bluuebunny/crossref_metadata_2025 huggingface dataset:
Termination of Ventricular Tachycardia in the Human Heart
Authors: Pogwizd Steven M. , Chung Mina K. , Cain Michael E.
Published: June 2012

Background
To define the electrophysiological basis for the termination of ventricular tachycardia (VT), three-dimensional cardiac mapping and analysis of the terminal beats of nonsustained VT and beats of sustained VT were performed in six patients with healed myocardial infarcts.

Methods and Results
Termination of VT was due to activation from multiple initiation sites that were discordant from those responsible for the maintenance of sustained VT in 45% of cases, to repetitive activation from single sites that were discordant from those responsible for the maintenance of sustained VT in 24% of cases, or to activation from sites concordant with the sites of repetitive activation during sustained VT in 31% of cases. Sustained VT was characterized by occasional shifting of initiation sites, even after the tachycardia entered the stable monomorphic phase. Mapping was of sufficient density to define the mechanisms for 21 terminating beats of VT. In 5 cases, termination was due to intramural reentry, which initiated with the total activation time of the preceding beat of 204±11 milliseconds (ms) but terminated primarily because of a decrease in total activation time (144±23 ms,
P
=.03) that was associated with the development of intramural conduction block or with significant changes in the activation sequence along the reentrant circuit. In 16 cases, terminal beats were initiated by a focal mechanism on the basis of the absence of intervening electrical activity from the termination of the preceding beat to the initiation of the terminating beat (172±9 ms). Focal activation was associated with less conduction delay of the preceding beat (115±6 ms) than terminating reentrant beats (
P
<.001) and usually terminated suddenly without oscillations in cycle length or total activation time.

Conclusions
Termination of VT is associated with alterations in initiation sites that are most often discordant from those maintaining sustained VT and is due to either reentrant or focal mechanisms.
Genetic Variant Showing a Positive Interaction With β-Blocking Agents With a Beneficial Influence on Lipoprotein Lipase Activity, HDL Cholesterol, and Triglyceride Levels in Coronary Artery Disease Patients
Authors: Groenemeijer Björn E. , Hallman Michael D. , Reymer Paul W.A. , Gagné Eric , Kuivenhoven Jan Albert , Bruin Taco , Jansen Hans , Lie Kong I. , Bruschke Albert V.G. , Boerwinkle Eric , Hayden Michael R. , Kastelein John J.P.
Published: June 2012

Background
Lipoprotein lipase (LPL) is the rate-limiting enzyme in the lipolysis of triglyceride-rich lipoproteins, and the gene coding for LPL is therefore a candidate gene in atherogenesis. We previously demonstrated that two amino acid substitutions in LPL, the Asn
291
-Ser and the Asp
9
-Asn, are associated with elevated triglycerides and lower HDL cholesterol and are present with greater frequency in coronary artery disease (CAD) patients than in normolipidemic control subjects. Conversely, a third frequent mutation in this gene, the Ser
447
-Stop, is reported by some investigators to underlie higher HDL cholesterol levels and would represent a beneficial genetic variant in lipoprotein metabolism. We therefore sought conclusive evidence for these allegations by investigating the effects of the LPL Ser
447
-Stop mutation on LPL and hepatic lipase (HL) activity, HDL cholesterol, and triglycerides in a large group of CAD patients (n=820) with normal to mildly elevated total and LDL cholesterol levels.

Methods and Results
Carriers of the Ser
447
-Stop allele (heterozygotes and homozygotes) had significantly higher postheparin LPL activity (
P
=.034), normal postheparin HL activity (
P
=.453), higher HDL cholesterol levels (
P
=.013), and lower triglyceride levels (
P
=.044) than noncarriers. The influence of the Ser
447
-Stop allele on LPL activity was pronounced in patients using β-blockers (
P
=.042) and not significant in those not using them (
P
=.881), suggesting a gene-environment interaction between the Ser
447
-Stop mutation and β-blockers.

