bluuebunny/crossref_metadata_2025 huggingface dataset:
Gene for Progressive Familial Heart Block Type I Maps to Chromosome 19q13
Authors: Brink Paul A. , Ferreira Alet , Moolman Johanna C. , Weymar Hettie W. , van der Merwe Pieter-Luttig , Corfield Valerie A.
Published: June 2012

Background
Progressive familial heart block type I (PF-HBI) is a dominantly inherited cardiac bundle-branch conduction disorder that has been traced through nine generations of a large South African kindred. Similar conduction disorders have been reported elsewhere; however, the cause of these diseases is unknown. The aim of the present study was to determine by linkage analysis the approximate chromosomal position of the gene causing PFHBI, thereby allowing family-based diagnosis and the development of positional cloning strategies to identify the causative gene.

Methods and Results
Eighty-six members of three pedigrees, 39 members of which were affected with PFHBI, were genotyped at four linked polymorphic marker loci mapped to chromosome 19, bands q13.2-q13.3 (chromosome 19q13.2-13.3). Maximum two-point logarithm of the odds scores (which represent the logarithm of the odds ratio of detecting linkage versus nonlinkage) generated were 6.49 (Θ=0) for the kallikrein locus, 5.72 (Θ=0.01) for the myotonic dystrophy locus, 3.44 (Θ=0) for the creatine kinase muscle-type locus and 4.51 (Θ=0.10) for the apolipoprotein C2 locus. The maximum multipoint logarithm of the odds score was 11.6, with the 90% support interval positioning the
PFHBI
locus within a 10 cM distance centering on the kallikrein 1 locus.

Conclusions
The gene for PFHBI maps to an area of approximately 10 cM on chromosome 19q13.2-13.3. There are several candidate genes in this interval; although a recombination event ruled out the myotonic dystrophy locus from direct involvement with PFHBI, the proximity of these two loci may be relevant to the observed cardiac abnormalities of myotonic dystrophy. The results provide a means of DNA-based diagnosis in the families studied and a foundation for cloning studies to identify the causative gene.
Impaired Endothelium-Dependent Vasodilation in Patients With Essential Hypertension
Authors: Panza Julio A. , García Carlos E. , Kilcoyne Crescence M. , Quyyumi Arshed A. , Cannon Richard O.
Published: June 2012

Background
Patients with essential hypertension have abnormal endothelium-dependent vascular relaxation, largely related to reduced bioactivity of nitric oxide (NO). The purpose of the present investigation was to determine whether this defect is due to a deficit at the specific intracellular signal-transduction pathway level or is a consequence of a more generalized endothelial abnormality.

Methods and Results
The responses of the forearm vasculature to acetylcholine and bradykinin (endothelium-dependent agents that act through different signal transduction pathways) and to sodium nitroprusside (a direct dilator of vascular smooth muscle) were studied in 10 hypertensive patients (5 men, 5 women; aged 48±9 years old [mean±SD]) and 12 control subjects (6 men, 6 women; aged 48±7 years old). To determine the contribution of NO to bradykinin-induced vasodilation, the vascular responses to bradykinin were also measured after administration of
N
G
-monomethyl-
l
-arginine, an arginine analogue that inhibits the synthesis of NO. Drugs were infused into the brachial artery, and forearm blood flow was measured by strain-gauge plethysmography. The response to acetylcholine was significantly blunted in hypertensive patients (maximal blood flow, 7.5±2 versus 16.6±8 mL · min
−1
· 100 mL
−1
in control subjects [mean±SD];
P
<.005). Similarly, the vasodilator effect of bradykinin was significantly reduced in hypertensive patients compared with control subjects (maximal blood flow, 8.7±2 versus 15.8±6 mL · min
−1
· 100 mL
−1
in control subjects;
P
<.005). A significant correlation was found between the maximal blood flow with acetylcholine and that with bradykinin (
r
=.89). No significant differences were found between the two groups for vascular response to sodium nitroprusside.
N
G
-monomethyl-
l
-arginine significantly blunted the response to bradykinin in control subjects (maximal blood flow decreased from 15.8±6 to 10.1±2 mL · min
−1
· 100 mL
−1
,
P
<.003). In contrast, inhibition of NO synthesis did not modify the response to bradykinin in hypertensive patients (maximal blood flow, 8.7±2 and 8.5±3 before and during infusion of
N
G
-monomethyl-
l
-arginine, respectively;
P
=NS). As a consequence, the response to bradykinin after inhibition of NO synthesis was not significantly different between the two groups.

Conclusions
Patients with essential hypertension have impaired endothelium-dependent vasodilator responses to both acetylcholine and bradykinin. These findings indicate that the endothelial dysfunction in this condition is not related to a specific defect of a single intracellular signal-transduction pathway and suggest a more generalized abnormality of endothelial vasodilator function.
Role of Neutrophils in Myocardial Ischemia and Reperfusion
Authors: Hansen Peter Riis
Published: June 2012

Abstract
In the intact organism, ischemic myocardial injury initiates an acute inflammatory response in which polymorphonuclear leukocytes (PMNs) are major participants. Evidence indicates that the interplaying inflammatory reactions are augmented by reperfusion and that accumulating PMNs can contribute to myocardial damage, eg, by release of oxygen-derived free radicals, proteases, and leukotrienes. In experimental models, interventions aimed at PMN inhibition can exert cardioprotective effects, and some of these strategies raise hope for future clinical applications. A greater understanding of the mechanisms involved in PMN-mediated myocardial damage is necessary for designing a rational approach to reduce the putative detrimental effects of PMNs without antagonizing their favorable consequences in tissue healing.
Aspirin Inhibits Nuclear Factor–κB Mobilization and Monocyte Adhesion in Stimulated Human Endothelial Cells
Authors: Weber Christian , Erl Wolfgang , Pietsch Angelika , Weber Peter C.
Published: June 2012

Background
The induction of vascular cell adhesion molecule–1 (VCAM-1) and E-selectin by tumor necrosis factor–α (TNF) is mediated by mobilization of the transcription factor nuclear factor–κB (NF-κB). Since salicylates have been reported to inhibit NF-κB activation by preventing the degradation of its inhibitor IκB, we studied a potential inhibition of this pathway by acetylsalicylate (aspirin) in human umbilical vein endothelial cells (HUVECs).

