bluuebunny/crossref_metadata_2025 huggingface dataset:
Lack of Evidence for Linkage of the Endothelial Cell Nitric Oxide Synthase Gene to Essential Hypertension
Authors: Bonnardeaux Alain , Nadaud Sophie , Charru Anne , Jeunemaitre Xavier , Corvol Pierre , Soubrier Florent
Published: June 2012

Background
The basal release of nitric oxide by the endothelium plays an important role in regulating blood flow and pressure and mediates most of the endothelium-dependent vasodilation. Impairment of nitric oxide production by specific inhibitors increases blood pressure in humans, and several reports suggest that hypertensive subjects have a blunted endothelium-dependent vasodilatation that might be secondary to decreased nitric oxide production from the vessel wall.

Methods and Results
To determine whether the endothelial nitric oxide synthase gene is involved in human essential hypertension, we identified informative biallelic and multiallelic markers of this locus and performed case-control and linkage studies in hypertensive subjects and normotensive control subjects. We used the affected sib pair method to test for potential linkage in 145 hypertensive pedigrees (269 sib pairs, 346 subjects) with a highly polymorphic marker of the nitric oxide synthase gene (polymorphism information content of 92%). There was no evidence for linkage among affected siblings. The 95% upper confidence limit of this value suggests that at most 1% of alleles in excess of expected are shared. We also identified two informative biallelic markers of this gene to perform a case-control study on white hypertensive and normotensive subjects. Similar genotype distributions between the two groups were noted for both markers. Estimated haplotype frequencies by maximum likelihood methods combining the two biallelic markers were also similar in both groups.

Conclusions
These findings do not suggest that common molecular variants of the endothelial nitric oxide synthase gene are involved in essential hypertension.
Dispersion of ‘Refractoriness’ in Noninfarcted Myocardium of Patients With Ventricular Tachycardia or Ventricular Fibrillation After Myocardial Infarction
Authors: Misier Anand R. Ramdat , Opthof Tobias , van Hemel Norbert M. , Vermeulen Jessica T. , de Bakker Jacques M.T. , Defauw Jo J.A.M. , van Capelle Frans J.L. , Janse Michiel J.
Published: June 2012

Background
Postinfarction ventricular tachycardias (VTs) may degenerate into ventricular fibrillation (VF), but this does not happen in all patients. The underlying mechanism is not exactly known, but dispersion of refractory periods is considered a major factor in both induction and persistence of reentrant arrhythmias in general. Hypertrophied, noninfarcted myocardium has altered electrophysiological characteristics. We hypothesized that noninfarcted ventricular tissue may provide the heterogeneities that cause the transition from VT into VF. Local fibrillation intervals, ie, the average interval between local activations during VF, have previously been shown to correlate well with local refractoriness in human and canine atrium and in porcine and canine ventricle and may therefore be used as an index of local refractoriness. This technique permits simultaneous assessment of refractoriness at multiple sites.

Methods and Results
We measured local fibrillation intervals at 32 to 64 sites in the noninfarcted part of the left ventricle in patients undergoing antiarrhythmic surgery for symptomatic, drug-refractory, postinfarction ventricular tachyarrhythmias. The grid of electrodes (interelectrode distance, 7 mm) was attached to the epicardium of the left ventricle remote from the infarcted tissue. Group 1 consisted of 7 patients with hemodynamically tolerable sustained VT (VT group). Group 2 consisted of 7 patients with cardiac arrest and documented VF (VF group). With the patients on cardiopulmonary bypass, VF was induced by multiple premature stimulation. The VF interval was not significantly different in the two study groups (VT group, 136±5.5 ms; VF group, 129±3.4 ms, mean±SEM). However, spatial dispersion of the VF intervals (remote from the infarcted area) expressed as the coefficient of variation of VF intervals (SD×100/mean VF interval in each heart) was significantly larger in the VF group. It was 3.63±0.56 in the VF group and 1.55±0.40 in the VT group (mean±SEM;
P
<.01). Differences between the shortest and longest VF intervals in one and the same heart and the largest difference between two adjacent sites were also larger in the VF group (
P
<.02 and
P
<.05, respectively).

Conclusions
This study shows larger dispersion in VF intervals and therefore suggests larger dispersion of refractory periods in parts of the myocardium remote from the infarction in patients with postinfarction VF than in patients with postinfarction VT.
Effect of Dual Atrioventricular Node Pathways on Atrioventricular Reentrant Tachycardia
Authors: Csanadi Zoltan , Klein George J. , Yee Raymond , Thakur Ranjan K. , Li Huagui
Published: June 2012

Background
Dual atrioventricular (AV) node pathway physiology is frequently observed in patients with AV accessory pathways.

Methods and Results
To examine the implications of this, we identified 36 patients (19 men and 17 women; mean±SD age, 30±13 years) with both phenomena. The 36 patients had 48 accessory pathways. Twenty-seven patients had bidirectional and 9 had unidirectional accessory pathways. Of the 34 patients with inducible atrioventricular reentry, 17 used the slow and 11 used the fast anterograde AV node pathway exclusively during AV reentrant tachycardia, whereas 6 patients used both the fast and the slow AV node pathways. AV node reentrant tachycardia was inducible in addition to AV reentry in 7 patients. Both the cycle length and AH intervals were significantly longer during slow pathway–dependent (cycle length, 411±58 milliseconds [ms]; AH, 229±42 ms) than during fast pathway–dependent (cycle length, 322±40 ms; AH, 121±25 ms;
P
<.05) reentrant tachycardias. Two patients had only AV node reentrant tachycardia inducible despite the presence of the accessory pathway. Four patients with technically difficult accessory pathways were managed by AV node modification with slow pathway (3) or fast pathway (1) ablation. Three of them remained free of symptoms 7, 14, and 25 months after the procedure whereas 1 patient had recurrence of arrhythmia.

