bluuebunny/crossref_metadata_2025 huggingface dataset:
Static Relationship of Cycle Length to Reentrant Circuit Geometry
Authors: Ciaccio Edward J. , Costeas Constantino , Coromilas James , Wit Andrew L.
Published: September 2007

Background

Knowledge of the pathway common to both wave fronts in figure-8 reentrant circuits (ie, the isthmus) is of importance for catheter ablation to stop reentrant ventricular tachycardia. It was hypothesized that quantitative measures of reentry isthmus geometry were interrelated and could be correlated with tachycardia cycle length.

Methods and Results

A canine infarct model of reentrant ventricular tachycardia in the epicardial border zone with a figure-8 pattern of conduction was used for initial analysis (experiments in 20 canine hearts with monomorphic reentry). Sinus-rhythm and reentry activation maps were constructed, and quantitative (skeletonized) geometric parameters of the isthmus and border zone were measured from the maps. Regression equations were used to determine significant correlation relationships between skeletonized variables, which can be described as follows. Tachycardia cycle length, measured from the ECG R-R interval, increases with increasing isthmus length, width, narrowest width, angle with respect to muscle fibers, and circuit path length determined by use of sinus-rhythm measurements. After this procedure, in 5 test-set experiments, tachycardia cycle length measured from the R-R interval, in combination with regression coefficients calculated from initial experiments, correctly predicted isthmus geometry (mean estimated/actual isthmus overlap 70.5%). Also, the circuit path length determined with sinus-rhythm measurements correctly estimated the tachycardia cycle length (mean error 6.2±2.5 ms).

Conclusions

Correlation relationships derived from measurements using reentry and sinus-rhythm activation maps are useful to assess isthmus geometry on the basis of tachycardia cycle length. Such estimates may improve catheter ablation site targeting during clinical electrophysiological study.
Selective Serotonin Reuptake Inhibitors and Myocardial Infarction
Authors: Sauer William H. , Berlin Jesse A. , Kimmel Stephen E.
Published: September 2007

Background

Depression is an independent risk factor for myocardial infarction (MI). Selective serotonin reuptake inhibitors (SSRIs) may reduce this risk through attenuation of serotonin-mediated platelet activation in addition to treatment of depression itself.

Methods and Results

A case-control study of first MI in smokers 30 to 65 years of age was conducted among all 68 hospitals in an 8-county area during a 28-month period. Cases were patients hospitalized with a first MI. Approximately 4 community control subjects per case were randomly selected from the same geographic area using random digit dialing. Detailed information regarding use of antidepressant medication as well as other clinical and demographic data were obtained by telephone interview. A total of 653 cases of first MI and 2990 control subjects participated. After adjustment, using multivariable logistic regression, for age, sex, race, education, exercise, quantity smoked per day, body mass index, aspirin use, family history of MI, number of physician encounters, and history of coronary disease, diabetes, hypertension, or hypercholesterolemia, the odds ratio for MI among current SSRI users compared with nonusers was 0.35 (95% CI 0.18, 0.68;
P
<0.01). Non-SSRI antidepressant users had a nonsignificant reduction in MI risk with wide confidence intervals (adjusted odds ratio 0.48, CI 0.17, 1.32;
P
=0.15). However, analysis of this group was limited by the small number of exposed subjects.

Conclusions

The use of SSRIs may confer a protective effect against MI. This could be attributable to the inhibitory effect SSRIs have on serotonin-mediated platelet activation or possibly amelioration of other factors associated with increased risk for MI in depression.
Dysfunctional Endothelial Nitric Oxide Biosynthesis in Healthy Smokers With Impaired Endothelium-Dependent Vasodilatation
Authors: Barua Rajat S. , Ambrose John A. , Eales-Reynolds Lesley-Jane , DeVoe Mary C. , Zervas John G. , Saha Dhanonjoy C.
Published: September 2007

Background

The mechanisms involved in the dysfunction of both endothelium-dependent vasodilatation (EDV) and NO biosynthesis related to smoking are unclear. In this study, EDV was assessed in healthy smokers and nonsmokers in vivo and, using serum from the same individuals, was related to the NO biosynthetic pathway in vitro.

Methods and Results

Flow-mediated EDV of the brachial artery was measured in 23 male patients (8 nonsmokers and 15 smokers). Serum was collected, added to confluent (≈85%) monolayers of human umbilical vein endothelial cells (HUVECs), and incubated for 12 hours. Basal and substance P–stimulated NO production was measured. The HUVECs used for measuring basal NO production were lysed, and both endothelial NO synthase (eNOS) protein expression and eNOS activity were determined. EDV was lower in smokers compared with nonsmokers (
P
<0.001). HUVECs treated with serum from smokers compared with nonsmokers showed significantly lower basal (
P
<0.0001) and stimulated (
P
<0.02) NO production, higher eNOS expression (
P
<0.0001), but lower eNOS activity (
P
<0.004). There was a significant positive correlation between in vivo EDV and in vitro substance P–stimulated NO production (rho=0.57,
P
<0.01) and between basal NO production and eNOS activity (
r
=0.54,
P
<0.008) and a negative correlation between basal NO production and eNOS protein expression (
r
=−0.60,
P
<0.003).

Conclusions

This is the first study to combine an in vivo model with a near-physiological in vitro model to demonstrate an association between decreased NO production and reduced EDV. Cigarette smoking was associated with reduced EDV, NO generation, and eNOS activity in the presence of increased eNOS protein expression.
Depression, Heart Rate Variability, and Acute Myocardial Infarction
Authors: Carney Robert M. , Blumenthal James A. , Stein Phyllis K. , Watkins Lana , Catellier Diane , Berkman Lisa F. , Czajkowski Susan M. , O’Connor Christopher , Stone Peter H. , Freedland Kenneth E.
Published: September 2007

Background

Clinical depression is associated with an increased risk for mortality in patients with a recent myocardial infarction (MI). Reduced heart rate variability (HRV) has been suggested as a possible explanation for this association. The purpose of this study was to determine if depression is associated with reduced HRV in patients with a recent MI.