Methods and Results
Gel-shift analyses demonstrated dose-dependent inhibition of TNF-induced NF-κB mobilization by aspirin at concentrations ranging from 1 to 10 mmol/L. Induction of VCAM-1 and E-selectin surface expression by TNF was dose-dependently reduced by aspirin over the same range, while induction of intercellular adhesion molecule–1 (ICAM-1) was hardly affected. Aspirin appeared to prevent VCAM-1 transcription, since it dose-dependently inhibited induction of VCAM-1 mRNA by TNF. As a functional consequence, adhesion of U937 monocytes to TNF-stimulated HUVECs was markedly reduced by aspirin due to suppression of VCAM-1 and E-selectin upregulation. These effects of aspirin were not related to the inhibition of cyclooxygenase activity, since indomethacin was ineffective.

Conclusions
Our data suggest that aspirin inhibits NF-κB mobilization, induction of VCAM-1 and E-selectin, and subsequent monocyte adhesion in endothelial cells stimulated by TNF, thereby providing an additional mechanism for therapeutic effects of aspirin.
Relation Among Stenosis Severity, Myocardial Blood Flow, and Flow Reserve in Patients With Coronary Artery Disease
Authors: Di Carli Marcelo , Czernin Johannes , Hoh Carl K. , Gerbaudo Victor H. , Brunken Richard C. , Huang Sung-Chen , Phelps Michael E. , Schelbert Heinrich R.
Published: June 2012

Background
Coronary arteriography is considered the “gold standard” for evaluating the severity of a coronary stenosis. Because the resistance to blood flow through a stenotic lesion depends on a number of lesion characteristics, the physiological significance of coronary lesions of intermediate severity is often difficult to determine from angiography alone. This study of patients with coronary artery disease seeks to determine the relation between myocardial blood flow and flow reserve measured by positron emission tomography (PET) and the percent area stenosis on quantitative coronary arteriography.

Methods and Results
We studied 28 subjects: 18 patients with coronary artery disease (66±8 years) and 10 age-matched healthy volunteers (64±13 years) with dynamic N-13 ammonia PET imaging at rest and after dipyridamole (0.56 mg/kg). The percent cross-sectional area stenosis was quantified on the coronary arteriograms as described by Brown et al. In the 18 patients, a total of 41 non–infarct-related coronary vessels were analyzed. Myocardial blood flows in normal regions of patients with coronary artery disease were not different than those in healthy volunteers, both at rest and after dipyridamole. As a result, the myocardial flow reserve was also similar in both groups (2.4±0.4 versus 2.6±0.7, respectively;
P
=NS). Quantitative PET estimates of hyperemic blood flow (
r
=.81,
P
<.00001), flow reserve (
r
=.78,
P
<.00001), and an index of the “minimal coronary resistance” (
r
=.78,
P
<.00001) were inversely and nonlinearly correlated with the percent area stenosis on angiography. Of note, PET estimates of myocardial flow reserve successfully differentiated coronary lesions of intermediate severity (50% to 70% and 70% to 90%; 2.4±0.4 versus 1.8±0.5, respectively;
P
=.04).

Conclusions
In patients with coronary artery disease, noninvasive measurements of myocardial blood flow and flow reserve by PET are inversely and nonlinearly related to stenosis severity as defined by quantitative angiography. Importantly, coronary lesions of intermediate severity have a differential flow reserve that decreases as stenosis increases that can be detected noninvasively by PET, thus allowing better definition of the functional importance of known coronary stenosis.
Association Between Increased Estrogen Status and Increased Fibrinolytic Potential in the Framingham Offspring Study
Authors: Gebara Otavio C. E. , Mittleman Murray A. , Sutherland Patrice , Lipinska Izabela , Matheney Travis , Xu Ping , Welty Francine K. , Wilson Peter W. F. , Levy Daniel , Muller James E. , Tofler Geoffrey H.
Published: June 2012

Background
Although extensive evidence indicates that estrogen is responsible for the markedly decreased cardiovascular risk of premenopausal women, the mechanism through which estrogen might exert its protective effect has not been adequately explained. Since thrombosis is now recognized to play an important role in the onset of cardiovascular disease, we investigated the relation between estrogen status and fibrinolytic potential, a determinant of thrombotic risk.

Methods and Results
We determined levels of plasminogen activator inhibitor (PAI-1) antigen and tissue plasminogen activator (TPA) antigen in 1431 subjects from the Framingham Offspring Study. Fibrinolytic potential was compared between subjects with high estrogen status (premenopausal women and postmenopausal women receiving hormone replacement therapy) and low estrogen status (men and postmenopausal women not receiving hormone replacement therapy). In all comparisons, subjects with high estrogen status had greater fibrinolytic potential (lower PAI-1 levels) than subjects with low estrogen status. First, postmenopausal women receiving estrogen replacement therapy had lower levels of PAI-1 than those not receiving therapy (13.0±0.5 versus 19.5±1.0 ng/mL,
P
<.001). Second, premenopausal women had lower levels of PAI-1 than men of a similar age (14.8±0.6 versus 20.3±0.8 ng/mL,
P
<.001); this sex difference diminished when postmenopausal women not receiving hormone replacement therapy were compared with men of a similar age (19.6±0.7 versus 21.1±0.7 ng/mL,
P
=.089). Third, premenopausal women had markedly lower levels of PAI-1 antigen than postmenopausal women not receiving estrogen therapy (14.8±0.6 versus 19.5±1.0 ng/mL,
P
<.001). The between-group differences observed for TPA antigen were similar to those for PAI-1 antigen.

