar Sandhya S. , Nelson Allen H. , Coatney Robert W. , Woods Tina N. , Sulpizio Anthony , Chandra Sudeep , Brooks David P. , Kumar Sanjay , Lee John C. , Ohlstein Eliot H. , Angermann Christiane E. , Adams Jerry L. , Sisko Joseph , Sackner-Bernstein Jonathan D. , Willette Robert N.
Published: September 2007

BackgroundNumerous pathological mediators of cardiac hypertrophy (eg, neurohormones, cytokines, and stretch) have been shown to activate p38 MAPK. The purpose of the present study was to examine p38 MAPK activation and the effects of its long-term inhibition in a model of hypertensive cardiac hypertrophy/dysfunction and end-organ damage.

Methods and ResultsIn spontaneously hypertensive stroke-prone (SP) rats receiving a high-salt/high-fat diet (SFD), myocardial p38 MAPK was activated persistently during the development of cardiac hypertrophy and inactivated during decompensation. Long-term oral treatment of SFD-SP rats with a selective p38 MAPK inhibitor (SB239063) significantly enhanced survival over an 18-week period compared with the untreated group (100% versus 50%). Periodic echocardiographic analysis revealed a significant reduction in LV hypertrophy and dysfunction in the SB239063-treatment groups. Little or no difference in blood pressure was noted in the treatment or vehicle groups. Basal and stimulated (lipopolysaccharide) plasma tumor necrosis factor-α concentrations were reduced in the SB239063-treatment groups. In vitro vasoreactivity studies demonstrated a significant preservation of endothelium-dependent relaxation in animals treated with the p38 MAPK inhibitor without effects on contraction or NO-mediated vasorelaxation. Proteinuria and the incidence of stroke (53% versus 7%) were also reduced significantly in the SB239063–treated groups.

ConclusionsThese results demonstrate a crucial role for p38 MAPK in hypertensive cardiac hypertrophy and end-organ damage. Interrupting its function with a specific p38 MAPK inhibitor halts clinical deterioration.
Imaging Dispersion of Myocardial Repolarization, II
Authors: Ghanem Raja N. , Burnes John E. , Waldo Albert L. , Rudy Yoram
Published: September 2007

Background

Dispersion of myocardial repolarization supports the development and maintenance of life-threatening arrhythmias. Current noninvasive approaches for detecting substrates with increased dispersion based on ECG measures (eg, QT dispersion) have shown limited success and inconsistencies. The companion article shows that, in contrast, epicardial potentials and derived measures reflect local dispersion of repolarization. Here, using a recently developed ECG imaging method, we evaluate the feasibility of noninvasive reconstruction of such epicardial measures from body-surface ECG data.

Methods and Results

Epicardial potentials were recorded with a 224-electrode sock from an open-chest dog during control, regional warming, cooling, and simultaneous adjacent warming and cooling to induce localized changes in myocardial repolarization and regions of increased dispersion. Body-surface potentials were generated from these epicardial potentials in a human torso model. Realistic geometric errors and measurement noise were added to the torso data, which were then used to noninvasively reconstruct epicardial measures of repolarization dispersion (activation recovery intervals [ARIs] and QRST integrals). Repolarization properties were accurately depicted by ECG imaging, including (1) shortened ARIs and increased QRST integrals over the warmed region, (2) prolonged ARIs and decreased QRST integrals over the cooled region, and (3) high gradients of ARIs and QRST integrals over the adjacent warmed and cooled regions.

Conclusions

ECG imaging can reconstruct repolarization properties accurately and localize areas of increased dispersion of repolarization in the heart noninvasively. Its clinical significance lies in the possibility of noninvasive risk stratification and in guidance and evaluation of therapy.
Novel MRI Contrast Agent for Molecular Imaging of Fibrin
Authors: Flacke Sebastian , Fischer Stefan , Scott Michael J. , Fuhrhop Ralph J. , Allen John S. , McLean Mark , Winter Patrick , Sicard Gregorio A. , Gaffney Patrick J. , Wickline Samuel A. , Lanza Gregory M.
Published: September 2007

Background

Molecular imaging of thrombus within fissures of vulnerable atherosclerotic plaques requires sensitive detection of a robust thrombus-specific contrast agent. In this study, we report the development and characterization of a novel ligand-targeted paramagnetic molecular imaging agent with high avidity for fibrin and the potential to sensitively detect active vulnerable plaques.