Methods and Results

Three hundred eighty acute MI patients with depression and 424 acute MI patients without depression were recruited. All underwent 24-hour ambulatory electrocardiographic monitoring after hospital discharge. In univariate analyses, 4 indices of HRV were significantly lower in patients with depression than in patients without depression. Variables associated with HRV were then compared between patients with and without depression, and potential confounds were identified. These variables (age, sex, diabetes, and present cigarette smoking) were entered into an analysis of covariance model, followed by depression status. In the final model, all but one HRV index (high-frequency power) remained significantly lower in patients with depression than in patients without depression.

Conclusions

We conclude that greater autonomic dysfunction, as reflected by decreased HRV, is a plausible mechanism linking depression to increased cardiac mortality in post-MI patients.
Elevated Circulating Level of Ghrelin in Cachexia Associated With Chronic Heart Failure
Authors: Nagaya Noritoshi , Uematsu Masaaki , Kojima Masayasu , Date Yukari , Nakazato Masamitsu , Okumura Hiroyuki , Hosoda Hiroshi , Shimizu Wataru , Yamagishi Masakazu , Oya Hideo , Koh Hideki , Yutani Chikao , Kangawa Kenji
Published: September 2007

Background

Ghrelin is a novel growth hormone (GH)-releasing peptide, isolated from the stomach, that may also cause a positive energy balance by stimulating food intake and inducing adiposity. We sought to investigate the pathophysiology of ghrelin in the cachexia associated with chronic heart failure (CHF).

Methods and Results

Plasma ghrelin was measured in 74 patients with CHF and 12 control subjects, together with potentially important anabolic and catabolic factors, such as GH and tumor necrosis factor (TNF-α). Patients with CHF were divided into two groups, those with cachexia (n=28) and those without cachexia (n=46). Plasma ghrelin did not significantly differ between all CHF patients and controls (181±10 versus 140±14 fmol/mL,

P

=NS). However, plasma ghrelin was significantly higher in CHF patients with cachexia than in those without cachexia (237±18 versus 147±10 fmol/mL,
P
<0.001). Circulating GH, TNF-α, norepinephrine, and angiotensin II were also significantly higher in CHF patients with cachexia than in those without cachexia. Interestingly, plasma ghrelin correlated positively with GH (
r
=0.28,
P
<0.05) and TNF-α (
r
=0.31,
P
<0.05) and negatively with body mass index (
r
=−0.35,
P
<0.01).

Conclusions

Plasma ghrelin was elevated in cachectic patients with CHF, associated with increases in GH and TNF-α and a decrease in body mass index. Considering ghrelin-induced positive energy effects, increased ghrelin may represent a compensatory mechanism under catabolic-anabolic imbalance in cachectic patients with CHF.
Mechanism of Syncope in Patients With Bundle Branch Block and Negative Electrophysiological Test
Authors: Brignole Michele , Menozzi Carlo , Moya Angel , Garcia-Civera Roberto , Mont Luis , Alvarez Miguel , Errazquin Francisco , Beiras Julio , Bottoni Nicola , Donateo Paolo ,   on behalf of the International Study on Syncope of Uncertain Etiology (ISSUE) Investigators
Published: September 2007

Background

In patients with syncope and bundle branch block (BBB), syncope is suspected to be attributable to a paroxysmal atrioventricular (AV) block, but little is known of its mechanism when electrophysiological study is negative.

Methods and Results

We applied an implantable loop recorder in 52 patients with BBB and negative conventional workup. During a follow-up of 3 to 15 months, syncope recurred in 22 patients (42%), the event being documented in 19 patients after a median of 48 days. The most frequent finding, recorded in 17 patients, was one or more prolonged asystolic pause mainly attributable to AV block; the remaining 2 patients had normal sinus rhythm or sinus tachycardia. The onset of the bradycardic episodes was always sudden but was sometimes preceded by ventricular premature beats. The median duration of the arrhythmic event was 47 seconds. An additional 3 patients developed nonsyncopal persistent III-degree AV block, and 2 patients had presyncope attributable to AV block with asystole. No patients suffered injury attributable to syncopal relapse.

Conclusions

In patients with BBB and negative electrophysiological study, most syncopal recurrences have a homogeneous mechanism that is characterized by prolonged asystolic pauses, mainly attributable to sudden-onset paroxysmal AV block.
Effect of the Distal-Balloon Protection System on Microembolization During Carotid Stenting
Authors: Al-Mubarak Nadim , Roubin Gary S. , Vitek Jiri J. , Iyer Sriram S. , New Gishel , Leon Martin B.
Published: September 2007

Background

The distal-balloon protection system is being evaluated for its efficacy in preventing embolic neurological events during carotid stenting (CAS). We sought to determine the effect of this system on the frequency of Doppler-detected microembolic signals (MES) during CAS.

Methods and Results

Using transcranial Doppler, we compared the frequency of MES during CAS in 2 groups: 39 patients without distal protection and 37 who used the distal-balloon protection system (GuardWire). There were no significant differences in the clinical or angiographic characteristics between the 2 groups. Three phases with increased MES counts were identified during unprotected CAS; these were stent deployment, predilation, and postdilation (75±57, 32±36, and 27±25 METS, respectively). The distal-balloon protection significantly reduced the frequency of MES during CAS (MES counts: 164±108 in the control versus 68±83 in the protection group;
P
=0.002), particularly during these 3 phases. MES in the protection group were detected predominantly during sheath placement, guidewire manipulation, and distal-balloon deflation.