Conclusions
Each of these comparisons indicates that the cardioprotective effect of estrogen may be mediated, in part, by an increase in fibrinolytic potential. These findings might provide at least a partial explanation for the protection against cardiovascular disease experienced by premenopausal women, and the loss of that protection following menopause.
Beat-to-Beat Analysis of Left Ventricular Pressure-Volume Relation and Stroke Volume by Conductance Catheter and Aortic Modelflow in Cardiomyoplasty Patients
Authors: Schreuder J.J. , van der Veen F.H. , van der Velde E.T. , Delahaye F. , Alfieri O. , Jegaden O. , Lorusso R. , Jansen J.R.C. , van Ommen V. , Finet G. , Wellens H.J.J.
Published: June 2012

Background
Since the clinical introduction of dynamic cardiomyoplasty, a discrepancy has been observed between unchanged measurements of cardiac function and improved clinical outcome.

Methods and Results
We performed a beat-to-beat analysis of cardiac performance at rest in nine cardiomyoplasty patients 6 to 24 months after operation. Conductance and micromanometer catheters were placed in left ventricle and aorta and used for measurements over a 15-second period, during which the wrapped latissimus dorsi (LD) muscle was stimulated for 10 seconds in a 1:2 synchronization mode followed by a 5-second period without LD stimulation. The synchronization delay between start of the QRS complex and the LD contraction was changed from 4 up to 125 ms at the patient’s clinical stimulation strength and at an increased supramaximal amplitude. Comparing the LD assisted period to the unassisted period, at the clinical settings no significant changes in stroke volume (SV) as measured by the conductance technique and the aortic Modelflow technique were observed. A significant (
P
<.05) rise in left ventricular end-diastolic pressure (LVEDP) was observed directly after the assisted 10-second period. The peak ejection rate (PER) of left ventricular volume increased (
P
<.05), with a mean of 28±23% during the LD stimulated beats. At the patient’s individual best setting, SV of the stimulated beats increased (
P
<.01) by a mean of 20±15%. Systolic aortic pressure increased (
P
<.01) by a mean of 7 mm Hg, peak negative dP/dt increased (
P
<.01), and PER increased, with a mean of 68±24% (
P
<.01). LVEDP was similar in stimulated and unstimulated beats and increased (
P
<.05) in the nonpaced 5-second period. The delay for the best setting ranged from 25 to 125 ms; the stimulus strength was 1.5 to 3 V higher than the clinical setting. At the patient’s individual worst setting, SV remained unchanged and PER was higher, with a mean of 30±25% (
P
<.05). The worst setting was observed at the 1.5- to 3-V-higher stimulus strength; in six patients, it was at a short delay (4 to 25 ms) and in three patients, at the longest delay (100 to 125 ms).

Conclusions
By the left ventricular conductance catheter and aortic Modelflow methods, improvement in cardiac function by dynamic cardiomyoplasty was demonstrated in this patient group. The synchronization interval, stimulus strength, and stimulus duration appeared to be critical for obtaining optimal improvement.
Blade Balloon Atrial Septostomy in Patients With Severe Primary Pulmonary Hypertension
Authors: Kerstein Diane , Levy Paul S. , Hsu Daphne T. , Hordof Allan J. , Gersony Welton M. , Barst Robyn J.
Published: June 2012

Background
Patients with severe primary pulmonary hypertension have a poor prognosis, but those with a patent foramen ovale may survive longer. A few reports of clinical improvement after blade balloon atrial septostomy in patients with severe pulmonary vascular disease have appeared. The purpose of this study was to systematically evaluate the effects of blade balloon atrial septostomy on clinical signs and symptoms, hemodynamics, and survival in patients with severe primary pulmonary hypertension.

Methods and Results
Blade balloon atrial septostomy was performed on 15 children and young adults with severe primary pulmonary hypertension. Despite maximal medical therapy, prior to septostomy all patients had recurrent syncope and 8 had severe right heart failure. Thirteen patients survived the procedure. After blade balloon atrial septostomy, no patient experienced further syncope, and signs and symptoms of right heart failure improved in all New York Heart Association Class IV patients. Within 24 hours after the procedure and at follow-up catheterization 7 to 27 months after septostomy, there was a significant increase in cardiac index, resulting in an increase in systemic oxygen transport. There was improved long-term survival in the 13 patients who survived blade balloon atrial septostomy compared with similar groups of primary pulmonary hypertension patients who received standard therapy (
P
<.05).

Conclusions
Blade balloon atrial septostomy resulted in clinical and hemodynamic improvement and improved survival in selected patients with severe primary pulmonary hypertension.
Bradykinin Antagonism Inhibits the Antigrowth Effect of Converting Enzyme Inhibition in the Dog Myocardium After Discrete Transmural Myocardial Necrosis
Authors: McDonald Kenneth M. , Mock James , D’Aloia Antonio , Parrish Todd , Hauer Kate , Francis Gary , Stillman Arthur , Cohn Jay N.
Published: June 2012

Background
Converting enzyme inhibitor (CEI) therapy, but not angiotensin II subtype I receptor blockade, has been shown to attenuate left ventricular remodeling in the dog after transmyocardial direct current (DC) shock. The purpose of this study was to address the importance of preservation of bradykinin to the antiremodeling effect of CEI treatment in this model.