Methods and Results

The nanoparticles were formulated with 2.5 to 50 mol% Gd-DTPA-BOA, which corresponds to >50 000 Gd
3+
atoms/particle. Paramagnetic nanoparticles were characterized in vitro and evaluated in vivo. In contradistinction to traditional blood-pool agents, T1 relaxation rate as a function of paramagnetic nanoparticle number was increased monotonically with Gd-DTPA concentration from 0.18 mL · s
−1
· pmol
−1
(10% Gd-DTPA nanoparticles) to 0.54 mL · s
−1
· pmol
−1
for the 40 mol% Gd-DTPA formulations. Fibrin clots targeted in vitro with paramagnetic nanoparticles presented a highly detectable, homogeneous T1-weighted contrast enhancement that improved with increasing gadolinium level (0, 2.5, and 20 mol% Gd). Higher-resolution scans and scanning electron microscopy revealed that the nanoparticles were present as a thin layer over the clot surface. In vivo contrast enhancement under open-circulation conditions was assessed in dogs. The contrast-to-noise ratio between the targeted clot (20 mol% Gd-DTPA nanoparticles) and blood was ≈118±21, and that between the targeted clot and the control clot was 131±37.

Conclusions

These results suggest that molecular imaging of fibrin-targeted paramagnetic nanoparticles can provide sensitive detection and localization of fibrin and may allow early, direct identification of vulnerable plaques, leading to early therapeutic decisions.
Angiotensin II Type 1 Receptor Blockade Prevents Lethal Malignant Hypertension
Authors: Hilgers Karl F. , Hartner Andrea , Porst Markus , Veelken Roland , Mann Johannes F.E.
Published: September 2007

Background—Angiotensin II is elevated in malignant hypertension. We tested the hypothesis that angiotensin II type 1 receptor blockade can prevent the development of malignant hypertension even in the absence of a blood pressure-lowering effect.

Methods and Results—Two-kidney, 1-clip rats were followed up for 28 days; blood pressure was measured by tail-cuff plethysmography and intra-arterially. After a 2-week run-in phase, rats received valsartan at a dose of 0.3 (n=14) or 3 (n=12) mg · kg−1· d−1or solvent (n=27). Only the higher dose of valsartan, but not the lower dose, decreased blood pressure. Both doses of valsartan prevented the development of lethal malignant hypertension. Twenty of 27 solvent-treated renovascular hypertensive rats died, but only 3 of 14 rats treated with the low dose and 1 of 12 rats treated with the high dose of valsartan died. Histological signs of malignant nephrosclerosis were found in all rats examined that had died throughout the study and in 6 of 7 surviving solvent-treated renovascular hypertensive animals. Increased expression of monocyte chemoattractant protein-1 and prominent interstitial influx of macrophages occurred in the nonclipped kidneys exposed to high pressure in solvent-treated rats. These alterations were prevented by valsartan at both doses, irrespective of blood pressure effects.

Conclusions—Angiotensin II type 1 receptor blockade by valsartan prevents lethal malignant hypertension independently of blood pressure. The results suggest that reduction of angiotensin-induced inflammation in the kidney may contribute to the protective effects of valsartan.
Human Evidence That the Apolipoprotein A-II Gene Is Implicated in Visceral Fat Accumulation and Metabolism of Triglyceride-Rich Lipoproteins
Authors: van ’t Hooft Ferdinand M. , Ruotolo Giacomo , Boquist Susanna , de Faire Ulf , Eggertsen Gösta , Hamsten Anders
Published: September 2007

Background

Apolipoprotein (apo) A-II is a major structural protein of plasma HDLs, but little is known regarding its functions.

Methods and Results

To investigate the physiological role of apoA-II in humans, we screened the promoter region of the apoA-II gene for a functional polymorphism and used this polymorphism as a tool in association studies. A common, functional polymorphism in the promoter region of the apoA-II gene, a T to C substitution at position −265, was found. Electrophoretic mobility shift assays demonstrated that the −265T/C polymorphism influences the binding of nuclear proteins, whereas transient transfection studies in human hepatoma cells showed a reduced basal rate of transcription of the −265C allele compared with the −265T allele. The −265C allele was associated with decreased plasma apoA-II concentration and decreased waist circumference in healthy 50-year-old men. In addition, oral fat tolerance tests provided evidence that the −265C allele enhances postprandial metabolism of large VLDLs.