Conclusion

Three phases with increased MES counts were identified during unprotected CAS (eg, stent deployment, predilation, and postdilation). The distal-balloon protection system significantly reduced the frequency of MES during CAS, particularly during these 3 phases.
Roles of Prostaglandin I
2
and Thromboxane A
2
in Cardiac Ischemia-Reperfusion Injury
Authors: Xiao Chun-Yang , Hara Akiyoshi , Yuhki Koh-ichi , Fujino Takayuki , Ma Hong , Okada Yuji , Takahata Osamu , Yamada Takehiro , Murata Takahiko , Narumiya Shuh , Ushikubi Fumitaka
Published: September 2007

Background

Prostaglandin (PG) I
2
and thromboxane (TX) A
2
, the most common prostanoids in the cardiovascular system, are produced abundantly during cardiac ischemia/reperfusion (I/R); their roles in I/R injury, however, remain undetermined. We intended to clarify these roles of PGI
2
and TXA
2
using mice lacking the PGI
2
receptor, IP
−/−
mice, or the TXA
2
receptor, TP
−/−
mice.

Methods and Results

The left anterior descending coronary artery was occluded for 1 hour and then reperfused for 24 hours. The size of myocardial infarct in IP
−/−
mice was significantly larger than that in wild-type mice, although the size of the area at risk was similar between the 2 groups of mice. In contrast, there was no such difference between TP
−/−
and wild-type mice. To further determine whether PGI
2
and TXA
2
act directly on the cardiac tissue or indirectly through their action on blood constituents, we perfused excised heart according to the Langendorff technique. The isolated heart was then subjected to global ischemia followed by reperfusion. In IP
−/−
mice, developed tension and coronary flow rate during reperfusion were significantly lower and release of creatine kinase was significantly higher than those in wild-type mice. There were no such differences, however, between TP
−/−
and wild-type mice.

Conclusions

PGI
2
, which was produced endogenously during cardiac I/R, exerts a protective effect on cardiomyocytes independent of its effects on platelets and neutrophils. In contrast, TXA
2
has little role in the cardiac I/R injury.
Effect of Hydroxymethylglutaryl Coenzyme A Reductase Inhibitors on the Progression of Calcific Aortic Stenosis
Authors: Novaro Gian M. , Tiong Irving Y. , Pearce Gregory L. , Lauer Michael S. , Sprecher Dennis L. , Griffin Brian P.
Published: September 2007

Background

Recent studies have supported the hypothesis that calcific aortic stenosis is the product of an active inflammatory process, with similarities to atherosclerosis. We sought to determine whether therapy with hydroxymethylglutaryl coenzyme A reductase inhibitors (statins) might slow the progression of aortic stenosis.

Methods and Results

A retrospective study of 174 patients (mean age 68±12 years) with mild to moderate calcific aortic stenosis was conducted. Patients required normal left ventricular function, ≤2+ aortic regurgitation, and ≥2 echocardiograms performed at least 12 months apart. Fifty-seven patients (33%) received treatment with a statin; the remaining 117 (67%) did not. The statin group was older and had a higher prevalence of hypertension, diabetes mellitus, and coronary disease. During a mean follow-up of 21 months, patients treated with statin had a smaller increase in peak and mean gradient and a smaller decrease in aortic valve area. When annualized, the decrease in aortic valve area for the nonstatin group was 0.11±0.18 cm
2
compared with 0.06±0.16 cm
2
for those treated with a statin (
P
=0.03). In multivariate analysis, statin usage was a significant independent predictor of a smaller decrease in valve area (
P
=0.01) and a lesser increase in peak gradient (
P
=0.02).

Conclusions

Statin-treated patients, despite a higher risk profile for progression, had reduced aortic stenosis progression compared with those not treated with a statin. These data provide justification for a prospective randomized trial to substantiate whether statin therapy slows the progression of aortic stenosis.
Sympathetic Neural Mechanisms in Normal and Hypertensive Pregnancy in Humans
Authors: Greenwood John P. , Scott Eleanor M. , Stoker John B. , Walker James J. , Mary David A.S.G.
Published: September 2007

Background

Direct recordings from peripheral sympathetic nerves have shown an increased sympathetic drive in pregnancy-induced hypertension (PIH) and preeclampsia (PE). It is unknown whether sympathetic drive is altered in normal pregnancy, when arterial blood pressure can be normal or relatively low. The aim of this study was to measure and compare peripheral sympathetic discharge, its vasoconstrictor effect and its baroreceptor control, during pregnancy and postpartum in women with normal pregnancy (NP) and PIH and in normotensive nonpregnant (NN) women.

Methods and Results

Twenty-one women with NP, 18 women with PIH, and 21 NN women had muscle sympathetic nerve activity assessed from multiunit discharges (MSNA) and from single units with defined vasoconstrictor properties (s-MSNA). The s-MSNA in NP (38±6.6 impulses/100 beats) was greater (
P
<0.05) than in NN women (19±1.8 impulses/100 beats) despite similar age and body weight but less than in PIH women (
P
<0.001) (146±23.5 impulses/100 beats). MSNA followed a similar trend. Cardiac baroreceptor reflex sensitivity (BRS) was impaired in NP and PIH women relative to NN. After delivery, sympathetic activity decreased to values similar to those obtained in NN, and there was an increase in BRS. In women with NP, the decrease in sympathetic output occurred despite an insignificant change in blood pressure.

Conclusions

Central sympathetic output was increased in women with normal pregnancy and was even greater in the hypertensive pregnant group. The findings suggest that the moderate sympathetic hyperactivity during the latter months of normal pregnancy may help to return the arterial pressure to nonpregnant levels, although when the increase in activity is excessive, hypertension may ensue.
Sequential Magnetic Resonance Monitoring of Pulmonary Flow With Endovascular Stents Placed Across the Pulmonary Valve in Growing Swine
Authors: Kuehne Titus , Saeed Maythem , Reddy Gautham , Akbari Haydar , Gleason Kelly , Turner Daniel , Teitel David , Moore Phillip , Higgins Charles B.
Published: September 2007

Background

Patients with endovascular stent implantation for the treatment of right ventricular outflow tract obstruction are often left with incomplete relief of the obstruction and significant pulmonary regurgitation. A noninvasive and reproducible method for monitoring such patients is desirable. MRI in the presence of a stent, however, has to overcome the problem of potential metallic artifacts.