Conclusions
We conclude that the LPL Ser
447
-Stop mutation has a significant positive effect on LPL activity and HDL cholesterol and triglyceride levels and that certain subgroups of CAD patients carrying the Ser
447
-Stop mutation will have less adverse metabolic effects when placed on β-blockers. The LPL Ser
447
-Stop mutation therefore should have a protective effect against the development of atherosclerosis and subsequent CAD.
Body-Surface QRST Integral Mapping
Authors: Peeters Heidi A.P. , SippensGroenewegen Arne , Schoonderwoerd Bas A. , Wever Eric F.D. , Grimbergen Cornelis A. , Hauer Richard N.W. , Robles de Medina Etienne O.
Published: June 2012

Background
Ventricular tachycardia originating in the right ventricle may arise in the presence or absence of structural heart disease. The two main causes of right ventricular tachycardia are arrhythmogenic right ventricular dysplasia (ARVD) and idiopathic right ventricular tachycardia (IRVT) originating from the outflow tract. This study was carried out to determine whether body-surface QRST integral mapping can differentiate patients with ARVD from patients with IRVT.

Methods and Results
Body-surface QRST integral maps were obtained during sinus rhythm in 8 patients with ARVD, 8 patients with IRVT, and 27 healthy control subjects. QRST integral maps were analyzed both visually and mathematically. All control subjects had a normal dipolar QRST integral map. In all patients with ARVD, a specific dipolar QRST integral map with an abnormally large negative area covering the entire inferior and right anterior thorax was recorded. In 6 of 8 patients with IRVT, a normal map pattern was found, whereas the remaining 2 patients showed an abnormally large negative area on the right anterior thorax.

Conclusions
Patients with ARVD display a specific abnormal QRST integral map that may be related to delayed repolarization in the structurally abnormal right ventricle. The majority of patients with IRVT demonstrate a normal QRST integral map. A slightly abnormal QRST integral map was noted in 2 of 8 patients with IRVT, which may be related to minor structural abnormalities, undetectable by the present routine diagnostic techniques. These preliminary results indicate that body-surface QRST integral mapping may become an important diagnostic tool to differentiate patients with ARVD from those with IRVT.
Depolarization-Repolarization Inhomogeneity After Repair of Tetralogy of Fallot
Authors: Gatzoulis Michael A. , Till Jan A. , Redington Andrew N.
Published: June 2012

Background
We have previously shown that QRS prolongation (≥180 ms) is a risk marker for sustained ventricular tachycardia (VT) late after repair of tetralogy of Fallot (rTOF). We have now examined the dispersion of QT and its components QRS and JT, in an attempt to determine whether any association exists between these measurements and the presence of VT in these patients.

Methods and Results
QRS duration and QT/QRS/JT dispersion were measured manually from standard ECGs in 10 syncopal rTOF patients (21.4±4.6 years after repair; group 1) with QRS≥180 ms and with documented VT and were compared with 9 rTOF patients with QRS ≥180 ms and no VT (group 2), 40 rTOF patients with QRS <180 ms and no clinical arrhythmias (group 3), and 40 nontetralogy control subjects (20 with right bundle-branch block [group 4] and 20 with normal ECG patterns [group 5]). Mean QT dispersion (62±36 ms) in the tetralogy patients was greater than in the nontetralogy control subjects (34±10 ms,
P
<.001). There were significant differences in all measured parameters between groups 1 and 3 and more importantly between groups 1 and 2. QRS dispersion in group 1 also correlated with QRS duration but not with JT dispersion.