Conclusions
AV reentrance with dual AV node pathways frequently depends exclusively on either the slow or the fast AV node pathway for clinical tachycardia. This may provide additional options for ablation in technically difficult cases when the accessory pathway is not otherwise problematic.
Measurement of Absolute Epicardial Coronary Artery Flow and Flow Reserve With Breath-Hold Cine Phase-Contrast Magnetic Resonance Imaging
Authors: Clarke Geoffrey D. , Eckels Robin , Chaney Curtis , Smith Dorothy , Dittrich Jason , Hundley W. Gregory , NessAiver Moriel , Li Hong Fang , Parkey Robert W. , Peshock Ronald M.
Published: June 2012

Background
Noninvasive measurement of absolute coronary arterial flow and coronary flow reserve would be of considerable use in the diagnosis and management of patients with coronary artery disease. Phase-contrast magnetic resonance imaging (MRI) has been used to measure flow in a variety of vessels. The goal of the present study was to determine if MRI measurements of coronary artery flow in a single breath-hold can be used to determine flow reserve and the severity of pericardial stenosis.

Methods and Results
In eight mongrel dogs, a closed chest model of partial left anterior descending coronary artery (LAD) occlusion was created. Coronary flows in the left circumflex artery (LCx) and LAD were measured at rest and during adenosine infusion using velocity-encoded, breath-hold MRI and perivascular ultrasound (US) flowmeters. MRI measurements of absolute coronary flow and coronary flow reserve were highly correlated with US (
r
=.96 and .94, respectively). Flow reserve measured in the constricted LAD was significantly lower than that in the unconstricted LCx by both US (
P
=.002) and MRI (
P
=.011).

Conclusions
MRI measurements of coronary flow and flow reserve were in good agreement with US measurements. In addition, MRI measurements of coronary flow reserve successfully discriminated stenotic from normal vessels. These results indicate that MRI is a useful method for the noninvasive assessment of coronary flow and stenosis.
Pulmonary and Left Ventricular Decompression by Artificial Pulmonary Valve Incompetence During Percutaneous Cardiopulmonary Bypass Support in Cardiac Arrest
Authors: Scholz Karl H. , Figulla Hans R. , Schröder Thomas , Hering Jens P. , Bock Herbert , Ferrari Marcus , Kreuzer Heinrich , Hellige Gerhard
Published: June 2012

Background
In cardiac arrest, use of percutaneous cardiopulmonary bypass support (PCPS) may lead to left ventricular loading, with deleterious effects on the myocardium, and is often accompanied by an increase in pulmonary artery pressure. The present study was designed to assess the potential of artificially induced pulmonary valve incompetency to retrogradely decompress the left ventricle during PCPS in ventricular fibrillation.

Methods and Results
Studies were performed using a standardized experimental animal model in sheep (n=12; body weight, 77 to 112 kg). When PCPS was used during fibrillation, an increase in left ventricular pressure (from 21.4±5.0 mm Hg after 1 minute to 28.4±9.5 mm Hg after 10 minutes of fibrillation) was observed in all animals, with a simultaneous increase in pulmonary artery pressure in 6 animals from 15.5± 3.8 to 24.3±5.4 mm Hg (group A). In these animals, artificial pulmonary valve incompetency, which was induced by a special “pulmonary valve spreading catheter,” led to effective decompression of both the pulmonary circulation (decrease in pulmonary artery pressure from 24.3 to 11.3 mm Hg) and the left ventricle (decrease in left ventricular pressure from 30.5 to 17.7 mm Hg). We simultaneously measured a decrease in the myocardial release of lactate (increase in arterial coronary-venous difference in lactate content from −0.01 to 0.14 mmol/L), demonstrating the myocardial protective effect of the procedure. In contrast, in 6 animals without an increase in pulmonary artery pressure during PCPS (group B), artificial pulmonary valve incompetency did not reduce left ventricular loading, which was probably because of competent mitral valves in these animals.

Conclusions
In case of increasing pulmonary artery pressure during PCPS in cardiac arrest, artificial pulmonary valve incompetency might be a useful tool for effective pulmonary and retrograde left ventricular decompression.
Recovery of Disturbed Endothelium-Dependent Flow in the Collateral-Perfused Rabbit Ischemic Hindlimb After Administration of Vascular Endothelial Growth Factor
Authors: Bauters Christophe , Asahara Takayuki , Zheng Lu P. , Takeshita Satoshi , Bunting Stuart , Ferrara Napoleone , Symes James F. , Isner Jeffrey M.
Published: June 2012

Background
Disturbed endothelium-dependent blood flow has been shown to be a feature of native collateral vessels. Recent studies have shown that recombinant angiogenic growth factors augment collateral development in animal models of hindlimb ischemia. We therefore investigated the hypothesis that the administration of an angiogenic growth factor, in this case vascular endothelial growth factor (VEGF), may promote recovery of disturbed endothelium-dependent blood flow in a rabbit model of hindlimb ischemia.