Methods and Results
Twenty-four hours after DC shock, adult mongrel dogs were assigned to one of three groups: a control group; a group treated with ramipril 10 mg BID; and a group treated with ramipril 10 mg BID along with a continuous subcutaneous infusion of HOE 140, a bradykinin antagonist. To assess change in left and right ventricular structure, a magnetic resonance imaging (MRI) study was performed 4 weeks after DC shock and compared with a baseline MRI study performed before DC shock. The increase in left ventricular mass (mean±SEM) in the control group was similar to that observed in the CEI–HOE 140 group (+0.73±0.19 versus +0.75±0.18 g/kg,
P
=NS), but both were greater than the change in mass in the ramipril group (−0.48±0.13 g/kg,
P
=.004 and
P
=.0005, respectively). No significant change occurred in left ventricular volume or right ventricular structure in any group. Mean arterial pressure was reduced by ramipril compared with the control group (−8±2 versus +7±2 mm Hg,
P
=.03), and this effect was not blunted by the addition of HOE 140 (−7±3 mm Hg).

Conclusions
Prevention by ramipril of the early increase in left ventricular mass in the DC shock model appears to be related to the preservation of bradykinin.
Identification of 92-kD Gelatinase in Human Coronary Atherosclerotic Lesions
Authors: Brown David L. , Hibbs Margaret S. , Kearney Marianne , Loushin Carrie , Isner Jeffrey M.
Published: June 2012

Background
Acute coronary ischemia is usually initiated by rupture of atherosclerotic plaque, leading to intracoronary thrombosis and clinical sequelae. The proximate cause of plaque rupture is unknown. Accordingly, we investigated the potential role of the 92-kD gelatinase member of the matrix metalloproteinase family in acute coronary ischemia.

Methods and Results
Coronary atherectomy specimens from patients with atherosclerosis and an acute ischemic syndrome consistent with recent plaque rupture (unstable angina) (n=12) were immunostained for the presence of 92-kD gelatinase; the results were compared with those obtained by identical study of atherectomy specimens from patients with atherosclerosis and angina but without acute ischemia (stable angina) (n=12). Positive immunostaining for 92-kD gelatinase was present in 83% of specimens from both unstable and stable angina patients. However, intracellular localization of enzyme (indicating active synthesis) was documented in 10 of 10 positively stained specimens from patients with unstable angina compared with 3 of 10 positively stained specimens from patients with stable angina. Macrophages and smooth muscle cells were the major sources of 92-kD gelatinase in all specimens examined by immunostaining of adjacent sections.

Conclusions
92-kD gelatinase is commonly expressed in coronary arterial atherosclerotic lesions. Active synthesis of 92-kD gelatinase by macrophages and smooth muscle cells in atherosclerotic lesions may play a pathogenic role in the development of acute coronary ischemia.
Multicenter, Randomized, Double-Blind, Placebo-Controlled Trial of the Platelet Integrin Glycoprotein IIb/IIIa Blocker Integrelin in Elective Coronary Intervention
Authors: Tcheng James E. , Harrington Robert A. , Kottke-Marchant Kandice , Kleiman Neal S. , Ellis Stephen G. , Kereiakes Dean J. , Mick Matthew J. , Navetta Frank I. , Smith Jack E. , Worley Seth J. , Miller Joyce A. , Joseph Diane M. , Sigmon Kristina N. , Kitt Michael M. , du Mée Charles P. , Califf Robert M. , Topol Eric J.
Published: June 2012

Background
Platelet aggregation and thrombosis have been implicated in the pathogenesis of coronary angioplasty complications. Integrelin, a synthetic cyclic heptapeptide with high affinity and marked specificity for platelet integrin glycoprotein IIb/IIIa, effectively blocks ADP-induced platelet aggregation.

Methods and Results
In 150 patients undergoing elective percutaneous coronary intervention, random assignment was made to one of three treatment regimens: placebo; a 90-μg/kg bolus of Integrelin before angioplasty followed by a 1.0-μg · kg
−1
· min
−1
infusion of Integrelin for 4 hours; or a 90-μg/kg bolus followed by a 1.0-μg · kg
−1
· min
−1
infusion of Integrelin for 12 hours. Patients were followed to 30 days for the composite occurrence of myocardial infarction, stent implantation, repeat urgent or emergency percutaneous intervention or coronary bypass surgery, or death. Pharmacodynamic data were obtained in a subset of 31 patients. Administration of a 90-μg/kg bolus of Integrelin achieved an 86% inhibition of platelet aggregation, and this inhibition was maintained by a 1.0-μg · kg
−1
· min
−1
infusion. There was a trend toward reduction in end-point events from 12.2% (placebo) to 9.6% (4-hour infusion) to 4.1% (12-hour infusion), although these differences were not statistically significant (
P
=.13 for the 12-hour group compared with placebo). Major bleeding occurred in 8%, 8%, and 2% of patients, while minor bleeding was observed in 14%, 33%, and 47% of patients, respectively. There was no difference in bleeding index among groups (1.5, 1.7, and 1.3, respectively), defined as [(change in hematocrit/3)+red blood cell units transfused].