Conclusions

ApoA-II appears to promote visceral fat accumulation and impair metabolism of large VLDLs.
Hypertrophic Cardiomyopathy
Authors: Varnava Amanda M. , Elliott Perry M. , Baboonian Christina , Davison Fergus , Davies Michael J. , McKenna William J.
Published: September 2007

Background
—

Patients with hypertrophic cardiomyopathy (HCM) are at increased risk of premature death; this is particularly apparent for patients with mutations of the troponin T gene. Myocyte disarray and interstitial fibrosis, pathological features of HCM, may be determinants in these deaths. The relation between genotype, pathological phenotype, and mode of death has not been explored.

Methods and Results
—

Seventy-five hearts with HCM were examined. DNA was available in 50 for screening of the troponin T gene. The macroscopic findings, percentage of disarray, percentage of fibrosis, and percentage of small-vessel disease were correlated with the genotype. A troponin T mutation was identified in 9 of the 50 patients, 8 of whom died suddenly. Patients with a troponin T mutation were younger (mean age, 21.0 years [range, 6 to 37] versus 39.1 years [range, 14 to 72];
P
<0.0001), had more sudden death (
P
=0.02), and had lower heart weights, less fibrosis, and greater disarray than other HCM patients (mean heart weight, 380.3±105.4 versus 585.0±245.7 g,
P
=0.002; mean fibrosis, 0.7±0.4% versus 2.6±2.8%,
P
=0.001; mean disarray, 46.2±7.2% versus 24.1±15.9%,
P
<0.0001; and mean small-vessel disease, 11.7±14.6 versus 14.1±8.7,
P
=0.6, respectively). Similarly, patients with troponin T mutations who died suddenly had lower heart weights and greater disarray than patients who died suddenly with unknown genotype (ie, troponin T mutation excluded) (mean heart weight, 429.8±75.4 versus 559.6±204.43 g,
P
=0.04, and mean disarray, 40.1±9.4% versus 20.2±12.6%,
P
=0.002, respectively).

Conclusions
—

Patients with troponin T mutations had severe disarray, with only mild hypertrophy and fibrosis. These patients died suddenly and at an especially early age. We propose that extensive myocyte disarray in the absence of marked hypertrophy is the pathological substrate for sudden death in these patients.
Effects of Cavotricuspid Isthmus Ablation on Atrioventricular Node Electrophysiology in Patients With Typical Atrial Flutter
Authors: Tai Ching-Tai , Tsai Chin-Feng , Hsieh Ming-Hsiung , Lin Wei-Shiang , Lin Yung-Kuo , Lee Shih-Huang , Yu Wen-Chung , Ding Yu-An , Chang Mau-Song , Chen Shih-Ann
Published: September 2007

Background

The atrial musculature in the cavotricuspid isthmus is a part of posterior inputs to the AV node. In patients with typical atrial flutter, effects of radiofrequency ablation of this isthmus on AV node conduction are still unknown.

Methods and Results

This study included 16 patients with clinically documented typical atrial flutter. Group 1 had 8 patients without and group 2 had 8 patients with dual AV nodal pathway physiology. Electrical pacing from the interatrial septum and low right atrium was performed to evaluate antegrade AV node function before and after ablation of the cavotricuspid isthmus. In group 1, the AV node conduction properties were similar before and after ablation. In group 2, the AV node Wenckebach cycle length and maximal AH interval during low right atrium (356±58 versus 399±49 ms,
P
=0.008; 303±57 versus 376±50 ms,
P
=0.008) and interatrial septum (365±62 versus 393±59 ms,
P
=0.008; 324±52 versus 390±60 ms,
P
=0.008) pacing were significantly longer after ablation. Elimination of the slow pathway after ablation was noted in 2 patients, including 1 with AV nodal reentrant echo beats.

Conclusions

Radiofrequency ablation of the cavotricuspid isthmus was effective in eliminating typical atrial flutter without injury of antegrade fast AV node conduction. The atrial musculature in the cavotricuspid isthmus significantly contributed to the slow AV node conduction.
Comparison of Real-Time and Intermittent Triggered Myocardial Contrast Echocardiography for Quantification of Coronary Stenosis Severity and Transmural Perfusion Gradient
Authors: Masugata Hisashi , Lafitte Stephane , Peters Barry , Strachan G. Monet , DeMaria Anthony N.
Published: September 2007

Background

Both intermittent triggered and real-time myocardial contrast echocardiography (MCE) have been proposed to detect impaired myocardial perfusion. We compared the ability of these 2 methods to quantify altered myocardial blood flow (MBF) and transmural distribution of MBF produced by graded coronary stenoses.