Methods and Results
Ischemia was induced by ligation of the external iliac artery and excision of the femoral artery in one limb of New Zealand White rabbits (day 0). Flow velocity was measured using a Doppler guide wire at rest and after administration of serotonin and acetylcholine. Blood flow (in mL/min) was calculated assuming a circular lumen geometry. In untreated control animals with an ischemic limb, serotonin administered at day 10 or 40 produced a decrease in hindlimb blood flow (71±2% and 33±6% reduction from baseline, respectively); in contrast, among animals treated with a single 500-μg bolus dose of VEGF administered selectively into the internal iliac artery at day 10 and studied at day 40, serotonin produced an increase in flow (119±8% from baseline;
P
<.05 versus control animals). Acetylcholine induced only a moderate increase in flow in control animals (152±15% at day 10 and 177±14% at day 40) in contrast to a profound increase among VEGF-treated animals studied at day 40 (254±25%;
P
<.05 versus control animals).

Conclusions
To our knowledge, these findings constitute the first demonstration of successful pharmacological modulation of disturbed endothelium-dependent flow in the arterial circulation subserved by collateral vessels. This physiological benefit complements previously reported anatomic findings suggesting a favorable impact of angiogenic growth factors on collateral-dependent limb ischemia.
Mechanisms of Ischemic Preconditioning in Rat Myocardium
Authors: Vuorinen Klaus , Ylitalo Kari , Peuhkurinen Keijo , Raatikainen Pekka , Ala-Rämi Antti , Hassinen Ilmo E.
Published: June 2012

Background
Adenosine has been proposed as one mediator for the preconditioning effect in the myocardium of some animals, but recent investigations have shown that this may not be the mechanism in the rat heart, although the effect itself is clearly demonstrable. The cellular energy state has been shown to be better in preconditioned hearts, and the role of ATP consumption has been discussed. The role of inhibition of mitochondrial F
1
F
o
-ATPase as a mechanism for the preservation of ATP in preconditioned hearts remains controversial.

Methods and Results
Three-minute global ischemia followed by 9 minutes of reperfusion was used to precondition Langendorff-perfused rat hearts, and control hearts were perfused under normoxic conditions for the same time. The duration of sustained ischemia in both groups of hearts was 21 minutes, after which the hearts were reperfused for 15 minutes to evaluate their mechanical and metabolic recovery. Separate experiments were performed for tissue metabolite determinations, mitochondrial ATPase activity measurements, and
31
P nuclear magnetic resonance studies. The recovery of the rate-pressure product was better in the preconditioned group. Three-minute preconditioning ischemia caused inhibition of the mitochondrial ATPase that persisted throughout the 9-minute intervening reperfusion so that at the early stages of sustained ischemia the enzyme activity was still more inhibited in preconditioned hearts. ATP was better preserved in preconditioned hearts than in control hearts during sustained ischemia. The accumulation of adenosine and its degradation products during sustained ischemia was greater in the control group. More lactate and H
+
ions accumulated in this group, indicating higher anaerobic glycolysis. Also, inhibition of mitochondrial ATPase by oligomycin slowed ATP depletion during ischemia.

Conclusions
The results indicate that preconditioning causes inhibition of rat heart mitochondrial ATPase that persists during reperfusion so that the enzyme is inhibited from the very beginning of the sustained ischemia. This inhibition leads to sparing of high-energy phosphates and improves the time-averaged energy state during ischemia. Although a causal relationship is difficult to prove, this reversible inhibition may contribute to postischemic recovery of the heart.
A Myosin Missense Mutation, Not A Null Allele, Causes Familial Hypertrophic Cardiomyopathy
Authors: Nishi Hirofumi , Kimura Akinori , Harada Haruhito , Koga Yoshinori , Adachi Kyo , Matsuyama Kohmei , Koyanagi Takeshi , Yasunaga Seikoh , Imaizumi Tsutomu , Toshima Hironori , Sasazuki Takehiko
Published: June 2012

Background
Hypertrophic cardiomyopathy (HCM) is characterized by myocardial hypertrophy of unknown etiology. Missense mutations of the cardiac β–myosin-heavy-chain (β-MHC) gene that may be responsible for cardiac hypertrophy have been detected in patients with HCM. On the other hand, gross structural abnormalities in the cardiac β-MHC gene, ie, an α/β hybrid gene and partial deletion of the gene, have also been reported. The direct correlation between gross abnormalities and development of HCM is not well understood.

Methods and Results
We analyzed the structure of the cardiac β-MHC gene from patients with HCM by using polymerase chain reaction–DNA conformation polymorphism analysis and found two sequence variations in exons 3 and 22 in one patient. These sequence variations at codon 54 (exon 3; nonsense mutation) and codon 870 (exon 22; Arg-to-His mutation) were identified by direct sequencing and dot-blot hybridization with allele-specific oligonucleotide probes. Relatives of this patient were examined for the mutations. It was revealed that the missense mutation was inherited from the affected father and the nonsense mutation from the unaffected grandmother through the unaffected mother. In addition, the missense mutation was also found in seven other patients from two other unrelated multiplex HCM families.

Conclusions
The Arg
870
His mutation was suggested to cause HCM. In contrast, the gene with the nonsense mutation would encode for a cardiac β-MHC protein of only 53 amino acid residues, which may be too short to be incorporated into the thick filament assembly of cardiac myosin chains and showed no dominant phenotype of heart disease. This is the first report of a nonsense mutation in the human cardiac β-MHC gene.
Association of Fibrinolytic Parameters With Early Atherosclerosis
Authors: Salomaa V. , Stinson JD V. , Kark J.D. , Folsom A.R. , Davis C.E. , Wu K.K.
Published: June 2012

Background
Thrombosis, provoked by a rupture of an atherosclerotic plaque, plays a crucial role in precipitating a coronary heart disease event. Its role at the early stage of atherosclerosis has, however, been unclear, but it has been hypothesized that thrombosis or defective fibrinolysis contributes to the progression of atherosclerotic lesions.