Conclusions
This first clinical investigation of Integrelin during routine, elective, low- and high-risk coronary intervention supports the potential efficacy of Integrelin in routine coronary interventions. Pharmacodynamic analyses demonstrate that profound and sustained inhibition of platelet function is achieved, although a higher bolus dose may be required. Definitive assessment of efficacy and safety will need to await a large-scale study powered to achieve statistical significance.
Comparative Validation of Quantitative Coronary Angiography Systems
Authors: Keane David , Haase Jürgen , Slager Cornelis J. , van Swijndregt Eline Montauban , Lehmann Kenneth G. , Ozaki Yukio , di Mario Carlo , Kirkeeide Richard , Serruys Patrick W.
Published: June 2012

Background
Computerized quantitative coronary angiography (QCA) has fundamentally altered our approach to the assessment of coronary interventional techniques and strategies aimed at the prevention of recurrence and progression of stenosis. It is essential, therefore, that the performance of QCA systems, upon which much of our scientific understanding has become integrally dependent, is evaluated in an objective and uniform manner.

Methods and Results
We validated 10 QCA systems at core laboratories in North America and Europe. Cine films were made of phantom stenoses of known diameter (0.5 to 1.9 mm) under four experimental conditions: in vivo (coronary arteries of pigs) calibrated at the isocenter or by use of the catheter as a scaling device and in vitro with 50% contrast and 100% contrast. The cine films were analyzed by each automated QCA system without observer interaction. Accuracy and precision were taken as the mean and SD of the signed differences between the phantom stenoses, and the measured minimal luminal diameters and the correlation coefficient (
r
), the SEE, the
y
intercept, and the slope were derived by their linear regression. Performance of the 10 QCA systems ranged widely: accuracy, +0.07 to +0.31 mm; precision, ±0.14 to ±0.24 mm; correlation (
r
), .96 to .89; SEE, ±0.11 to ±0.16 mm; intercept, +0.08 to +0.31 mm; and slope, 0.86 to 0.64.

Conclusions
There is a marked variability in performance between systems when assessed over the range of 0.5 to 1.9 mm. The range of accuracy, intercept, and slope values of this report indicates that absolute measurements of luminal diameter from different multicenter angiographic trials may not be directly comparable and additionally suggests that such absolute measurements may not be directly applicable to clinical practice using an on-line QCA system with a different edge detection algorithm. Power calculations and study design of angiographic trials should be adjusted for the precision of the QCA system used to avoid the risk of failing to detect small differences in patient populations. This study may guide the fine-tuning of algorithms incorporated within each system and facilitate the maintenance of high standards of QCA for scientific studies.
Reversal of Heparin Anticoagulation by Recombinant Platelet Factor 4 in Humans
Authors: Dehmer Gregory J. , Fisher Melrose , Tate David A. , Teo Steve , Bonnem Eric M.
Published: June 2012

Background
Protamine is used to reverse the anticoagulant effects of heparin, but it can have important side effects. Platelet factor 4 (PF4) is a protein found in platelet alpha granules that binds to and thereby neutralizes heparin. We evaluated the safety and effectiveness of intravenous recombinant PF4 to neutralize heparin anticoagulation after cardiac catheterization in a phase 1, open-label trial.

Methods and Results
The study group consisted of 18 patients having diagnostic cardiac catheterization. Heparin (5000 U) was given after vascular access was obtained. In the first 12 patients, additional heparin was given at the conclusion of the procedure so that all patients had activated coagulation times >300 seconds before rPF4 was given. Three patients each received 0.5, 1.0, 2.5, or 5.0 mg/kg rPF4 over a period of 3 minutes at the conclusion of the catheterization procedure. In 6 additional patients, extra heparin was not given at the conclusion of the procedure, and 1.0 mg/kg rPF4 was given. Hemodynamic measurements, cardiac output, and serial blood tests were performed 5, 10, 20, and 30 minutes after rPF4 and then into the next 24 hours. There were no serious side effects in any patient, despite transient rPF4 levels as high as 14 870 ng/mL in the patients receiving 5.0 mg/kg. One patient receiving 2.5 mg/kg had a slight transient rise in liver enzymes possibly related to the rPF4. There were no important hemodynamic effects of rPF4 administration at any dose used. Doses of 2.5 and 5.0 mg/kg were uniformly effective in reversing the anticoagulant effect of heparin. At lower doses, rPF4 neutralized the effects of heparin in most but not all patients. Pharmacokinetic analysis suggested a monophasic and one-compartment clearance of the PF4-heparin complex. No neutralizing factors to rPF4 were detected in the samples collected 7 days after dosing.

Conclusions
rPF4, in doses ranging from 0.5 to 5.0 mg/kg over 3 minutes, had no serious side effects. Given in sufficient amounts, rPF4 can completely and rapidly reverse the anticoagulant effects of heparin.
Vascular Smooth Muscle Cell Heme Oxygenases Generate Guanylyl Cyclase–Stimulatory Carbon Monoxide
Authors: Christodoulides Nick , Durante William , Kroll Michael H. , Schafer Andrew I.
Published: June 2012

Background
Carbon monoxide (CO), like nitric oxide (NO), stimulates soluble guanylyl cyclase and thereby raises intracellular levels of cGMP. We examined the endogenous capacity of vascular smooth muscle cells (SMCs) to produce CO from heme through the activity of heme oxygenases.

Methods and Results
Cultured SMCs from rat aorta (RASMCs) expressed immunoreactive inducible heme oxygenase-1 (HO-1) and constitutive HO-2. Treatment of RASMCs with hemin and sodium arsenite, which are inducers of HO-1, stimulated RASMC cGMP without stimulating nitrite release or inducible NO synthase expression, and the induced elevations of cGMP were not inhibited by the NO synthase inhibitor
N
G
-methyl-
l
-arginine. Induced CO from RASMCs likewise caused elevation of cGMP levels in platelets coincubated with the vascular cells. Zinc protoporphyrin IX, an inhibitor of HO, reversed the inducible increases in platelet cGMP.