Methods and Results

In 8 open-chest dogs, we created 4 graded left anterior descending coronary artery (LAD) stenoses: 3 levels of reduced adenosine hyperemia (non–flow-limiting at rest) and 1 grade of flow-limiting at rest. Real-time MCE was performed with SonoVue infusion using low-energy power pulse inversion (ATL) imaging, whereas ECG-gated intermittent triggered imaging used high energy at pulsing intervals from 1:1 to 1:10. LAD signal intensity (SI) was plotted versus time by real-time MCE and versus pulsing intervals by triggered MCE and was fitted to a 1-exponential function to obtain plateau SI (A) and the rate of SI rise (b). Visual detection of decreased opacification was equivalent by triggered and real-time MCE. Fluorescent microsphere–derived MBF ratio in LAD/left circumflex artery beds demonstrated close correlation with both real-time imaging (b,
r
=0.79; A×b,
r
=0.81) and triggered imaging (b,
r
=0.78; A×b,
r
=0.80). The endocardial/epicardial ratio of MBF in the LAD bed demonstrated closer correlation with the endocardial/epicardial ratios of b (
r
=0.71) and A×b (
r
=0.67) obtained by real-time than triggered imaging (b,
r
=0.42; A×b,
r
=0.52).

Conclusions

Real-time and triggered MCE are equivalent in their ability to identify coronary stenosis and quantify altered MBF.
Regional Cerebral Hyperperfusion and Nitric Oxide Pathway Dysregulation in Fabry Disease
Authors: Moore David F. , Scott Leland T.C. , Gladwin Mark T. , Altarescu Gheona , Kaneski Christine , Suzuki Kinuko , Pease-Fye Meg , Ferri Raymond , Brady Roscoe O. , Herscovitch Peter , Schiffmann Raphael
Published: September 2007

BackgroundFabry disease is an X-linked lysosomal deficiency of α-galactosidase A that results in cellular accumulation of galacto-conjugates such as globotriosylceramide, particularly in blood vessels. It is associated with early-onset stroke and kidney and heart failure.

Methods and ResultsUsing [15O] H2O and PET, we found increased resting regional cerebral blood flow in Fabry disease without evidence of occlusive vasculopathy or cerebral hypoperfusion. Because nitric oxide is known to play an important role in vascular tone and reactivity, we studied plasma nitrate, nitrite, and low-molecular-weightS-nitrosothiol levels by chemiluminescence. Skin biopsy specimens and archived brain tissue were also examined immunohistochemically for nitrotyrosine. Plasma nitrate, nitrite, and low-molecular-weightS-nitrosothiol were in the normal range; however, enhanced nitrotyrosine staining was observed in dermal and cerebral blood vessels. After a double-blind, placebo-controlled trial of α-galactosidase A therapy, the resting regional cerebral blood flow in the treated group was significantly reduced, with a notable decrease of nitrotyrosine staining in dermal blood vessels.

ConclusionsThese findings suggest a chronic alteration of the nitric oxide pathway in Fabry disease, with critical protein nitration that is reversible with enzyme replacement therapy.
Complement Activation in Patients With Congestive Heart Failure
Authors: Aukrust Pål , Gullestad Lars , Lappegård Knut T. , Ueland Thor , Aass Halfdan , Wikeby Lisbeth , Simonsen Svein , Frøland Stig S. , Mollnes Tom E.
Published: September 2007

Background

Increasing evidence implicates innate immunity in the pathogenesis of congestive heart failure (CHF). In the present study, we examined the possible role of complement, an important part of innate immunity, in CHF.

Methods and Results

Complement activation was analyzed in systemic and coronary circulation in 39 patients with CHF and 20 healthy control subjects. In a double-blind, placebo-controlled study, we have recently reported that high-dose intravenous immunoglobulin (IVIG) improves left ventricular ejection fraction (LVEF) in these patients. To examine if this improvement was related to IVIG-induced effects on complement, we also examined complement activation during induction (first week) and maintenance therapy (6 months) with IVIG or placebo. Our main findings were: (1) We found enhanced systemic complement activation involving classic, alternative, as well as terminal pathway in patients with CHF compared with healthy control subjects. (2) Particularly enhanced complement activation was found in coronary sinus, representing venous drainage from the heart. (3) The systemic complement activation was further enhanced during IVIG but not during placebo therapy, particularly during induction therapy. (4) Although IVIG improved LVEF in patients with CHF, the degree of IVIG-mediated complement activation was negatively correlated with this improvement of LVEF.