Methods and Results

Under x-ray fluoroscopic guidance, endovascular nitinol stents were placed across the pulmonary valve in 6 young pigs to induce pulmonary regurgitation. Five additional pigs served as controls. Initial MRI was performed after 2 days (13.5±1.8 kg) and follow-up after 3 months (32±2.9 kg). Pulmonary flow volumes and regurgitant fraction were quantified by velocity-encoded cine (VEC) MRI through (VEC-TS) and distal to (VEC-DS) the stent. VEC-TS was compared with VEC-DS and volumetric measurements of left and right ventricular stroke volumes provided by cine MRI (“gold standard”). Antegrade and retrograde pulmonary flow volumes by VEC-TS were slightly but significantly less than those with VEC-DS and cine MRI. Excellent correlations (
r
>0.97) for phasic pulmonary flow volumes as measured by VEC-TS and VEC-DS were shown. Pulmonary regurgitant fraction increased from 32.8±15% to 49.6±17% (
P
<0.05) over the course of 3 months with VEC-TS.

Conclusions

MRI demonstrates the progression of pulmonary regurgitation in growing swine. VEC MRI has the ability to quantify pulmonary blood flow inside the lumen of nitinol stents. MRI appears to be ideally suited for monitoring patients with endovascular nitinol stents in the pulmonary artery or pulmonary valve position.
Muscle Ergoreceptor Overactivity Reflects Deterioration in Clinical Status and Cardiorespiratory Reflex Control in Chronic Heart Failure
Authors: Ponikowski Piotr P. , Chua Tuan P. , Francis Darrel P. , Capucci Alessandro , Coats Andrew J.S. , Piepoli Massimo F.
Published: September 2007

Background

In chronic heart failure (CHF), overactivation of ergoreceptors (afferents sensitive to the metabolic effects of muscular work) may be a link between peripheral changes, sympathetic overactivation, and increased hemodynamic and ventilatory responses to exercise. The relationship between ergoreceptors, autonomic changes, and the progression of the syndrome has not yet been studied.

Methods and Results

Thirty-eight stable CHF patients (age, 57±1 years; ejection fraction, 26±2%) were compared with 12 age-matched normal control subjects. The ergoreflex contribution to the ventilatory and hemodynamic responses to exercise, together with peripheral and central chemoreceptor sensitivity, arterial baroreflex sensitivity, plasma norepinephrine, epinephrine, and heart rate variability, were measured. Enhanced ergoreflex effects on ventilation (78±2% versus 50±8%), peripheral chemosensitivity (0.6±0.4 versus 0.2±0.1 L/min per percent Sa
o
2
), and central chemosensitivity (2.9±0.2 versus 2.0±0.2 L · min
−1
· mm Hg
−1
) and an impaired baroreflex function (4.1±0.6 versus 9.1±5.6 ms/mm Hg) were confirmed in CHF compared with control subjects (
P
<0.01 in all comparisons). Ergoreceptor overactivity was associated with a worse symptomatic state (NYHA class,
P
<0.05), lower exercise tolerance (peak V
o
2
,
P
<0.05), and pronounced exercise hyperventilation (V̇
e
/V
co
2
,
P
<0.01). It was also a strong predictor of increased central chemosensitivity (independently of clinical parameters), baroreflex impairment, and sympathetic activation (plasma catecholamines and heart rate variability indexes; all
P
<0.05). In multivariate analysis, among all reflexes studied, the ventilatory component of the ergoreflex was the only independent predictor of peak V
o
2
and V̇
e
/V
co
2
.

Conclusions

In CHF, overactivation of the ergoreflex is associated with abnormal cardiorespiratory reflex control, independently of clinical severity. Among impaired reflexes, overactivation of the ergoreflex is an important determinant of exercise hyperventilation and reduced exercise tolerance.
Intracoronary β-Radiation Exacerbates Long-Term Neointima Formation in Balloon-Injured Pig Coronary Arteries
Authors: Coussement Patrick K. , de Leon Hector , Ueno Takafumi , Salame Mahomed Y. , King Spencer B. , Chronos Nicolas A.F. , Robinson Keith A.
Published: September 2007

Background

Long-term biological effects of ionizing radiation on coronary arteries remain poorly defined. We examined late arterial responses 6 months after balloon angioplasty and β-radiation in normal pig coronary arteries.

Methods and Results

Coronary arteries of 25 adult pigs were randomized to receive 20 Gy (n=8) or 30 Gy (n=9) of
186
Re β-radiation or sham radiation (n=8) immediately after balloon angioplasty. Aspirin was given daily during follow-up. The study vessels were analyzed histopathologically at 6 months. β-Radiation decreased lumen area (20 Gy, 1.55±0.99 mm
2
; 30 Gy, 1.03±0.82 mm
2
; and 0 Gy, 2.05±0.80 mm
2
;
P
<0.05) but not overall vessel area. The neointimal area was significantly larger within the injured segment with β-radiation (20 Gy, 1.92±1.23 mm
2
; 30 Gy, 1.51±0.97 mm
2
; and 0 Gy, 0.89±0.31 mm
2
; 0 Gy versus 20 Gy,
P
<0.05), and a significant increase of edge stenosis was observed with β-radiation. Irradiated vessels also had larger thrombus areas within the neointima (30 Gy, 0.24±0.61 mm
2
; 20 Gy, 0.98±1.57 mm2; and 0 Gy, 0.00±0.01 mm
2
;
P
<0.05) and larger adventitial areas (20 Gy, 2.25±0.75 mm
2
; 30 Gy, 2.38±0.98 mm
2
; and 0 Gy, 1.23±0.29 mm
2
; 0 Gy versus 20 or 30 Gy,
P
<0.05) that showed substantial collagen accumulation.