Conclusions
These results indicate that vascular SMCs have both constitutive and inducible HO activity, and they respond to specific stimuli to generate guanylyl cyclase–stimulatory CO in the same SMCs and in coincubated platelets.
Delayed Improvement in Exercise Capacity With Restoration of Sinoatrial Node Response in Patients After Combined Treatment With Surgical Repair for Organic Heart Disease and the Maze Procedure for Atrial Fibrillation
Authors: Tamai Jun , Kosakai Yoshio , Yoshioka Takao , Ohnishi Etsuko , Takaki Hiroshi , Okano Yoshiaki , Kawashima Yasunaru
Published: June 2012

Background
Although the Maze procedure successfully restores sinus rhythm in patients with heart disease and atrial fibrillation, it is still uncertain whether an addition of the Maze procedure in cardiac surgery is beneficial for exercise performance of the patients after surgery.

Methods and Results
The Maze procedure was performed in 25 patients (age, 37 to 70 years) during valve surgery (18 patients) or closure of atrial septal defect (7 patients). A cardiopulmonary exercise test using ramp incremental protocol (15 W/min) was performed before and 1 month, 6 months, and 1 year after surgery. Sinus conversion was obtained in 23 of 25 patients 1 month after surgery. However, sinoatrial (SA) node response to exercise was attenuated by surgery: Mean heart rate (HR) was 83±13/min at rest, 94±13/min at 60 W, and 107±17/min at peak exercise. Peak oxygen uptake (Pȯ
2
) was unchanged at this period (before, 17.6±4.5 mL · min
−1
· kg
−1
; 1 month after, 17.5±4.2 mL · min
−1
· kg
−1
). Thereafter, SA node response was restored 6 months after surgery: Mean HR was 84±13/min at rest, 104±16/min at 60 W, and 130±20/min at peak exercise (
P
<.01 versus 1 month). Pȯ
2
was also improved at this period (20.7±4.0 mL · min
−1
· kg
−1
,
P
<.01). The increase in Pȯ
2
from 1 month to 6 months after surgery was correlated with the increase in peak HR (
y
=0.73
x
±3.6,
r
=.79). There were no further changes in heart rate response or Pȯ
2
from 6 months to 1 year after surgery.

Conclusions
Atrial fibrillation was successfully treated by combined treatment with surgical repair for organic heart disease and the Maze procedure. However, SA node response to exercise was attenuated early after surgery. Thus, exercise capacity was improved at the late phase after surgery, which was related to the extent of restoration in SA node response.
Nonstationary Vortexlike Reentrant Activity as a Mechanism of Polymorphic Ventricular Tachycardia in the Isolated Rabbit Heart
Authors: Gray Richard A. , Jalife José , Panfilov Alexandre , Baxter William T. , Cabo Cándido , Davidenko Jorge M. , Pertsov Arkady M.
Published: June 2012

Background
Ventricular tachycardia may result from vortexlike reentrant excitation of the myocardium. Our general hypothesis is that in the structurally normal heart, these arrhythmias are the result of one or two nonstationary three-dimensional electrical scroll waves activating the heart muscle at very high frequencies.

Methods and Results
We used a combination of high-resolution video imaging, electrocardiography, and image processing in the isolated rabbit heart, together with mathematical modeling. We characterized the dynamics of changes in transmembrane potential patterns on the epicardial surface of the ventricles using optical mapping. Image processing techniques were used to identify the surface manifestation of the reentrant organizing centers, and the location of these centers was used to determine the movement of the reentrant pathway. We also used numerical simulations incorporating Fitzhugh-Nagumo kinetics and realistic heart geometry to study how stationary and nonstationary scroll waves are manifest on the epicardial surface and in the simulated ECG. We present epicardial surface manifestations (reentrant spiral waves) and ECG patterns of nonstationary reentrant activity that are consistent with those generated by scroll waves established at the right and left ventricles. We identified the organizing centers of the reentrant circuits on the epicardial surface during polymorphic tachycardia, and these centers moved during the episodes. In addition, the arrhythmias that showed the greatest movement of the reentrant centers displayed the largest changes in QRS morphology. The numerical simulations showed that stationary scroll waves give rise to monomorphic ECG signals, but nonstationary meandering scroll waves give rise to undulating ECGs characteristic of torsade de pointes.

Conclusions
Polymorphic ventricular tachycardia in the healthy, isolated rabbit heart is the result of either a single or paired (“figure-of-eight”) nonstationary scroll waves. The extent of the scroll wave movement corresponds to the degree of polymorphism in the ECG. These results are consistent with our numerical simulations that showed monomorphic ECG patterns of activity for stationary scroll waves but polymorphic patterns for scroll waves that were nonstationary.
Morphological Observations on the Pathogenetic Process of Transposition of the Great Arteries Induced by Retinoic Acid in Mice
Authors: Yasui Hiroshi , Nakazawa Makoto , Morishima Masae , Miyagawa-Tomita Sachiko , Momma Kazuo
Published: June 2012

Background
The pathogenesis of complete transposition of the great arteries (TGA) is still controversial because useful animal models have not been established. We previously reported that all-trans retinoic acid induced complete TGA at a high proportion in mice. The aim of the present study was to clarify the morphogenesis of the cardiac outflow tract in the retinoic acid–treated embryos destined to develop TGA.