Conclusions

This study further supports the involvement of innate immunity in the pathogenesis of CHF. Our findings suggest that complement may be added to the list of possible therapeutic targets in CHF and that future studies with specific complement inhibitors may be of interest in this disorder.
Novel Platelet Membrane Glycoprotein VI Dimorphism Is a Risk Factor for Myocardial Infarction
Authors: Croft S. A. , Samani N. J. , Teare M. D. , Hampton K. K. , Steeds R. P. , Channer K. S. , Daly M. E.
Published: September 2007

Background

Glycoprotein (GP) VI plays a crucial role in platelet activation and aggregation. We investigated whether polymorphic variation at the GP VI locus confers an increased risk of myocardial infarction (MI).

Methods and Results

Coding and 5′ and 3′ non-coding regions of the GP VI gene were analyzed by polymerase chain reaction and conformation sensitive gel electrophoresis in 21 healthy subjects. Ten dimorphisms, 5 of which predicted amino acid substitutions (T13254C, A19871G, A21908G, A22630T, C22644A), were identified. Two core haplotypes involving 7 dimorphisms (C10781A and G10873A and all those predicting amino acid substitutions) were apparent. The contribution of the T13254C dimorphism, which predicted the substitution of serine 219 by proline, to risk of MI was assessed in 525 patients with acute MI and 474 controls, all aged <75 years. The allelic odds ratio (OR) for MI associated with the 13254C allele was 1.16 (95% CI, 0.91 to 1.46;
P
=0.23). Compared with corresponding control subgroups, the 13254CC genotype was more common among cases who were female (OR, 4.52; 95% CI, 1.23 to 16.64;
P
=0.029), nonsmokers (OR, 2.50; 95% CI, 0.98 to 6.38;
P
=0.048), aged ≥60 years (OR, 6.48; 95% CI, 1.47 to 28.45;
P
=0.009) or carried the β-fibrinogen -148T allele associated with increased fibrinogen levels (OR, 10.49; 95% CI, 1.32 to 83.42;
P
=0.02). In logistic regression analysis that took other cardiovascular risk factors into account, the interactions of GP VI genotype with age (
P
=0.005) and β-fibrinogen genotype (
P
=0.035) remained significant.

Conclusions

The GP VI 13254CC genotype increases the risk of MI, particularly in older individuals, and the interaction of the GP VI 13254C allele with other candidate risk alleles may accentuate this risk.
Improved Arterial Compliance by a Novel Advanced Glycation End-Product Crosslink Breaker
Authors: Kass David A. , Shapiro Edward P. , Kawaguchi Miho , Capriotti Anne R. , Scuteri Angelo , deGroof Robert C. , Lakatta Edward G.
Published: September 2007

Background

Arterial stiffening with increased pulse pressure is a leading risk factor for cardiovascular disease in the elderly. We tested whether ALT-711, a novel nonenzymatic breaker of advanced glycation end-product crosslinks, selectively improves arterial compliance and lowers pulse pressure in older individuals with vascular stiffening.

Methods and Results

Nine US centers recruited and randomly assigned subjects with resting arterial pulse pressures >60 mm Hg and systolic pressures >140 mm Hg to once-daily ALT-711 (210 mg; n=62) or placebo (n=31) for 56 days. Preexisting antihypertensive treatment (90% of subjects) was continued during the study. Morning upright blood pressure, stroke volume, cardiac output, systemic vascular resistance, total arterial compliance, carotid-femoral pulse wave velocity, and drug tolerability were assessed. ALT-711 netted a greater decline in pulse pressures than placebo (−5.3 versus −0.6 mm Hg at day 56;
P
=0.034 for treatment effect by repeated-measures ANOVA). Systolic pressure declined in both groups, but diastolic pressure fell less with ALT-711 (
P
=0.056). Mean pressure declined similarly in both groups (−4 mm Hg;
P
<0.01 for each group,
P
=0.34 for treatment effect). Total arterial compliance rose 15% in ALT-711–treated subjects versus no change with placebo (
P
=0.015 versus ALT-711), an effect that did not depend on reduced mean pressure. Pulse wave velocity declined 8% with ALT-711 (
P
<0.05 at day 56,
P
=0.08 for treatment effect). Systemic arterial resistance, cardiac output, and heart rate did not significantly change in either group.