Conclusions

Intracoronary β-radiation did not inhibit neointima formation in balloon-injured normal pig coronary arteries 6 months after the interventional procedure. Unresorbed thrombus contributed to, but was not the sole component of, augmented neointima formation. Irradiated vessels demonstrated more adventitial thickening and fibrosis. These observations may have relevance for long-term clinical outcomes after intracoronary β-radiation.
Allopurinol Improves Myocardial Efficiency in Patients With Idiopathic Dilated Cardiomyopathy
Authors: Cappola Thomas P. , Kass David A. , Nelson Gregory S. , Berger Ronald D. , Rosas Gisele O. , Kobeissi Zoulficar A. , Marbán Eduardo , Hare Joshua M.
Published: September 2007

Background

Dilated cardiomyopathy is characterized by an imbalance between left ventricular performance and myocardial energy consumption. Experimental models suggest that oxidative stress resulting from increased xanthine oxidase (XO) activity contributes to this imbalance. Accordingly, we hypothesized that XO inhibition with intracoronary allopurinol improves left ventricular efficiency in patients with idiopathic dilated cardiomyopathy.

Methods and Results

Patients (n=9; ejection fraction, 29±3%) were instrumented to assess myocardial oxygen consumption (MV̇
o
2
), peak rate of rise of left ventricular pressure (dP/dt
max
), stroke work (SW), and efficiency (dP/dt
max
/MV̇
o
2
and SW/MV̇
o
2
) at baseline and after sequential infusions of intracoronary allopurinol (0.5, 1.0, and 1.5 mg/min, each for 15 minutes). Allopurinol caused a significant decrease in MV̇
o
2
(peak effect, −16±5%;
P
<0.01; n=9) with no parallel decrease in dP/dt
max
or SW and no change in ventricular load. The net result was a substantial improvement in myocardial efficiency (peak effects: dP/dt
max
/MV̇
o
2
, 22±9%, n=9; SW/MV̇
o
2
, 40±17%, n=6; both
P
<0.05). These effects were apparent despite concomitant treatment with standard heart failure therapy, including ACE inhibitors and β-blockers. XO and its parent enzyme xanthine dehydrogenase were more abundant in failing explanted human myocardium on immunoblot.

Conclusions

These findings indicate that XO activity may contribute to abnormal energy metabolism in human cardiomyopathy. By reversing the energetic inefficiency of the failing heart, pharmacological XO inhibition represents a potential novel therapeutic strategy for the treatment of human heart failure.
Acute Hemodynamic Effects of Conivaptan, a Dual V
1A
and V
2
Vasopressin Receptor Antagonist, in Patients With Advanced Heart Failure
Authors: Udelson James E. , Smith William B. , Hendrix Grady H. , Painchaud Christopher A. , Ghazzi Maha , Thomas Ignatius , Ghali Jalal K. , Selaru Paulina , Chanoine Francoise , Pressler Milton L. , Konstam Marvin A.
Published: September 2007

Background

Arginine vasopressin may contribute to abnormalities in hemodynamics and fluid balance in heart failure through its actions on V
1A
(vascular and myocardial effects) and V
2
receptors (renal effects). Inhibiting the action of vasopressin may be beneficial in patients with heart failure.

Methods and Results

A total of 142 patients with symptomatic heart failure (New York Heart Association class III and IV) were randomized to double-blind, short-term treatment with conivaptan, a dual V
1a
/V
2
vasopressin receptor antagonist, at a single intravenous dose (10, 20, or 40 mg) or placebo. Compared with placebo, conivaptan at 20 and 40 mg significantly reduced pulmonary capillary wedge pressure (−2.6±0.7, −5.4±0.7, and −4.6±0.7 mm Hg for placebo and 20 and 40 mg groups, respectively;
P
<0.05) and right atrial pressure (−2.0±0.4, −3.7±0.4, and −3.5±0.4 mm Hg for placebo and 20 and 40 mg groups, respectively;
P
<0.05) during the 3- to 6-hour interval after intravenous administration. Conivaptan significantly increased urine output in a dose-dependent manner (−11±17, 68±17, 152±19, and 176±18 mL/hour for placebo and 10, 20, and 40 mg groups, respectively;
P
<0.001) during the first 4 hours after the dose. Changes in cardiac index, systemic and pulmonary vascular resistance, blood pressure, and heart rate did not significantly differ from placebo.

Conclusions

In patients with advanced heart failure, vasopressin receptor antagonism with conivaptan resulted in favorable changes in hemodynamics and urine output without affecting blood pressure or heart rate. These data suggest that vasopressin is functionally significant in advanced heart failure and that further investigations are warranted to examine the effects of conivaptan on symptom relief and natural history in such patients.
Hypertension Does Not Account for the Accelerated Atherosclerosis and Development of Aneurysms in Male Apolipoprotein E/Endothelial Nitric Oxide Synthase Double Knockout Mice
Authors: Chen Jiqiu , Kuhlencordt Peter J. , Astern Joshua , Gyurko Robert , Huang Paul L.
Published: September 2007

Background

Apolipoprotein E (apoE)/endothelial nitric oxide synthase (eNOS) double knockout (DKO) mice demonstrate accelerated atherosclerosis and develop abdominal aortic aneurysms and aortic dissection, suggesting a role for eNOS in suppressing atherogenesis. To test whether accelerated atherosclerosis and aortic aneurysms were due to hypertension, we administered hydralazine to male apoE/eNOS DKO mice to reduce blood pressure.