Methods and Results
We first examined the morphology of TGA in mouse fetuses treated with retinoic acid to establish an animal model of TGA (experiment 1) and then examined the retinoic acid–treated embryonic hearts by means of ink injection and histology (experiment 2). All mouse fetuses and embryos showed visceroatrial situs solitus and d-ventricular loop. In experiment 1, among 45 embryos treated with retinoic acid 70 mg/kg at day 8.5 of gestation, 35 (78%) had TGA and 3 (6.7%) had a double-outlet right ventricle with a subpulmonary ventricular septal defect. In experiment 2, all hearts already exhibited d-loop at gestation day 8.5. At gestation day 9.5, conus swellings, composed of acellular cardiac jelly, were hypoplastic, and the conotruncal cavity was nonspiral or tubular. At gestation day 11.0, aberrant conus swellings located anteroposteriorly to give a straight orientation to the conotruncal cavity. At gestation day 12.0, side-by-side great arteries were transposed in that the aorta arose from the right ventricle and the pulmonary artery arose above the interventricular foramen.

Conclusions
These results suggest that a reproducible animal model of TGA can be produced in mice by treatment with retinoic acid; that there was no loop anomaly, such as an A-loop or L-loop, in our model; and that hypoplasia of the conus swellings appears to be the primary event leading to TGA.
Atherosclerosis: Basic Mechanisms
Authors: Berliner Judith A. , Navab Mohamad , Fogelman Alan M. , Frank Joy S. , Demer Linda L. , Edwards Peter A. , Watson Andrew D. , Lusis Aldons J.
Published: June 2012

Abstract
The clinical events resulting from atherosclerosis are directly related to the oxidation of lipids in LDLs that become trapped in the extracellular matrix of the subendothelial space. These oxidized lipids activate an NFκB-like transcription factor and induce the expression of genes containing NFκB binding sites. The protein products of these genes initiate an inflammatory response that initially leads to the development of the fatty streak. The progression of the lesion is associated with the activation of genes that induce arterial calcification, which changes the mechanical characteristics of the artery wall and predisposes to plaque rupture at sites of monocytic infiltration. Plaque rupture exposes the flowing blood to tissue factor in the lesion, and this induces thrombosis, which is the proximate cause of the clinical event. There appear to be potent genetically determined systems for preventing lipid oxidation, inactivating biologically important oxidized lipids, and/or modulating the inflammatory response to oxidized lipids that may explain the differing susceptibility of individuals and populations to the development of atherosclerosis. Enzymes associated with HDL may play an important role in protecting against lipid oxidation in the artery wall and may account in part for the inverse relation between HDL and risk for atherosclerotic clinical events.
Hyperhomocysteinemia and Low Pyridoxal Phosphate
Authors: Robinson Killian , Mayer Ellen L. , Miller Dave P. , Green Ralph , van Lente Frederick , Gupta Anjan , Kottke-Marchant Kandice , Savon Susan R. , Selhub Jacob , Nissen Steven E. , Kutner Michael , Topol Eric J. , Jacobsen Donald W.
Published: June 2012

Background
High plasma homocysteine is associated with premature coronary artery disease in men, but the threshold concentration defining this risk and its importance in women and the elderly are unknown. Furthermore, although low B vitamin status increases homocysteine, the link between these vitamins and coronary disease is unclear.

Methods and Results
We compared 304 patients with coronary disease with 231 control subjects. Risk factors and concentrations of plasma homocysteine, folate, vitamin B12, and pyridoxal 5′-phosphate were documented. A homocysteine concentration of 14 μmol/L conferred an odds ratio of coronary disease of 4.8 (
P
<.001), and 5-μmol/L increments across the range of homocysteine conferred an odds ratio of 2.4 (
P
<.001). Odds ratios of 3.5 in women and of 2.9 in those 65 years or older were seen (
P
<.05). Homocysteine correlated negatively with all vitamins. Low pyridoxal 5′-phosphate (<20 nmol/L) was seen in 10% of patients but in only 2% of control subjects (
P
<.01), yielding an odds ratio of coronary disease adjusted for all risk factors, including high homocysteine, of 4.3 (
P
<.05).

Conclusions
Within the range currently considered to be normal, the risk for coronary disease rises with increasing plasma homocysteine regardless of age and sex, with no threshold effect. In addition to a link with homocysteine, low pyridoxal-5′-phosphate confers an independent risk for coronary artery disease.
Development and Characterization of a Rapid Assay for Bedside Determinations of Cardiac Troponin T
Authors: Müller-Bardorff Margit , Freitag Helmut , Scheffold Thomas , Remppis Andrew , Kübler Wolfgang , Katus Hugo A.
Published: June 2012

Background
The appearance of cardiac proteins in blood is the most specific and sensitive indicator of acute myocardial cell necrosis. The measurement of cardiac markers, however, is time consuming and requires sophisticated equipment. To facilitate the biochemical detection for acute myocardial cell necrosis, a whole-blood rapid assay device for cardiac troponin T detection was developed that provides a test result within 20 minutes.

Methods and Results
Monoclonal antibody M7 is labeled with gold particles, and antibody 1B10 is labeled with biotin. Both antibodies, as well as buffer substances and detergents, are adsorbed onto paper fleeces mounted below an application well. Heparinized blood (160 μL) applied to this well solubilizes the dry chemistry reagents. Blood cells are separated from plasma via a glass-fiber fleece. The immunocomplexes formed are concentrated within the reading zone by binding of the biotin-labeled antibody with streptavidine immobilized to the test device. Troponin T bound to the test device serves as a control. The detection limit of this assay is 0.18 μg/L with a cross-reactivity with skeletal troponin T of 0.5%. In clinical analyses involving 25 healthy volunteers, 62 patients with chest pain but without myocardial ischemia, 35 patients with acute myocardial infarction, 24 patients with minor myocardial cell damage due to radiofrequency ablation, and 35 patients with unstable angina, the rapid assay was comparable to the troponin T enzyme immunoassay in regard to sensitivity and specificity.