Conclusions
Our data suggest that both depolarization and repolarization abnormalities are associated with VT after rTOF. Furthermore, increased QT, QRS, and JT dispersions, combined with a QRS≥180 ms, refine risk stratification for VT in these patients.
Characterization of the Hyperpolarization-Activated Current, I
f
, in Ventricular Myocytes From Human Failing Heart
Authors: Cerbai Elisabetta , Pino Roberto , Porciatti Francesco , Sani Guido , Toscano Michele , Maccherini Massimo , Giunti Gabriele , Mugelli Alessandro
Published: June 2012

Background
Disease-associated electrophysiological alterations may contribute to the increased predisposition to arrhythmias of the hypertrophied or failing myocardium. An I
f
-like current is expressed in rat left ventricular myocytes (LVMs), its amplitude being linearly related to the severity of cardiac hypertrophy. Here, we report the occurrence and electrophysiological properties of I
f
in human LVMs.

Methods and Results
LVMs were isolated from hearts of three male patients undergoing cardiac transplantation for terminal heart failure due to ischemic dilated cardiomyopathy. The patch-clamp technique was used to record I
f
, ie, a barium-insensitive, cesium-sensitive, time-dependent increasing inward current elicited on hyperpolarization. Membrane capacitance was 244±27 pF (n=25). I
f
occurred in all cells tested; its density measured at −120 mV was 2.1±0.3 pA/pF. Activation curves of I
f
(n=24) were fitted by a Boltzmann function; the threshold was −55 mV; midpoint, −70.9±2.1 mV; slope, −5.4±0.3 mV; and maximal specific conductance, 19.6±2.5 pS/pF. I
f
blockade by extracellular cesium was voltage dependent. Reducing extracellular potassium concentration from 25 to 5.4 mmol/L caused a shift of the reversal potential from −12.7±0.5 to −24.8±2.1 mV and a 64% decrease of current conductance.

Conclusions
I
f
is present in human LVMs. Its electrophysiological characteristics resemble those previously described in hypertrophied rat LVMs and suggest that I
f
could be an arrhythmogenic mechanism in patients with severe heart failure.
Incidence of Induced Atrial Fibrillation/Flutter in Complete Atrioventricular Block
Authors: Yamashita Takeshi , Murakawa Yuji , Ajiki Kohsuke , Omata Masao
Published: June 2012

Background
Atrial fibrillation/flutter (Af) has been considered to occur coincidentally with atrioventricular (AV) block. However, a case with complete AV block was reported to histologically show fibrotic changes solely in the atrial muscles but neither in the AV node nor in the His bundle, indicating a possible relation between AV block and atrial tachyarrhythmias. To test a hypothesis that AV block and Af are causally interrelated, we investigated the incidence and electrophysiological characteristics of Af in complete AV block.

Methods and Results
Forty-two patients with persistent complete AV block underwent the electrophysiological study. Patients with spontaneous/electrically induced Af were compared with the other patients with respect to their electrophysiological variables. Of the 42 patients, Af was transiently induced by electrical stimulation in 5 patients (11.9%), while persistent Af was observed in 2 patients (4.8%, AH and HV block). AV block in the 5 patients with induced Af was invariably due to AH block. AH block complicated by persistent/induced Af was marked by relatively short RR intervals, significantly short junctional recovery time, and impaired intra-atrial conduction.

Conclusions
Electrically induced Af in complete AV block was associated frequently with complete AH block. These patients were characterized differently from the commonly recognized AV block and therefore may stand as a unique subgroup of AH block.
Complement C5a, TGF-β1, and MCP-1, in Sequence, Induce Migration of Monocytes Into Ischemic Canine Myocardium Within the First One to Five Hours After Reperfusion
Authors: Birdsall Holly H. , Green David M. , Trial JoAnn , Youker Keith A. , Burns Alan R. , MacKay Charles R. , LaRosa Gregory J. , Hawkins Hal K. , Smith C. Wayne , Michael Lloyd H. , Entman Mark L. , Rossen Roger D.
Published: June 2012

Background
Recent studies suggest that reperfusion promotes healing of formerly ischemic heart tissue even when myocardial salvage is no longer possible. Since monocyte-macrophage infiltration is the hallmark of the healing infarct, we have attempted to identify mechanisms that attract monocytes into the heart after reperfusion of ischemic canine myocardium.