Methods and Results

Male apoE/eNOS DKO mice were treated with hydralazine in their drinking water (250 mg/L) using a dose that lowers the blood pressure to levels seen in apoE KO mice. The mice were fed a Western-type diet for 16 weeks, and lesion formation was assessed by inspection of the vessel and staining with Sudan IV. Hydralazine-treated, normotensive male apoE/eNOS DKO mice developed increased aortic lesion areas (30.0±2.8%, n=11) compared with male apoE KO mice (14.6±0.8%, n=7). The extent of lesion formation was not significantly different from male apoE/eNOS DKO mice that were not given hydralazine (28.3±3.1%, n=9). Four of 11 hydralazine-treated male apoE/eNOS DKO mice developed abdominal aortic aneurysms.

Conclusions

Hypertension is not required for the accelerated atherosclerosis seen in apoE/eNOS DKO animals, and control of hypertension during a 16-week period does not prevent aortic aneurysm formation.
NKX2.5 Mutations in Patients With Tetralogy of Fallot
Authors: Goldmuntz Elizabeth , Geiger Elizabeth , Benson D. Woodrow
Published: September 2007

Background

Recent reports have implicated mutations in the transcription factor NKX2.5 as a cause of tetralogy of Fallot (TOF). To estimate the frequency of NKX2.5 mutations in TOF patients and to further investigate the genotype-phenotype correlation of NKX2.5 mutations, we genotyped 114 TOF patients.

Methods and Results

Patients were recruited prospectively (November 1992 through June 1999) and tested for a 22q11 deletion; those with 22q11 deletion or recognized chromosomal alteration were excluded from the present study. Patients were screened for NKX2.5 alterations by conformation-sensitive gel electrophoresis and sequencing of fragments with aberrant mobility. Four heterozygous mutations were identified in 6 unrelated patients with cases of TOF, including 3 with pulmonary atresia and 5 with right aortic arch; none had ECG evidence of PR interval prolongation. Three of 4 mutations (Glu21Gln, Arg216Cys, and Ala219Val) altered highly conserved amino acids, of which 2 mapped in the conserved NK2 domain. The fourth mutation (Arg25Cys) was identified in 3 unrelated probands in the present study and has been previously reported. No homeodomain mutations were identified.

Conclusions

NKX2.5 mutations are the first gene defects identified in nonsyndromic TOF patients. NKX2.5 mutation is present in ≥4% of TOF patients. Mutations identified in the present study mapped outside of the homeodomain, were not associated with atrioventricular conduction disturbances, and were not fully penetrant, in contrast to mutations previously reported that impair homeodomain function.
Activated Interstitial Myofibroblasts Express Catabolic Enzymes and Mediate Matrix Remodeling in Myxomatous Heart Valves
Authors: Rabkin Elena , Aikawa Masanori , Stone James R. , Fukumoto Yoshihiro , Libby Peter , Schoen Frederick J.
Published: September 2007

Background

The mechanisms of extracellular matrix changes accompanying myxomatous valvular degeneration are uncertain.

Methods and Results

To test the hypothesis that valvular interstitial cells mediate extracellular matrix degradation in myxomatous degeneration by excessive secretion of catabolic enzymes, we examined the functional characteristics of valvular interstitial cells in 14 mitral valves removed for myxomatous degeneration from patients with mitral regurgitation and in 11 normal mitral valves obtained at autopsy. Immunohistochemical staining assessed (1) cell phenotype using antibodies to α-actin (microfilaments), vimentin and desmin (intermediate filaments), smooth muscle myosin (SM1), and SMemb (a nonmuscle myosin produced by activated mesenchymal cells) and (2) the expression of proteolytic activity using antibodies to collagenases (matrix metalloproteinase [MMP]-1, MMP-13), gelatinases (MMP-2, MMP-9), cysteine endoproteases (cathepsin S and K), and interleukin-1β, a cytokine that can induce secretion of proteolytic enzymes. Although interstitial cells in normal valves stained positively for vimentin, but not α-actin or desmin, cells in myxomatous valves contained both vimentin and α-actin or desmin (characteristics of myofibroblasts). Moreover, cells in myxomatous valves strongly expressed SMemb, MMPs, cathepsins, and interleukin-1β, which were weakly stained in controls. Nevertheless, interstitial cells in both groups strongly expressed procollagen-I mRNA (in situ hybridization), suggesting preserved ability to synthesize collagen in myxomatous valves.

Conclusions

Interstitial cells in myxomatous valves have features of activated myofibroblasts and express excessive levels of catabolic enzymes, without altered levels of interstitial collagen mRNA. We conclude that valvular interstitial cells regulate matrix degradation and remodeling in myxomatous mitral valve degeneration.
Estrogen-Induced Vasoprotection Is Independent of Inducible Nitric Oxide Synthase Expression
Authors: Tolbert Todd , Thompson J. Anthony , Bouchard Philippe , Oparil Suzanne
Published: September 2007

Background

Estrogen is vasoprotective in animal models of vascular injury, yet the mechanisms involved are incompletely understood. The role of inducible nitric oxide synthase (iNOS) in vascular repair is controversial, but many lines of evidence indicate that it plays a role in neointima formation after arterial injury and that 17β-estradiol (E
2
) modulates iNOS expression. This study tested the hypothesis that E
2
reduces neointima formation after vascular injury via a mechanism that is dependent on modulation of iNOS expression.

Methods and Results

Male and female wild-type (iNOS
+/+
) mice and mice with homozygous deletion of the iNOS gene (iNOS
−/−
) were studied intact (INT) or after ovariectomy (OVX) and implantation of E
2
or vehicle (V) pellets. Mice were randomized to 8 groups based on sex, iNOS status, OVX, and treatment with E
2
or V. Twenty-eight days after carotid artery ligation, mice were euthanized, and occluded vessels were evaluated for neointima formation by morphometric analysis. There was a marked sexual dimorphism in neointima formation in both the iNOS
+/+
mice and the iNOS
−/−
mice. iNOS
+/+
INT females had a >90% reduction in neointima formation compared with iNOS
+/+
males, and iNOS
−/−
INT females had a 65% reduction in neointima formation compared with iNOS
−/−
males. The sexually dimorphic response was attenuated by OVX and restored by E
2
replacement in both iNOS
+/+
and iNOS
−/−
mice.