Conclusions

ALT-711 improves total arterial compliance in aged humans with vascular stiffening, and it may provide a novel therapeutic approach for this abnormality, which occurs with aging, diabetes, and isolated systolic hypertension.
Effect of Short Pulsed Nonablative Infrared Laser Irradiation on Vascular Cells In Vitro and Neointimal Hyperplasia in a Rabbit Balloon Injury Model
Authors: Kipshidze Nicholas , Nikolaychik Victor , Muckerheidi Michael , Keelan Michael H. , Chekanov Valeri , Maternowski Michelle , Chawla Paramjit , Hernandez Irina , Iyer Sriram , Dangas George , Sahota Harry , Leon Martin B. , Roubin Gary , Moses Jeffrey W.
Published: September 2007

Background

Neointimal hyperplasia after PTCA is an important component of restenosis.

Methods and Results

Cultures of rabbit endothelial cells and smooth muscle cells (SMCs) were irradiated with different doses of nonablative infrared (1064-nm) radiation. Normalized viability index detected with nondestructive Alamar Blue assay and direct cell count were studied. Our experiments demonstrated dose-dependent cytostatic or cytotoxic effects of laser irradiation. We also evaluated the long-term effect of endoluminal nonablative infrared laser irradiation on neointimal hyperplasia in a rabbit balloon injury model. PTCA of both iliac arteries of 23 New Zealand White rabbits was performed. One iliac artery was subjected to intra-arterial subablative infrared irradiation via a diffuse tip fiber. The contralateral vessel served as control. The diet was supplemented with 0.25% cholesterol and 2% peanut oil for 10 days before and 60 days after PTCA. Morphometry after 60 days showed that intimal areas were 0.76±0.18 and 1.85±0.30 mm
2
in the laser and control arteries, respectively (
P
=2.2×10
−11
).

Conclusions

We conclude that nonablative infrared laser inhibited neointimal hyperplasia after PTCA in cholesterol-fed rabbits for up to 60 days.
Birth Weight and Blood Pressure in Young Adults
Authors: Loos Ruth J.F. , Fagard Robert , Beunen Gaston , Derom Catherine , Vlietinck Robert
Published: September 2007

Background

The intrauterine environment may be a critical period for the development of hypertension in later life. In the present study, we applied the twin approach to estimate the contribution of genetic and environmental causes that may underlie the birth weight–adult blood pressure association.

Methods and Results

Birth weights of 418 twin pairs were obtained prospectively, and resting and 24-hour ambulatory blood pressures were obtained at the age of 18 to 34 years. In women, resting systolic blood pressure decreased 4.27 mm Hg (
P
<0.001) and diastolic pressure decreased 2.18 mm Hg (
P
=0.02) per kilogram increase in birth weight. Similar associations were found for ambulatory measurements, although these were somewhat less pronounced. Pair-wise analysis confirmed these findings: twin pairs of whom both members had a low birth weight (<2500 g) had a higher systolic blood pressure compared with twins who both had a high birth weight (≥2500 g). Systolic blood pressure of the lightest of a low-birth-weight pair was ≥4.7 mm Hg (
P
=0.02) higher and of the heaviest ≥2.4 mm Hg higher (
P
=0.2) than similar measurements in high-birth-weight pairs. Intrapair differences in blood pressure between the lightest and the heaviest at birth were only present in low-birth-weight pairs. The results were similar for monozygotic and dizygotic twin pairs. In men, no associations were found between birth weight and adult blood pressure.

Conclusions

These findings suggest that prenatal programming of adult blood pressure occurs at least in female twins. We suggest that particularly maternal influences, experienced by both twin members, may underlie the association between birth weight and blood pressure. The fetoplacental unit seems to influence blood pressure only when both fetuses had low birth weight.
Reduction of Cardiovascular Risk by Regression of Electrocardiographic Markers of Left Ventricular Hypertrophy by the Angiotensin-Converting Enzyme Inhibitor Ramipril
Authors: Mathew James , Sleight Peter , Lonn Eva , Johnstone David , Pogue Janice , Yi Qilong , Bosch Jackie , Sussex Bruce , Probstfield Jeffrey , Yusuf Salim
Published: September 2007

Background

Electrocardiographic markers of left ventricular hypertrophy (LVH) predict poor prognosis. We determined whether the ACE inhibitor ramipril prevents the development and causes regression of ECG-LVH and whether these changes are associated with improved prognosis independent of blood pressure reduction.