Methods and Results
We studied the association of plasminogen activator inhibitor antigen (PAI-1), tissue-type plasminogen activator antigen (TPA), and D-dimer with early atherosclerosis in a cross-sectional case-control study involving 457 pairs chosen from the biracial cohort of the Atherosclerosis Risk in Communities (ARIC) Study. As examined by B-mode ultrasound, patients (cases) had intima-media thickness of carotid arteries above the 90th percentile and control subjects had thickness below the 75th percentile of the ARIC cohort. Persons with a history of heart disease, stroke, or claudication were excluded from the case-control selection. PAI-1, TPA, and D-dimer were higher in patients than in control subjects (
P
≤.001, Wilcoxon signed rank statistic). In conditional logistic regression analyses, the odds ratios of carotid atherosclerosis were, for PAI-1, for example, 1.22, 1.54, and 1.60 in the second, third, and fourth quartiles compared with the first quartile (
P
<.0001, test of linear trend, adjusting for age, systolic blood pressure, total cholesterol, acetylsalicylic acid use, and time of blood draw). Corresponding tests for D-dimer and TPA also showed an increasing trend (
P
<.0001).

Conclusions
The findings support the hypothesis that thrombosis and fibrinolysis play a role at the early stage of the atherosclerotic process.
Differential Expression of Tissue Factor Protein in Directional Atherectomy Specimens From Patients With Stable and Unstable Coronary Syndromes
Authors: Annex Brian H. , Denning Stephen M. , Channon Keith M. , Sketch Michael H. , Stack Richard S. , Morrissey James H. , Peters Kevin G.
Published: June 2012

Background
Tissue factor (TF) is a cell membrane–associated protein that catalyzes the rate-limiting step of the extrinsic coagulation pathway, which is the major source of thrombin production in vivo. To explore the potential role that TF may play in ischemic coronary syndromes, directional coronary atherectomy specimens were tested for the presence of TF protein using immunohistochemical techniques.

Methods and Results
Frozen sections from atherectomy specimens in 61 patients were examined for TF expression using an IgG murine monoclonal antibody against human TF. Patients were classified according to their admission diagnosis as having either an unstable or a stable coronary syndrome. An unstable coronary syndrome was defined as either angina pectoris occurring at rest or post–myocardial infarction (<1 week) angina. Stable coronary syndromes included patients with stable, progressive, and new-onset (<6 weeks) angina without rest pain. TF was detected in 15 (43%) of 35 patients with unstable coronary syndromes versus only 3 (12%) of 26 patients with stable coronary syndromes (odds ratio, 5.7; 95% confidence interval, 1.3 to 24.3;
P
=.018). Within the subgroup of patients with unstable coronary syndromes, TF was detected in 14 (60%) of 25 patients with de novo lesions versus only 1 (10%) of 10 patients with a restenosis lesion (
P
<.02). An additional 8 patients with stable coronary syndromes due to a restenosis lesion were also negative for TF. Therefore, the overall incidence of TF expression was only 6% (1 of 18) in restenosis lesions compared with 33% (14 of 43) in de novo lesions (
P
<.03).

Conclusions
This study provides the first description of TF protein expression in human coronary artery lesions in vivo. Tissue factor was readily detected in de novo lesions in patients with unstable coronary syndromes, suggesting a role for TF in the pathogenesis of this disease process. Conversely, TF was rarely detected in patients with restenosis lesions even if the resulting clinical presentation was an unstable coronary syndrome. These results may have implications for the management of patients with unstable angina from de novo lesions and patients with ischemic symptoms from a restenosis lesion.
Radiofrequency Ablation of Intra-Atrial Reentrant Tachycardia After Surgical Palliation of Congenital Heart Disease
Authors: Triedman John K. , Saul J. Philip , Weindling Steven N. , Walsh Edward P.
Published: June 2012

Background
Intra-atrial reentrant tachycardia (IART), also called atrial flutter, is a common and potentially lethal complication of surgical correction of congenital heart disease. Medical management of IART is often problematic, which prompts an investigation of the utility of radiofrequency (RF) ablation for management of these arrhythmias.

Methods and Results
Ten consecutive patients referred for treatment of recurrent IART after surgery for congenital heart disease were studied. Median age was 18.4 years, and median duration of arrhythmia was 6.4 years; a median of three antiarrhythmic drugs had been tried. Surgical procedures used were Fontan (6), Mustard/Senning (2), and biventricular repair (2). Intracardiac electrophysiological study demonstrated 30 distinct IART circuits, defined by activation sequence and cycle length. Mean IART cycle length was 323±114 ms. Cycle length was significantly longer in IART circuits that were successfully ablated compared with those that were not (381 versus 248 ms,
P
<.001). RF ablation was attempted in 22 of these circuits. Ablation sites were targeted to presumed exit points from zones of slow conduction by electrophysiological criteria. Sites chosen in this manner clustered in four distinct areas of the right atrium. Of 22 IART circuit ablations attempted, 17 (77%) resulted in acute termination of the tachycardia. In 8 of 10 patients in whom at least one IART circuit was successfully ablated, 4 are free of clinical tachycardia and 3 are improved over short-term follow-up. No complications were encountered.