Conclusions

These results demonstrate that the vasoprotective effects of E
2
after ligation vascular injury are, at least in part, independent of iNOS expression.
Complete Transposition of the Great Arteries
Authors: Digilio Maria Cristina , Casey Brett , Toscano Alessandra , Calabrò Raffaele , Pacileo Giuseppe , Marasini Maurizio , Banaudi Elena , Giannotti Aldo , Dallapiccola Bruno , Marino Bruno
Published: September 2007

Background

Transposition of the great arteries (TGA) is considered to be associated only rarely with genetic syndromes and to have a low risk of precurrence among relatives of affected patients. Because most family studies have involved a relatively small number of patients and evaluated all types of TGA as a single group, we performed a large, prospective study investigating the precurrence of congenital heart disease in families of children with complete, nonsyndromic TGA.

Methods and Results

From January 1997 through December 2000, 370 patients with nonsyndromic, complete TGA were consecutively evaluated and enrolled in the study. The occurrence of cardiac and noncardiac anomalies among relatives of the probands was investigated. Relatives with congenital heart disease were found in 37 of 370 families (10%), including 5 of 37 families (13.5%) with more than one affected relative. TGA itself was the most common precurrent malformation: complete TGA occurred in 6 families and congenitally corrected TGA occurred in 5 families. Precurrence risks for congenital heart disease were calculated at 1.8% (8 of 436) for siblings, 0.5% (4 of 740) for parents, 0.5% (16 of 3261) for first cousins, 0.2% (4 of 2101) for uncles/aunts, and 0.06% (1 of 1480) for grandparents.

Conclusions

The present study shows that TGA is not always sporadic in families. Precurrence of concordant cardiac defects within affected family members supports monogenic or oligogenic inheritance of TGA in certain kindreds. Moreover, the occurrence of complete TGA and congenitally corrected TGA among first-degree relatives in several different families strongly suggests an underlying pathogenetic link between these 2 malformations that has been previously unrecognized.
Phospholipid Metabolite 1-Palmitoyl-Lysophosphatidylcholine Enhances Human
Ether-a-Go-Go
-Related Gene (HERG) K
+
Channel Function
Authors: Wang Jingxiong , Wang Huizhen , Han Hong , Zhang Yiqiang , Yang Baofeng , Nattel Stanley , Wang Zhiguo
Published: September 2007

Background

Lysophosphatidylcholine (LPC), a naturally occurring phospholipid metabolite, accumulates in the ischemic heart and causes extracellular K
+
accumulation and action potential shortening. LPC has been incriminated as a biochemical trigger of lethal cardiac arrhythmias, but the underlying mechanisms remain poorly understood.

Methods and Results

We studied the effect of 1-palmitoyl-LPC (Pal-LPC) on currents resulting from human
ether-a-go-go
-related gene (HERG) expression in human embryonic kidney (HEK) cells using whole-cell patch-clamp techniques. Bath application of Pal-LPC consistently and reversibly increased HERG current (I
HERG
). The effects of Pal-LPC were apparent as early as 3 minutes after application of the drug, reached maximum within 10 minutes, and were reversible on washout. Pal-LPC increased I
HERG
at voltages between −20 and +30 mV, with greater effects at stronger depolarization. However, Pal-LPC did not affect the voltage-dependence of I
HERG
activation. In contrast, Pal-LPC significantly shifted the inactivation curve toward more positive potentials, causing a mean 20.0±2.2 mV shift in half-inactivation voltage relative to control.

Conclusions

Our results indicate that apart from being a well-recognized target for drug inhibition, I
HERG
can also be enhanced by natural substances. An increase in I
HERG
by Pal-LPC may contribute to K
+
loss, abnormal electrophysiology, and arrhythmia occurrence in the ischemic heart.
Radiofrequency Catheter Ablation in Infants ≤18 Months Old
Authors: Blaufox Andrew D. , Felix Gary L. , Saul J. Philip ,   Participating Members of the Pediatric Catheter Ablation Registry
Published: September 2007

Background

The objective of this study was to determine the indications, the safety, and the efficacy of pediatric radiofrequency catheter ablation (RFCA) in infants.

Methods and Results

Data from the pediatric RFCA registry were reviewed. Between August 1989 and January 1999, 137 infants, defined by age 0 to 1.5 years (median 0.7 years; weight 1.9 to 14.8 kg, median 10 kg), underwent 152 procedures in 27 of 49 registry centers (55%), compared with 5960 noninfants undergoing 6610 procedures during a comparable period. Structural heart disease was present in 36% of infants, compared with 11.2% of noninfants (
P
<0.0001). RFCA in infants was performed more commonly for drug resistance or life-threatening arrhythmias than in noninfants. No differences were found between infants and noninfants in success for all tachycardia substrates (87.6% versus 90.6%,
P
=0.11), for single accessory pathways (94.5% versus 91.5%,
P
=0.4), or for total (7.8% versus 7.4%,
P
=1) and major (4.6% versus 2.9%,
P
=0.17) complications. Neither success for infants with a single accessory pathway nor complications for the entire infant group were related to weight, age, center size, or the presence of structural heart disease. Centers that performed infant procedures, however, enrolled more patients overall in the registry than those that did not perform infant procedures, and successful procedures in infants were performed by more experienced physicians than failed procedures.