Methods and Results
Isolated autologous
99m
Tc-labeled mononuclear leukocytes injected into the left atrium localized preferentially in previously ischemic myocardium within the first hour after reperfusion. Histological studies revealed CD64+ monocytes in small venules and the perivascular connective tissue within the first hour after reperfusion. Flow cytometric analysis of cells in cardiac lymph showed systematically increasing numbers of neutrophils and monocytes between 1 and 4 hours after reperfusion; monocyte enrichment was eventually greater than neutrophil enrichment. Monocyte chemotactic activity in cardiac lymph collected in the first hour after reperfusion was wholly attributable to C5a. Transforming growth factor (TGF)-β1 contributed significantly to this chemotactic activity after 60 to 180 minutes, and after 180 minutes, monocyte chemotactic activity in lymph was largely dependent on monocyte chemoattractant protein (MCP)-1 acting in concert with TGF-β1.

Conclusions
Beginning in the first 60 minutes after reperfusion, C5a, TGF-β1, and MCP-1, acting sequentially, promote infiltration of monocytes into formerly ischemic myocardium. These events may promote the healing of myocardial injury facilitated by reperfusion.
Automated Cardiac Output Measurement by Spatiotemporal Integration of Color Doppler Data
Authors: Sun Jing Ping , Pu Min , Fouad Fetnat M. , Christian Raymond , Stewart William J. , Thomas James D.
Published: June 2012

Background
A new Doppler echocardiographic technique has been developed for automated cardiac output measurement (ACOM) that assumes neither a flat flow profile nor collinearity with the scan line, but clinical validation of this method is lacking.

Methods and Results
In 165 subjects (50 intensive care patients, 10 dobutamine echocardiography patients, and 105 normal volunteers; age, 49.4±19.3 years; 92 men), ACOM was performed in the left ventricular outflow tract (LVOT), with the color baseline shifted to avoid aliasing. ACOM was also tested in a pulsatile in vitro model. Stroke volume was calculated by double integration of Doppler signals in space (across the LVOT) and in time (through the systolic period), assuming hemiaxial symmetry: ∫∫π r v(r,t) dr dt, where v(r,t) is the velocity at a distance r from the center of the LVOT at time t during systole. Stroke volume from ACOM was compared with thermodilution (TD), aortic valve pulsed-wave Doppler (PWAO), and left ventricular echocardiographic (two-dimensional [2D]) methods. There was good correlation between ACOM and PWAO (
r
=.93), TD (
r
=.86), and 2D (
r
=.74), with close agreement seen. ACOM had higher correlation and agreement with TD than did either PWAO (
P
<.02) or 2D (
P
<.01). ACOM was also able to track accurately the changes in cardiac output with dobutamine infusion in comparison with PWAO (
r
=.94). In vitro assessment demonstrated excellent correlation (
r
=.98,
y
=1.0
x
+1.94) with little impact of pulse repetition frequency or misalignment up to 30°. Gain dependency was noted but could be optimized by visual inspection of the color image.

Conclusions
Automatic integration of numerical data within color Doppler flow fields is a feasible new method for quantifying flow. It is simpler and faster, requires fewer assumptions, and uses only one apical view. ACOM is a promising new approach to echocardiographic quantification that deserves further study and refinement.
Head-up Tilt Test
Authors: Englund Anders , Fredrikson Mia , Rosenqvist Ma˚rten
Published: June 2012

Background
Patients with bifascicular block have an increased risk of syncopal attacks, but the underlying mechanism often remains unclear despite an extensive diagnostic workup. The head-up tilt test has been established as an important diagnostic tool in the unmasking of vasovagal syncope in patients with unexplained syncope. Its role in the evaluation of patients with bifascicular block has not been studied.