Conclusions
Multiple IART circuits may be present in patients after surgery for congenital heart defects. Activation sequences observed were diverse and different from those observed in atrial flutter in patients with normal anatomy. Interruption of IART circuits by RF ablation is feasible using mapping techniques aimed at identifying an exit point from a zone of slow conduction. Short-term follow-up suggests that RF ablation may be a useful adjunct in management of IART in these difficult patients.
Do Patients With Primary Pulmonary Hypertension Develop Extensive Central Thrombi?
Authors: Moser Kenneth M. , Fedullo Peter F. , Finkbeiner Walter E. , Golden Jeffrey
Published: June 2012

Background
Distinguishing chronic major vessel thromboembolic pulmonary hypertension from primary pulmonary hypertension is critical because the treatment options differ markedly. Surgical thromboendarterectomy is potentially curative in the former condition, whereas oxygen, vasodilators, perhaps anticoagulation, and lung transplantation are the options for the latter. The development of large thrombi in the main, right, or left pulmonary arteries has not been previously described in patients with primary pulmonary hypertension.

Methods and Results
Three pulmonary hypertensive patients with massive thrombi in the central pulmonary arteries are described. The data indicate that the large central thrombi in these three patients were not hemodynamically significant. In none did perfusion lung scans demonstrate segmental or larger defects.

Conclusions
Large central thrombi can develop in patients with primary pulmonary hypertension. Perfusion lung scans that do not demonstrate segmental or larger defects should alert physicians to this possibility. Chest computed tomography and other studies identifying such thrombi are not adequate in distinguishing such a development from operable chronic major vessel thromboembolic hypertension. Careful review of lobar and segmental artery findings and the pulmonary angiogram, angioscopy, and cardiac catheterization data demonstrating the hemodynamic significance (or lack thereof) of these thrombi are essential in making this important distinction. Furthermore, these observations may constitute an additional indication for anticoagulant therapy in primary pulmonary hypertension.
Comparison Between
201
Tl and
99m
Tc Sestamibi Uptake During Adenosine-Induced Vasodilation as a Function of Coronary Stenosis Severity
Authors: Glover David K. , Ruiz Mirta , Edwards Nathaniel C. , Cunningham Michael , Simanis Juris P. , Smith William H. , Watson Denny D. , Beller George A.
Published: June 2012

Background
Myocardial uptake of either
201
Tl or
99m
Tc-sestamibi (sestamibi) is known to plateau at high coronary flow rates. However, few direct comparisons have been made between these tracers to determine what effect differences in the uptake plateau for the two tracers may have on the detection of coronary stenoses of various severities.

Methods and Results
Twenty-two dogs were instrumented with flow transducers on the left anterior descending (LAD) and circumflex (LCx) arteries. In 6 nonstenotic dogs, adenosine was infused directly into the LAD, whereas 16 dogs with either critical (n=7) or mild (n=9) LAD stenoses received an intravenous infusion. At peak flow,
201
Tl (0.5 mCi), sestamibi (5 to 8 mCi), and radiolabeled microspheres were injected simultaneously. Five minutes later, dogs were killed, and ex vivo imaging of heart slices and gamma-well counting of multiple myocardial samples was performed. Neither
201
Tl nor sestamibi uptake increased in direct proportion to flow. In the 6 nonstenotic dogs, a fivefold increase in LAD flow increased
201
Tl and sestamibi uptake by only 202±6% and 138±4%, respectively (
P
<.0001). In the dogs with critical stenosis, the ratios of stenotic to normal activity by well counting for
201
Tl (0.37±0.05) and sestamibi (0.53±0.06) underestimated the microsphere-determined flow disparity (0.17±0.03) (
P
<.005), but the degree of underestimation was greater for sestamibi (
P
=.001). Similarly, in the dogs with mild stenosis, the stenotic-to-normal ratio for
201
Tl (0.62±0.04) approximated the flow ratio (0.43±0.04) better than sestamibi (0.79±0.03) (
P
<.0001). Sestamibi defects, however, were visually identifiable on the images of the myocardial slices. By image quantification, sestamibi defect magnitude (LAD-to-LCx count ratio) in the critical stenosis group (0.62±0.05) was significantly less than in the mild stenosis group (0.80±0.02) (
P
<.01).

Conclusions
Thus, with adenosine-induced hyperemic flow, both
201
Tl and sestamibi significantly underestimated the magnitude of the flow disparity between stenotic and normal perfusion beds. The degree of underestimation was greater for sestamibi. The clinical implication of these experimental findings for vasodilator perfusion imaging remains to be determined, since factors such as greater redistribution and scatter with
201
Tl could offset its advantages.
Metabolic Determinants of Defibrillation
Authors: Lerman Bruce B. , Engelstein Erica D.
Published: June 2012

Background
The single most important determinant of cardiac arrest outcome is the duration of ventricular fibrillation (VF) preceding delivery of a high-energy shock, because of the adverse effect of VF duration on defibrillation threshold (DFT). Although a metabolic mechanism has been proposed, hypoxia, metabolic acidosis, or alkalosis do not adversely affect DFT. However, since (1) catecholamines and adenosine levels are markedly increased during hypoxia, (2) exogenous catecholamines decrease DFT, and (3) adenosine is a potent antagonist of the electrophysiological effects of catecholamines on ventricular myocardium, we hypothesized that release of adenosine during prolonged VF adversely affects DFT and that this effect occurs through an antiadrenergic mechanism.

Methods and Results
DFT was determined in dogs during infusion of adenosine (300 μg · kg
−1
· min
−1
) and dipyridamole (0.25 mg/kg), an adenosine uptake blocker, a regimen that resulted in adenosine levels in the myocardial effluent equivalent to those achieved after 5 minutes of VF. Adenosine increased transthoracic DFT in each dog by 49±14% (n=21) (mean±SEM) and transmyocardial DFT in a separate group of 10 dogs by 103±16%,
P
=.0003. Pretreatment with the specific A
1
adenosine receptor antagonist 8-cyclopentyltheophylline (CPT) 5 mg/kg completely abolished the effects of adenosine on DFT. The effects of adenosine on DFT were also examined in the denervated state (propranolol 0.2 mg/kg plus bilateral vagotomy). In contrast to its effect in the innervated condition, adenosine had no effect on DFT in the same dogs when denervated, 49±11 versus 53±10 J (
P
=NS).