Conclusions
This newly developed assay allows accurate, rapid, and convenient diagnosis of acute myocardial cell necrosis.
Exercise Capacity in Hypertrophic Cardiomyopathy
Authors: Lele Suhas S. , Thomson Helen L. , Seo Hiromi , Belenkie Israel , McKenna William J. , Frenneaux Michael P.
Published: June 2012

Background
We previously showed that exercise capacity in patients with hypertrophic cardiomyopathy (HCM) is related to peak exercise cardiac output. Cardiac output augmentation during exercise is normally dependent on heart rate (HR) response and stroke volume (SV) augmentation by increased left ventricular end-diastolic volume and/or increased contractility. We hypothesized that in contrast to normal subjects, peak exercise capacity in patients with HCM is determined by the diastolic filling characteristics of the left ventricle during exercise, which would in turn determine the degree to which SV is augmented, and that HR is a relatively unimportant determinant of peak exercise capacity.

Methods and Results
Twenty-three patients with HCM underwent invasive hemodynamic evaluation and measurement of maximal oxygen consumption (V̇
o
2max
) during erect treadmill exercise to assess the relative importance of changes in HR and SV in determining exercise capacity. Hemodynamic responses to erect and supine exercise were compared in 10 of these patients. In a separate group of 46 patients with HCM, the relation between V̇
o
2max
and exercise diastolic filling indexes was assessed. Peak HR during erect exercise was 92±8% of predicted maximum. V̇
o
2max
was 29.0±6.4 mL · kg
−1
· min
−1
and was related significantly to peak exercise cardiac index and SV index (
r
=.71,
P
<.0001 and
r
=.66,
P
=.001, respectively) but not to peak HR, HR deficit, or resting or peak pulmonary capillary wedge pressure. Peak cardiac output during erect exercise was not related to peak HR (
r
=.13,
P
=NS). When erect and supine exercise were compared, peak HR was lower in the supine position (153.3±19.9 beats per minute supine versus 172.0±17.6 beats per minute erect,
P
=.003), but peak exercise cardiac index was similar (7.9±2.6 L · min
−1
· m
−2
supine versus 7.5±2.8 L · min
−1
· m
−2
erect). Pulmonary capillary wedge pressure was higher at rest in the supine versus erect position (15.3±5.2 versus 8.1±6.1 mm Hg) but was not significantly higher at peak exercise in the supine versus erect position (28.5±8 versus 22.4±11.6 mm Hg erect,
P
=NS). In the separate group of 46 patients with HCM, V̇
o
2max
was significantly inversely related to time to peak filling at peak exercise (
r
=−.60,
P
<.0001) but did not correlate with time to peak filling at rest, resting ejection fraction, peak filling rate, or peak exercise peak filling rate.

Conclusions
SV is the major determinant of peak exercise capacity in the erect position in patients with hypertrophic cardiomyopathy. This in turn is determined by the exercise left ventricular diastolic filling characteristics. HR augmentation does not appear to be a major determinant of peak cardiac output in the erect position.
ECG T-Wave Patterns in Genetically Distinct Forms of the Hereditary Long QT Syndrome
Authors: Moss Arthur J. , Zareba Wojciech , Benhorin Jesaia , Locati Emanuela H. , Hall W. Jackson , Robinson Jennifer L. , Schwartz Peter J. , Towbin Jeffrey A. , Vincent G. Michael , Lehmann Michael H. , Keating Mark T. , MacCluer Jean W. , Timothy Katherine W.
Published: June 2012

Background
The long QT syndrome is an inherited disorder with prolonged ventricular repolarization and a propensity to ventricular tachyarrhythmias and sudden arrhythmic death. Recent linkage studies have demonstrated three separate loci for this disorder on chromosomes 3, 7, and 11, and specific mutated genes for long QT syndrome have been identified on two of these chromosomes. We investigated ECG T-wave patterns (phenotypes) in members of families linked to three genetically distinct forms of the long QT syndrome.

Methods and Results
Five quantitative ECG repolarization parameters, ie, four Bazett-corrected time intervals (QT
onset-c
, QT
peak-c
, QT
c
, and T
duration-c
, in milliseconds) and the absolute height of the T wave (T
amplitude
, in millivolts), were measured in 153 members of six families with long QT syndrome linked to markers on chromosomes 3 (n=47), 7 (n=30), and 11 (n=76). Genotypic data were used to define each family member as being affected or unaffected with long QT syndrome. Affected members of all six families had longer QT intervals (QT
onset-c
, QT
peak-c
, or QT
c
) than unaffected family members (
P
<.01). Each of the three long QT syndrome genotypes was associated with somewhat distinctive ECG repolarization features. Among affected individuals, the QT
onset-c
was unusually prolonged in those individuals with mutations involving the cardiac sodium channel gene
SCN5A
on chromosome 3 (lead II QT
onset-c
[mean±SD]: chromosome 3, 341±42 ms; chromosome 7, 290±56 ms; chromosome 11, 243±73 ms;
P
<.001); T
amplitude
was generally quite small in the chromosome 7 genotype (lead II T
amplitude
, mV: chromosome 3, 0.36±0.14; chromosome 7, 0.13±0.07; chromosome 11, 0.37±0.17;
P
<.001); and T
duration
was particularly long in the chromosome 11 genotype (lead II T
duration-c
: chromosome 3, 187±33 ms; chromosome 7, 191±51 ms; chromosome 11, 262±65 ms;
P
<.001). Similar ECG findings were observed in leads aVF and V
5
. A considerable variability exists in the quantitative repolarization parameters associated with each genotype, with overlap in the T-wave patterns among the three genotypes.

Conclusions
Three separate genetic loci for the long QT syndrome including mutations in two cardiac ionic channel genes were associated with different phenotypic T-wave patterns on the ECG. This study provides insight into the influence of genetic factors on ECG manifestations of ventricular repolarization.