Methods and Results
A head-up tilt test, using a 60° angle of tilt for 45 minutes without pharmacological provocation, was performed in 25 patients with bifascicular block and syncope that remained unexplained after an extensive invasive and noninvasive electrophysiological investigation. As a control group, 25 subjects with bifascicular block without syncope, matched for age, sex, left ventricular function, and underlying heart disease, were included. A positive head-up tilt test was found in 7 (28%) of the syncope patients and in 8 (32%) of the control subjects (
P
=NS). Six patients, of whom 3 had a positive tilt test, had recurrent syncopal attacks during 32 months of follow-up. None of the control subjects had syncope during follow-up.

Conclusions
This study gives rise to serious concern regarding the specificity of the head-up tilt test in patients with bifascicular block. A head-up tilt test should therefore be interpreted with caution, and its role as a diagnostic tool in this patient category remains to be established.
Effects of Monoclonal Antibody to P-Selectin and Analogue of Sialyl Lewis X on Cyclic Flow Variations in Stenosed and Endothelium-Injured Canine Coronary Arteries
Authors: Ueyama Takahisa , Ikeda Hisao , Haramaki Nobuya , Kuwano Kazunori , Imaizumi Tsutomu
Published: June 2012

Background
A fundamental role of cell adhesion molecules is implicated in the disease processes of acute coronary syndromes. We have shown an increase in the soluble form of P-selectin in these syndromes, suggesting the important interaction between P-selectin and sialyl Lewis X (SLe
X
) for the pathophysiology of these syndromes. To further test this, we examined the effects of a monoclonal antibody against P-selectin (PB1.3) and a carbohydrate analogue of SLe
X
(SLe
X
-OS) on cyclic flow variations (CFVs) in stenosed and endothelium-injured canine coronary arteries.

Methods and Results
Anesthetized, open-chest dogs (n=48) were divided into six groups after CFVs were established. Dogs received intravenous normal saline, PB1.3 (1 mg/kg bolus), a low dose (5 mg/kg bolus) or a high dose (40 mg/kg bolus) of SLe
X
-OS followed by an infusion (5 mg·kg
−1
·h
−1
) for 60 minutes, a combination of PB1.3 and SLe
X
-OS (low dose), or a combination of a nonblocking antibody against P-selectin (PNB1.6, 1 mg/kg) and SLe
X
-OS (low dose). Although saline, PB1.3, SLe
X
-OS (low dose), and the combination of PNB1.6 and SLe
X
-OS (low dose) did not affect CFVs, the high dose of SLe
X
-OS and the combination of PB1.3 and SLe
X
-OS (low dose) significantly reduced CFVs.

Conclusions
These findings indicate that the high dose of SLe
X
-OS and the combination of PB1.3 and the low dose of SLe
X
-OS provide protection against CFVs. Thus, the adhesive interaction between P-selectin and SLe
X
may play an important role in mediating CFVs in this model.
Angiotensin AT
1
Receptor Inhibition
Authors: Weinberg Ellen O. , Lee Min Ae , Weigner Marilyn , Lindpaintner Klaus , Bishop Sanford P. , Benedict Claude R. , Ho Kalon K. L. , Douglas Pamela S. , Chafizadeh Edward , Lorell Beverly H.
Published: June 2012

Background
We tested the hypothesis that long-term administration of the specific angiotensin II subtype 1 (AT
1
)–receptor blocker BMS-186295 will regress hypertrophy and modify left ventricular angiotensin converting enzyme (ACE) expression in rats with ascending aortic stenosis.