Conclusions
Adenosine significantly increases transthoracic and transmyocardial DFT, effects that are mediated by the A
1
adenosine myocardial receptor through an antiadrenergic mechanism. These results suggest that enhanced release of adenosine during VF may have a deleterious effect on defibrillation and that intramyocardial delivery of a specific A
1
adenosine antagonist during VF may facilitate defibrillation and significantly reduce defibrillation threshold.
Reentrant Arrhythmias in the Subacute Infarction Period
Authors: Restivo Mark , Yin Hong , Caref Edward B. , Patel Archana I. , Ndrepepa Gjin , Avitable Matthew J. , Assadi Mahshid A. , Isber Nidal , El-Sherif Nabil
Published: June 2012

Background
The Cardiac Arrhythmia Suppression Trial has shown that flecainide was associated with an increased incidence of sudden cardiac death in postinfarction patients. The exact mechanism(s) of the proarrhythmic effects of flecainide remain unclear. We performed a detailed analysis of the electrophysiological and proarrhythmic effects of flecainide in a well-characterized model of reentrant arrhythmias in the subacute phase of myocardial infarction.

Methods and Results
Sixteen dogs were studied 4 days after ligation of the left anterior descending coronary artery. Isochronal mapping of ventricular activation showed that flecainide facilitated both the induction and sustenance of ventricular tachycardia, especially at shorter basic cycle lengths. Flecainide had negligible effect on the length of the arc of functional conduction block but markedly depressed conduction of the common reentrant wave front that was usually oriented parallel to fiber axis. Whole heart mapping was analyzed in combination with basic measurements of the effects of flecainide on conduction and refractory properties of both normal and ischemic myocardia using a high-resolution cross electrode consisting of four orthogonal arms, each comprised of 16 poles with an interelectrode spacing of 500 μm. The electrode was especially designed to study the effects of the drug on anisotropic conduction as determined by a linear regression of activation time and distance in each direction. Flecainide resulted preferentially in more marked rate-dependent depression of conduction in ischemic compared with normal myocardium. On the other hand, the effect of flecainide on refractoriness in both normal and ischemic myocardia was negligible.

Conclusions
Because flecainide caused no significant change in refractoriness in both normal and ischemic myocardia, there was no difference in the dimension of the potential reentrant pathway, that is, the continuous line of functional conduction block, around which the reentrant wave fronts circulate. Yet, flecainide resulted in significant rate-dependent slowing of conduction preferentially in ischemic myocardium. The additional slowing of conduction of the common reentrant wave front coupled with minimal changes in the length of the reentrant pathway allowed additional time for the wave front to reexcite normal myocardium on the proximal side of the arc of block. After flecainide, reentry could be induced in hearts in which reentry could not be induced during control. The same proarrhythmic mechanism explains the propensity of nonsustained figure-8 reentrant tachycardias to become sustained after flecainide.
Cardiovascular Health at the Crossroads: Outlook for the 21st Century
Authors: Oparil Suzanne
Published: June 2012

There is nothing more vulnerable than entrenched success.

—George Romney
Genetic Heterogeneity of Heart-Hand Syndromes
Authors: Basson Craig T. , Solomon Scott D. , Weissman Barbara , MacRae Calum A. , Poznanski Andrew K. , Prieto Felix , de la Fuente Salvador Ruiz , Pease William E. , Levin S.E. , Holmes Lewis B. , Seidman J.G. , Seidman Christine E.
Published: June 2012

Background
Heart-hand syndromes compose a class of combined congenital cardiac and limb deformities. The prototypical heart-hand disorder is Holt-Oram syndrome, which is characterized by cardiac septation defects and radial ray limb deformity. We have recently mapped the Holt-Oram syndrome gene defect to the long arm of human chromosome 12 in two families. The role of this disease locus in the pathogenesis of related conditions such as heart-hand syndrome type III (cardiac conduction disease accompanied by skeletal malformations) or familial atrial septal defects is unknown.

Methods and Results
Clinical evaluations and genetic linkage analyses were performed in five additional kindreds with Holt-Oram syndrome and also in one kindred with heart-hand syndrome type III and one kindred with familial atrial septal defect and conduction disease. Holt-Oram syndrome in all five kindreds mapped to chromosome 12q2. These studies and previous data provide odds of greater than 10
25
:1 that the Holt-Oram syndrome disease gene is at chromosome 12q2. In contrast, neither the phenotypically similar disorder heart-hand syndrome type III nor the locus responsible for a familial atrial septal defect with atrioventricular block maps to chromosome 12q2.

Conclusions
We demonstrate that heart-hand syndromes are genetically heterogeneous. Conditions that clinically appear to be partial phenocopies of Holt-Oram syndrome arise from distinct disease genes.
Restenosis After Delayed Coronary Angioplasty of the Culprit Vessel in Patients With a Recent Myocardial Infarction Treated by Thrombolysis
Authors: Bauters Christophe , Khanoyan Patrick , Mc Fadden Eugène P. , Quandalle Philippe , Lablanche Jean-Marc , Bertrand Michel E.
Published: June 2012

Background
Clinical follow-up after percutaneous transluminal coronary angioplasty (PTCA) of an infarct-related lesion has demonstrated a low incidence of recurrent symptoms and repeated revascularization. In the absence of systematic angiographic follow-up, this low rate of clinical restenosis may reflect either a truly lower incidence of anatomic restenosis or the lack of recurrent symptoms in patients with extensive infarction in the territory of the restenotic vessel.