Conclusions

Compared with noninfants, RFCA in infants is usually performed for drug resistance or life-threatening arrhythmias, often in the presence of structural heart disease. The data support the use of RFCA by experienced physicians in selected infants.
Isoform-Specific Effects of Apolipoprotein E on Atherogenesis
Authors: Yoshida Hiroaki , Hasty Alyssa H. , Major Amy S. , Ishiguro Hiroyuki , Su Yan Ru , Gleaves Linda A. , Babaev Vladimir R. , Linton MacRae F. , Fazio Sergio
Published: September 2007

Background

We recently used a bone marrow–based gene therapy approach to show that small amounts of retrovirus-derived human apolipoprotein E3 (apoE3) produced by macrophages are protective against early atherosclerosis in apoE-deficient mice.

Methods and Results

In the present study, we evaluated whether the effect produced by macrophage-derived apoE3 is related to its ability to bind cellular membranes. To this end, we used apoE2 and apoEcys142, dysfunctional human variants with reduced binding to the LDL receptor or to heparan sulfate proteoglycans, respectively. ApoE-deficient mice, 5 weeks of age, received transplants of apoE
−/−
bone marrow cells transduced with either parental retrovirus or apoE3, apoE2, or apoEcys142 retroviral vectors. Human apoE was detected by ELISA in the serum of apoE3, apoE2, and apoEcys142 mice as early as 4 weeks after bone marrow transplantation, and at 8 weeks, plasma apoE levels were 55.5±20.3, 50.5±8.7, and 15.3±7.3 μg/dL, respectively. In all groups, cholesterol levels increased with age but were not affected by apoE expression. As previously demonstrated, the lesion area in male apoE3 mice (3808±2224 μm
2
/section) was 40% smaller than that in control mice (6503±3475 μm
2
/section). In apoE2 mice, however, the lesion area was similar to that of controls (5991±2771 μm
2
/section), and apoEcys142 mice showed an unexpected and significant increase in lesion size (10 320±6128 μm
2
/section). Thus, transplantation with marrow transfected with receptor binding–defective apoE variants did not replicate the antiatherogenic effect of apoE3.

Conclusions

These data provide in vivo evidence suggesting that macrophage-derived apoE delays development of atherosclerosis through a receptor-dependent pathway.
Imaging Time After Gd-DTPA Injection Is Critical in Using Delayed Enhancement to Determine Infarct Size Accurately With Magnetic Resonance Imaging
Authors: Oshinski John N. , Yang Zequan , Jones Jeffrey R. , Mata Jaime F. , French Brent A.
Published: September 2007

Background

In patients with acute myocardial infarction (MI), delayed enhancement is seen in MRI 5 to 7 minutes after gadolinium–diethylenetriamine pentaacetic acid (Gd-DTPA) injection, and the enhancement occurs in regions that later show recovery of function. However, in a canine model of acute MI, delayed enhancement 20 to 30 minutes after injection only occurs in necrotic regions and not in surrounding, reversibly injured myocardium. The objective of the present study was to determine (1) if the size of the enhanced region varies with time after Gd-DTPA injection and (2) if and when the size of the enhanced region corresponds to the true infarct size.

Methods and Results

The left coronary artery was occluded in 15 Lewis rats for 30 minutes (n=9) or 2 hours (n=6); this was followed by reperfusion. MRI scans were performed 48±2 hours after-MI. Midventricular short-axis images were obtained continuously for 40 minutes after Gd-DTPA injection (0.3 mmol/kg). The sizes of enhanced regions at each time were determined by threshold analysis and compared with triphenyltetrazolium chloride–stained sections of the excised rat heart. In all animals, the enhanced region overestimated infarct size (28±5%) immediately after the injection of Gd-DTPA, although it then gradually receded to match the size of the infarct. The time required for enhancement to accurately determine infarct size was significantly different between 2-hour infarcts (16±2 minutes) and 30-minute (26±4 minutes) infarcts (
P
<0.05).

Conclusions

In reperfused acute MI, accurate determination of infarct size by delayed enhancement MRI requires imaging at specific times after Gd-DTPA injection, and this time varies with the duration of occlusion.
Collateral Function in Chronic Total Coronary Occlusions Is Related to Regional Myocardial Function and Duration of Occlusion
Authors: Werner Gerald S. , Ferrari Markus , Betge Stefan , Gastmann Oliver , Richartz Barbara M. , Figulla Hans R.
Published: September 2007

Background

Collateral circulation can maintain myocardial function and viability in chronic total coronary occlusion (TCO). The present study evaluates the relation of myocardial function and duration of occlusion to collateral function.

Methods and Results

A total of 50 patients underwent a successful recanalization of a TCO (>4 weeks’ duration). Collateral function was assessed by intracoronary Doppler and pressure recordings before the first balloon inflation and after PTCA had been completed. Collateral function was assessed by Doppler- (CFI
D
) and pressure-derived collateral flow indices (CFI
P
), as well as indices of collateral (R
Coll
) and peripheral resistance (R
P
). Patients with normokinesia had lower R
Coll
(4.9±2.5 versus 11.8±8.2 mm Hg · cm
−1
· s
−1
;
P
=0.033) and lower R
P
(3.8±1.9 versus 6.1±4.1 mm Hg · cm
−1
· s
−1
;
P
=0.031) than those with akinesia. Patients with akinesia and a TCO duration of ≤3 months had the highest R
Coll
and R
P
, whereas those with akinesia and a longer TCO duration had similar collateral function as patients with normokinesia. After PTCA, CFI
D
and CFI
P
decreased from 0.37±0.20 to 0.21±0.17 (
P
<0.001) and from 0.44±0.12 to 0.36±0.11 (
P
<0.001), respectively, with an increase in R
Coll
of 139±128% (
P
<0.001) and R
P
by 65±99% (
P
=0.003). This attenuation of collateral function was less pronounced with epicardial collaterals than with intramyocardial collaterals.

Conclusions

Collateral function was better in patients with TCO and normal regional function than in those with impaired regional function. In the latter group, collateral function improvement was time dependent. After recanalization, the recruitable collateral function was attenuated because of an increase of R
Coll
and R
P
.