Methods and Results
Six weeks after surgery, rats with ascending aortic stenosis were randomized to receive either the AT
1
-receptor blocker BMS-186295 50 mg·kg
−1
·d
−1
(n=49), amlodipine 2.5 mg·kg
−1
·d
−1
(n=48) as a positive control for systemic vasodilation, or no drug (n=48) and compared with sham-operated rats (n=39). Drug treatment was continued for 15 weeks. Left ventricular ACE mRNA levels were measured by ribonuclease protection assay. The left ventricular/body weight ratio was increased 43% in hearts from rats with untreated left ventricular hypertrophy (LVH) versus control hearts (
P
<.05). However, there was no difference in either the left ventricular/body weight ratio (2.78±0.08 versus 2.81±0.20 mg/g;
P
=NS) or myocyte cross-sectional area in the AT
1
-blocker–treated versus untreated LVH hearts. Amlodipine also showed no effect on regression of hypertrophy. In vivo left ventricular systolic pressure was significantly higher in untreated LVH versus sham-operated rats (193±8 versus 118±4 mm Hg;
P
<.05), and there was a similar severe elevation of left ventricular systolic pressure in the AT
1
-blocker– and amlodipine-treated LVH groups (189±9 and 188±16 mm Hg;
P
=NS versus untreated LVH). In vivo left ventricular end-diastolic pressure was higher in the untreated LVH than in the sham-operated rats (14.8±2.3 versus 7.0±0.5 mm Hg;
P
<.05). Left ventricular end-diastolic pressure was lower in the AT
1
-blocker–treated (11.0±1.7 mm Hg) and amlodipine-treated rats (11.5±1.8 mm Hg) and was similar to left ventricular end-diastolic pressure in the sham-operated rats (
P
=NS). Left ventricular ACE mRNA levels were elevated in untreated LVH rats but were normalized in both the AT
1
-blocker–treated rats and amlodipine-treated rats.

Conclusions
Long-term AT
1
-receptor blockade did not regress LVH in rats with persistent systolic pressure overload due to ascending aortic stenosis. However, both AT
1
-receptor blockade and amlodipine improved in vivo left ventricular end-diastolic pressure in association with the normalization of left ventricular ACE mRNA levels.
Induction of Autoimmune Myocarditis in Interleukin-2–Deficient Mice
Authors: Grässl Gerhard , Pummerer Christian L. , Horak Ivan , Neu Nikolaus
Published: June 2012

Background
Interleukin (IL)-2 is an important growth and survival factor for T cells and plays a crucial role in inflammation. Myosin-induced myocarditis is strictly dependent on activated T cells and is a model for postinfectious inflammatory heart disease in humans. To explore the role of IL-2 in myocarditis, we injected mice genetically deficient for IL-2 with cardiac myosin. Because it is conceivable that the lack of IL-2 either promotes or ameliorates the disease, we selected mouse strains that differ in their susceptibility to cardiac myosin–induced myocarditis.

Methods and Results
Mice from a susceptible strain (C3H) that were rendered IL-2 deficient by gene targeting (IL-2
−/
−
mice) and littermate controls were immunized twice with purified cardiac myosin at a 7-day interval. Three weeks after the first immunization, hearts were obtained for histopathological and immunohistochemical analysis. Sera were tested for autoantibodies to the cardiac myosin isoform by enzyme-linked immunosorbent assay. The majority of C3H IL-2
−/
−
mice developed severe myocarditis accompanied by high-titer myosin autoantibodies. In C57BL/6 mice, which develop only little myocarditis on myosin immunization, lack of IL-2 did not increase susceptibility to the disease. Moreover, the composition of the inflammatory infiltrate in C3H IL-2
−/
−
mice was virtually identical to that seen in the wild-type strain.

Conclusions
Our data provide the first genetic evidence that in cardiac myosin–immunized mice, IL-2 has no essential role for the development of autoimmune heart disease and the generation of myosin autoantibodies.
Concomitant Endothelin Receptor Subtype-A Blockade During the Progression of Pacing-Induced Congestive Heart Failure in Rabbits
Authors: Spinale Francis G. , Walker Jennifer D. , Mukherjee Rupak , Iannini Julie P. , Keever Anthony T. , Gallagher Kim P.
Published: June 2012

Background
Plasma levels of endothelin-1 (ET-1) are increased in patients and animals with severe congestive heart failure (CHF). It remains unknown, however, whether ET-1 plays a direct and contributory role in the progression of CHF. Accordingly, the present project tested the hypothesis that chronic blockade of the ET
A
receptor would have direct and beneficial effects on left ventricular (LV) and myocyte function in a model of CHF.