Methods and Results
We studied 300 consecutive patients who, after a thrombolysis for myocardial infarction, underwent delayed (10.5±6 days after the myocardial infarction) PTCA of the infarct-related lesion. Procedural success was obtained in 253 patients (84%), and angiographic follow-up was performed in 205 of this group (81%) at a mean of 7.3±1.9 months. Restenosis (defined as the recurrence of >50% stenosis) was present in 105 patients (51%). Only 34 of the 105 patients (32%) with angiographic restenosis were symptomatic; the other 68% had clinically silent restenosis. Of these 105 patients, 27 (13% of the total population undergoing follow-up angiography) had reocclusion at the dilated site at follow-up. The severity of the stenosis at follow-up and the late loss in minimal lumen diameter followed a nearly Gaussian distribution if the lesions that were totally occluded at follow-up were excluded. By multivariate analysis, two independent predictors of reocclusion were identified: a small reference diameter (
P
<.0005) and the presence of collateral vessels before the procedure (
P
<.01). Only one factor was associated with restenosis in the 178 patients who did not have reocclusion at follow-up: a Thrombolysis in Myocardial Infarction grade ≤2 before the procedure (
P
<.0001). At follow-up, there was a significantly (
P
<.01) higher ejection fraction in patients without restenosis (56.1±13.4%) and in patients with restenosis without total occlusion (56.0±13.8%) than in patients with reocclusion (46.4±13.0%).

Conclusions
Despite a satisfactory clinical outcome, delayed PTCA of an infarct-related lesion is associated with a high rate of angiographic recurrence. Two distinct mechanisms account for recurrent stenosis: progressive luminal renarrowing as documented after angioplasty of stable lesions and reocclusion of the infarct-related lesion. Only reocclusion is associated with a deterioration in left ventricular function at follow-up.
Shear-Induced Platelet Aggregation Is Inhibited by In Vivo Infusion of an Anti–Glycoprotein IIb/IIIa Antibody Fragment, c7E3 Fab, in Patients Undergoing Coronary Angioplasty
Authors: Konstantopoulos Konstantinos , Kamat Suraj G. , Schafer Andrew I. , Bañez Eugenio I. , Jordan Robert , Kleiman Neal S. , Hellums J. David
Published: June 2012

Background
Elevated levels of shear stress such as those that occur in stenotic arterial vessels can directly activate and aggregate platelets and thus contribute to the pathogenesis of acute arterial thrombosis. This shear-induced platelet aggregation (SIPA) is mediated by von Willebrand factor binding to platelet membrane glycoprotein (GP) Ib and GPIIb/IIIa. The chimeric Fab fragment of the monoclonal antibody 7E3 (c7E3 Fab) that binds selectively to GPIIb/IIIa is under clinical evaluation in patients undergoing percutaneous transluminal coronary angioplasty (PTCA). This study was undertaken to investigate the effects on ex vivo SIPA of c7E3 Fab administered to patients undergoing PTCA.

Methods and Results
Six patients received aspirin (325 mg) and boluses of heparin (12 000 U) followed by c7E3 Fab 0.25 mg/kg. Blood collected from each patient before and after heparin treatment and at various time points after c7E3 Fab administration was subjected to laminar shear stress in a cone-and-plate viscometer. Flow cytometry was used to quantify the extents of platelet aggregation and of antibody binding to GPIIb/IIIa. Results indicate that c7E3 Fab injection resulted in a rapid, extensive blockade of GPIIb/IIIa receptors (98.6±0.2%) and a 50% inhibition of ex vivo platelet aggregation induced by shear stress. c7E3 Fab also completely abolished the formation of large platelet aggregates (“large” refers to particles >10 μm in equivalent sphere diameter), which are presumably the aggregates of greatest clinical significance. Partial reversibility of the inhibition was noted within 2 days after drug administration, but even after 1 week, platelet function had not been fully restored.

Conclusions
This study demonstrates that c7E3 Fab is a potent inhibitor of SIPA, which may be an important mechanism of its beneficial effect in the treatment of arterial occlusive diseases and in the prevention of thrombotic complications of coronary artery disease after angioplasty.
Early Balloon Dilatation of the Pulmonary Valve in Infants With Tetralogy of Fallot
Authors: Sluysmans T. , Neven B. , Rubay J. , Lintermans J. , Ovaert C. , Mucumbitsi J. , Shango P. , Stijns M. , Vliers A.
Published: June 2012

Background
Balloon dilatation, an established treatment for pulmonary valve stenosis, remains a controversial procedure in tetralogy of Fallot.

Methods and Results
Balloon dilatation of the pulmonary valve was performed in 19 infants with tetralogy of Fallot. Its effects on the severity of cyanosis, the growth of the pulmonary valve and pulmonary arteries, and the need for transannular patching were evaluated. Clinical, echographic, angiographic, hemodynamic, and operative data were analyzed. The procedure was safe in all, without significant complications. After balloon dilatation, systemic oxygen saturation increased from a mean value of 79% to 90%. This increase proved to be short-lasting in 4 patients, who required surgery before the age of 6 months. Balloon dilatation increased pulmonary annulus size in each case, from a mean value of 4.9 to 6.9 mm (
P
<.001). This gain in size remained stable over time, with a mean
Z
score of −4.8 SD before dilatation, −3.1 SD immediately after the procedure, and −2.7 SD at preoperative catheterization (
P
<.001). Pulmonary artery dimensions remained unchanged immediately after balloon dilatation but increased at follow-up from a
Z
score mean value of −2.5 to −0.06 SD and from −2.2 to 0.04 SD for right and left pulmonary arteries, respectively (
P
<.001). At the time of corrective surgery, the pulmonary annulus was considered large enough to avoid a transannular patch in 69% of the infants. This represented a 30% to 40% reduction in the need for a transannular patch compared with the incidence of transannular patch expected before balloon dilatation.