Methods and Results

In the Heart Outcomes Prevention Evaluation (HOPE) study, patients at high risk were randomly assigned to ramipril or placebo and followed for 4.5years. ECGs were recorded at baseline and at study end. We compared prevention/regression and development/persistence of ECG-LVH in the two groups and related these changes to outcomes. At baseline, 676 patients had LVH (321 in the ramipril group and 355 in the placebo group) and 7605 patients did not have LVH (3814 in the ramipril group and 3791 in the placebo group). By study end, 336 patients in the ramipril group (8.1%) compared with 406 in the placebo group (9.8%) had development/persistence of LVH; in contrast, 3799 patients in the ramipril group (91.9%) compared with 3740 in the placebo group (90.2%) had regression/prevention of LVH (
P
=0.007). The effect of ramipril on LVH was independent of blood pressure changes. Patients who had regression/prevention of LVH had a lower risk of the predefined primary outcome (cardiovascular death, myocardial infarction, or stroke) compared with those who had development/persistence of LVH (12.3% versus 15.8%,
P
=0.006) and of congestive heart failure (9.3% versus 15.4%,
P
<0.0001).

Conclusions

The ACE inhibitor ramipril decreases the development and causes regression of ECG-LVH independent of blood pressure reduction, and these changes are associated with reduced risk of death, myocardial infarction, stroke, and congestive heart failure.
Effect of Medroxyprogesterone Acetate on Endothelium-Dependent Vasodilation in Postmenopausal Women Receiving Estrogen
Authors: Wakatsuki Akihiko , Okatani Yuji , Ikenoue Nobuo , Fukaya Takao
Published: September 2007

Background

Estrogen increases endothelium-dependent vasodilation in postmenopausal women. However, use of progestins in combination with estrogen may counter beneficial effects of estrogen on endothelium. We investigated the effect of medroxyprogesterone acetate (MPA) on estrogen-induced increase in endothelium-dependent vasodilation in postmenopausal women.

Methods and Results

Postmenopausal women were treated daily with conjugated equine estrogen (CEE) 0.625 mg (n=14), CEE 0.625 mg and MPA 2.5 mg (n=15) or CEE 0.625 mg and MPA 5.0 mg (n=16) for 3 months. Plasma lipids and hormones were measured before and after treatment. Vasodilatory responses of the brachial artery were evaluated by measuring flow-mediated vasodilation (FMD) and nitroglycerin-induced vasodilation by use of high-resolution ultrasonography. Susceptibility of LDL to oxidation was analyzed by incubation with CuSO
4
while kinetics of conjugated diene formation was monitored. Plasma total and LDL cholesterol concentrations were decreased significantly in all groups. CEE increased FMD significantly, from 4.5±1.7% to 8.5±2.8% (
P
<0.001). Addition of MPA reversed this effect in a concentration-dependent manner (for MPA 2.5 mg, from 5.0±3.2% to 6.2±3.1%; for MPA 5.0 mg, from 4.9±3.4% to 3.6±3.7%;
P
=NS for each). No treatment significantly altered nitroglycerin-induced dilation. Lag time for conjugated diene formation was prolonged significantly in all groups, and the oxidation rate was significantly reduced.

Conclusions

Concurrent MPA administration may offset favorable effects of estrogen on endothelial function in postmenopausal women. Because MPA did not diminish LDL-lowering and antioxidant effects of estrogen, MPA-induced inhibition of endothelium-dependent vasodilation may be independent of changes in oxidative susceptibility and plasma concentration of LDL.
Vasopeptidase Inhibitors
Authors: Corti Roberto , Burnett Jr John C. , Rouleau Jean L. , Ruschitzka Frank , Lüscher Thomas F.
Published: September 2007