Methods and Results
Global LV and isolated myocyte function were examined in rabbits in the following groups (12 per group): chronic rapid ventricular pacing (RVP; 400 bpm, 3 weeks), RVP and concomitant administration of the selective ET
A
receptor antagonist (PD 156707 24 mg/d), and sham controls. LV fractional shortening decreased after RVP (17±5 versus 42±3%) and end-diastolic dimension increased (2.36±0.44 versus 1.24±0.18 cm) compared with controls (
P
<.05). With RVP plus ET
A
blockade, LV fractional shortening was increased (33±6%) and end-diastolic dimension decreased (2.02±0.30 cm) compared with RVP-only values (
P
<.05). Plasma norepinephrine and endothelin increased twofold in the RVP group. In the RVP plus ET
A
blockade group, plasma endothelin increased threefold compared with RVP values. Isolated myocyte shortening velocity declined after RVP (42±13 versus 72±10 μm/s,
P
<.05) compared with controls but was normalized with RVP plus ET
A
blockade (77±16 μm/s). Myocyte inotropic response to extracellular Ca
2+
, β-receptor stimulation, and ET-1 was reduced in the RVP group and returned to control levels with RVP and concomitant ET
A
receptor blockade.

Conclusions
The results from this study suggest that chronically elevated ET-1 levels and subsequent activation of the ET
A
receptor play a direct and contributory role in the progression of the CHF process. Thus, specific ET
A
receptor blockade may provide a new and useful therapeutic modality in the setting of CHF.
Effect of Single-Drug Therapy on Reduction of Left Ventricular Mass in Mild to Moderate Hypertension
Authors: Gottdiener John S. , Reda Domenic J. , Massie Barry M. , Materson Barry J. , Williams David W. , Anderson Robert J.
Published: June 2012

Background
Antihypertensive drugs may differ in their ability to reduce LV mass. Covariates other than drug selection, such as pretreatment LV mass, body weight, the magnitude of blood pressure reduction, race, and age may modify the response of LV mass to therapy.

Methods and Results
Patients with mild to moderate hypertension (diastolic blood pressure, 95 to 109 mm Hg) were randomly allocated to treatment with atenolol, captopril, clonidine, diltiazem, hydrochlorothiazide, or prazosin in a double-masked trial. Patients achieving the goal diastolic blood pressure of <90 mm Hg during drug titration entered a 1-year maintenance period. Longitudinal analysis examined changes from baseline echocardiogram in LV mass at 8 weeks and at 1 year, statistically adjusted for pretreatment LV mass, systolic blood pressure, body weight, sodium excretion, physical activity, race, and age. Significant reductions at 1 year in adjusted LV mass were seen for patients in the highest tertile of pretreatment LV mass treated with hydrochlorothiazide (mean, −42.9; 95% confidence limits, −65.5, −20.2 g), captopril (mean, −38.7; 95% confidence limits, −61.0, −16.4 g), and atenolol (mean, −28.1; 95% confidence limits, −50.9, −5.3 g). These treatment effects differed from those of prazosin, diltiazem, or clonidine.

Conclusions
Antihypertensive drugs have disparate effects on LV mass independent of the magnitude of blood pressure reduction. Patients with adequate blood pressure control on captopril, hydrochlorothiazide, and atenolol show a reduction of LV mass after 1 year of treatment, whereas patients on diltiazem, clonidine, or prazosin do not.
Vesnarinone Limits Infarct Size via Adenosine-Dependent Mechanisms in the Canine Heart
Authors: Kitakaze Masafumi , Minamino Tetsuo , Funaya Hiroharu , Node Koichi , Shinozaki Yoshiro , Mori Hidezo , Hori Masatsugu
Published: June 2012

Background
Recently, vesnarinone, a synthetic inotropic agent, was reported to inhibit adenosine transport into cells, which may increase adenosine levels in the heart and in turn mediate cardioprotection. Thus, vesnarinone may also have protective effects in sustained ischemia-reperfusion, because adenosine limits infarct size.