Conclusions
Pulmonary valve dilatation in infants with tetralogy of Fallot is a relatively safe procedure and appears to produce adequate palliation in most patients. It allowed the growth of the pulmonary annulus and of the pulmonary arteries, resulting in a mean gain of 2 SD for those structures.
Protection From Oxidized LDL–Induced Leukocyte Adhesion to Microvascular and Macrovascular Endothelium In Vivo by Vitamin C but Not by Vitamin E
Authors: Lehr Hans-Anton , Frei Balz , Olofsson A. Maria , Carew Thomas E. , Arfors Karl-E.
Published: June 2012

Background
The ability of oxidized LDL (oxLDL) to stimulate leukocyte–endothelium interaction is considered to be an important aspect of its proatherogenic action. Using intravital fluorescence microscopy in the dorsal skinfold chamber model in hamsters, we have previously shown that systemic administration of oxLDL stimulates leukocyte adhesion to microvascular endothelium through a mechanism that involves the generation and action of reactive oxygen species (ROS).

Methods and Results
Through the combined use of scanning electron microscopy and intravital microscopy in the same animal model, we demonstrate that oxLDL-induced leukocyte adhesion is not confined to the microcirculation but can also be observed on aortic endothelium. OxLDL-induced leukocyte adhesion to both microvascular and macrovascular endothelium was almost entirely prevented by pretreatment of the hamsters with dietary or intravenous vitamin C, which has the capacity to scavenge and neutralize ROS (arterioles: 20.5±16.4 cells/mm
2
[diet] and 16.3±23.8 cells/mm
2
[IV] versus 74.2±47.5 cells/mm
2
[control,
P
<.01]; aorta: 1.0±0.4 cells/mm
2
[diet] and 1.1±0.5 cells/mm
2
[IV] versus 14.7±6.0 cells/mm
2
[control,
P
<.01], 15 minutes after oxLDL, n=7 animals per group). Vitamin C pretreatment also completely prevented oxLDL-induced leukocyte-platelet aggregate formation in the bloodstream but did not affect leukocyte rolling along the microvascular endothelium. No inhibitory effect on any of the studied parameters was observed as a result of pretreatment of the animals with the lipid-soluble antioxidants vitamin E and probucol.

Conclusions
The protective effects of vitamin C on oxLDL-induced leukocyte adhesion and aggregate formation were seen at vitamin C plasma levels that can easily be reached in humans by diet or supplementation, suggesting that this could be one of the mechanisms by which vitamin C contributes to the well-documented protraction of atherogenesis as observed in large epidemiological surveys.
Gadolinium Attenuates the Upward Shift of the Left Ventricular Diastolic Pressure-Volume Relation During Pacing-Induced Ischemia in Dogs
Authors: Takano Hiroshi , Glantz Stanton A
Published: June 2012

Background
The mechanism of the reversible upward shift of the left ventricular diastolic pressure-volume relation during demand ischemia is controversial. To assess the possibility that cation influx through stretch-activation channels may contribute to the upward shift, we asked whether gadolinium, a blocker of the stretch-activated channels, attenuates the upward shift of the diastolic pressure-volume relation during pacing-induced ischemia in 5 dogs.

Methods and Results
To produce pacing-induced ischemia, we constricted the left anterior descending and circumflex coronary arteries to reduce their flows by approximately 30% and paced the left atrium at 150 to 180 beats per minute for 3 minutes. We measured left ventricular pressure, volume, and two segment lengths with micromanometers, a conductance catheter, and ultrasonic crystals, respectively. We recorded these variables during baseline, coronary stenosis, and pacing-induced ischemia (immediately after rapid pacing). After injecting 20 mg/kg (76 μmol/kg) gadolinium, we repeated the measurements during coronary stenosis (gadolinium experiment) and pacing-induced ischemia (pacing-induced ischemia plus gadolinium experiment). For each measurement, we recorded the variables in steady state to obtain diastolic pressure-volume and pressure–segment length loops and then during a brief (within 25 seconds) inferior vena caval occlusion to obtain the left ventricular end-diastolic pressure-volume relation. We found that left ventricular diastolic pressure-volume and pressure–segment length loops in steady-state beats shifted upward from coronary stenosis to pacing-induced ischemia. After injection of gadolinium, the upward shift from gadolinium to pacing-induced ischemia plus gadolinium was smaller than the shift from coronary stenosis to pacing-induced ischemia. Similarly, the left ventricular end-diastolic pressure-volume relation obtained during vena caval occlusion shifted upward (by 2.2±0.6 [SE] mm Hg) from coronary stenosis to pacing-induced ischemia. After injection of gadolinium, the upward shift from gadolinium to pacing-induced ischemia plus gadolinium was smaller (by −2.1±0.4 mm Hg).

Conclusions
These results indicate that gadolinium, a blocker of stretch-activated channels, attenuates the upward shift of the diastolic pressure-volume relation during pacing-induced ischemia, suggesting that the cation influx through stretch-activated channels may contribute to this upward shift.