The cardiovascular system is regulated by hemodynamic and neurohumoral mechanisms. These regulatory systems play a key role in modulating cardiac function, vascular tone, and structure. Although neurohumoral systems are essential in vascular homeostasis, they become maladaptive in disease states such as hypertension, coronary disease, and heart failure. The clinical success of ACE inhibitors has led to efforts to block other humoral systems. Neutral endopeptidase (NEP) is an endothelial cell surface zinc metallopeptidase with similar structure and catalytic site. NEP is the major enzymatic pathway for degradation of natriuretic peptides, a secondary enzymatic pathway for degradation of kinins, and adrenomedullin. The natriuretic peptides can be viewed as endogenous inhibitors of the renin angiotensin system. Inhibition of NEP increases levels of atrial natriuretic peptide (ANP), brain natriuretic peptide (BNP) of myocardial cell origin, and C-type natriuretic peptide (CNP) of endothelial cell origin as well as bradykinin and adrenomedullin. By simultaneously inhibiting the renin-angiotensin-aldosterone system and potentiating the natriuretic peptide and kinin systems, vasopeptidase inhibitors reduce vasoconstriction, enhance vasodilation, improve sodium/water balance, and, in turn, decrease peripheral vascular resistance and blood pressure and improve local blood flow. Within the blood vessel wall, this leads to a reduction of vasoconstrictor and proliferative mediators such as angiotensin II and increased local levels of bradykinin (and, in turn, nitric oxide) and natriuretic peptides. Preliminary clinical experiences with vasopeptidase inhibitors are encouraging. Thus, the combined inhibition of ACE and neutral endopeptidase is a new and promising approach to treat patients with hypertension, atherosclerosis, or heart failure.
Multimodal Fetal Transesophageal Echocardiography for Fetal Cardiac Intervention in Sheep
Authors: Kohl Thomas , Westphal Martin , Strümper Danja , Achenbach Sarah , Halimeh Susan , Petry Philipp , Aryee Sebastian , Buller Tim , Aleksiene Rasa , Asfour Boulos , Witteler Ralf , Vogt Johannes , Van Aken Hugo , Scheld Hans H.
Published: September 2007

Background

The overall performance of available mechanical intravascular ultrasound catheters for fetal transesophageal echocardiography during fetoscopic fetal cardiac interventions in sheep has been limited by radioelectronic interference, low system frame rates, and low acoustic outputs. Therefore, a more reliable device is desired for human fetoscopic surgical procedures.

Methods and Results

We assessed the potential of a newly available 10-French phased-array intravascular ultrasound catheter for multimodal fetal transesophageal echocardiography in 5 fetal sheep between 78 and 98 days of gestation (term, 145 to 150 d). The intravascular ultrasound catheter was easily inserted through the mouth into the esophagus in all 5 sheep fetuses (mean weight, 600 g), and it permitted high-quality 2D imaging of the fetal heart in vertical imaging planes that were validated by MRI. Color Doppler and pulsed Doppler imaging permitted clear assessment of fetal cardiovascular flows and recording of velocity-time integral tracings of the fetal heart and great vessels. The vertical imaging planes were particularly useful to demonstrate interventional material inside the fetal heart and great vessels.

Conclusions

Our early experience with the phased-array intravascular ultrasound catheter indicates that multimodal fetal transesophageal echocardiography has now become possible in these smallest of patients.
Paradoxic Decrease in Ischemic Mitral Regurgitation With Papillary Muscle Dysfunction
Authors: Messas Emmanuel , Guerrero J. Luis , Handschumacher Mark D. , Chow Chi-Ming , Sullivan Suzanne , Schwammenthal Ehud , Levine Robert A.
Published: September 2007

Background

Ischemic mitral regurgitation (MR) was first ascribed to papillary muscle (PM) contractile dysfunction. Current theories include apical leaflet tethering caused by left ventricular (LV) distortion, but PM dysfunction is still postulated and commonly diagnosed. PM contraction, however, parallels apical tethering, suggesting the hypothesis that PM contractile dysfunction can actually diminish MR due to ischemic distortion of the inferior base alone.

Methods and Results

We therefore occluded the proximal circumflex circulation in 7 sheep while maintaining PM perfusion, confirmed by contrast echocardiography. By 3D echocardiography, we measured the tethering distance between the ischemic medial PM tip and anterior annulus and LV ejection volume to give MR (by subtracting flowmeter LV outflow). In 6 sheep without initial MR, inferior ischemia alone produced PM tip retraction with restricted leaflet closure and mild-to-moderate MR (regurgitant fraction, 25.2±2.8%). Adding PM ischemia consistently decreased MR and tethering distance (5.2±0.3 to 1.4±0.3 mL; +3.8±0.5 mm to −2.2±0.7 mm axially relative to baseline;
P
<0.001) as PM strain rate decreased from +0.78±0.07 per second (contraction) to −0.42±0.06 per second (elongation,
P
<0.001) and leaflet tenting decreased. In one sheep, prolapse and MR resolved with inferior ischemia and recurred with PM ischemia.

Conclusions

PM contractile dysfunction can paradoxically decrease MR from inferobasal ischemia by reducing leaflet tethering to improve coaptation. This emphasizes the role of geometric factors in ischemic MR mechanism and potential therapy.