Methods and Results
In open-chest dogs, the left anterior descending coronary arteries were occluded for 90 minutes followed by 6 hours of reperfusion. Vesnarinone limited infarct size compared with controls (6.8±2.2% versus 44.7±3.9%), which was completely reversed by a nonselective adenosine receptor antagonist, 8-sulfophenyltheophylline (44.1±6.8%), and partially blunted by an inhibitor of ecto-5′-nucleotidase, α,β-methyleneadenosine 5′-diphosphate (AMP-CP, 28.9±4.7%). Dipyridamole, an inhibitor of adenosine uptake into cells, only modestly limited infarct size (27.4±5.5%). Furthermore, vesnarinone increased adenosine release during coronary hypoperfusion, which was attenuated by AMP-CP. In vitro, vesnarinone increased the activity of ecto-5′-nucleotidase of the myocardium.

Conclusions
We conclude that vesnarinone potently limits infarct size via adenosine-dependent mechanisms, mainly through activation of ecto-5′-nucleotidase.
Cold Stress Provokes Sympathoinhibitory Presyncope in Healthy Subjects and Hemodialysis Patients With Low Cardiac Output
Authors: Ligtenberg G. , Blankestijn P. J. , Oey P. L. , Wieneke G. H. , van Huffelen A. C. , Koomans H. A.
Published: June 2012

Background
Sudden hypotension in progressive hypovolemia or during hemodialysis is attributed to sudden inhibition of sympathetic activity. Critical ventricular underfilling seems responsible for this paradox, but it is unknown why the transition from sympathoactivation accompanying hypovolemia to sympathoinhibition is so abrupt. We studied whether brief fluctuation of sympathetic activity induced by cold pressor test (CPT) evokes sympathoinhibition if applied during low cardiac output.

Methods and Results
Fourteen healthy subjects underwent CPT, lower-body negative pressure (LBNP; −45 mm Hg for 60 minutes), or the combination thereof. CPT alone caused vasoconstriction and increased muscle sympathetic nerve activity, followed by uneventful relaxation. When applied during reduced cardiac output, tachycardia, and vasoconstriction induced by prior LBNP for 6 minutes, CPT again caused vasoconstriction, now followed by acute hypotension in 10 subjects, and was associated with vasorelaxation, relative bradycardia, and fall in muscle sympathetic nerve activity. Eight subjects also experienced acute LBNP-induced hypotension in the absence of CPT, but not until 17±6 minutes of LBNP. We also performed CPT before and in the final phase of hemodialysis in 8 patients. Before dialysis, the patients tolerated CPT uneventfully, but during hemodialysis, CPT provoked acute hypotension in 5 cases, showing similar withdrawal of vasoconstriction.

Conclusions
This is the first study showing that brief cold stress, tolerated well in normal circulatory conditions, can provoke sudden sympathoinhibition and hypotension when applied during decreased cardiac output induced by LBNP or hemodialysis. We suggest that during conditions of a decreased cardiac output, subtle sympathetic relaxation such as follows cold stress triggers self-enhancing relaxation that cannot be controlled.
Silent Myocardial Ischemia in Kawasaki Disease
Authors: Ogawa Shunichi , Fukazawa Ryuji , Ohkubo Takashi , Zhang Jiakun , Takechi Nobuyuki , Kuramochi Yukio , Hino Yoshiaki , Jimbo Osamu , Katsube Yasuhiro , Kamisago Mitsuhiro , Genma Yukiko , Yamamoto Masao
Published: June 2012

Background
Myocardial ischemia and myocardial infarction are the most serious complications of coronary artery lesions in children with Kawasaki disease (KD). Therefore, early detection and treatment of myocardial ischemia in patients with KD is essential. We studied the effectiveness of percutaneous transluminal coronary angioplasty (PTCA) in patients with silent myocardial ischemia detected by dobutamine stress
99m
Tc myocardial scintigraphy (TMS), body surface mapping (BMS), and signal-averaged ECG late potentials (ELP).

Methods and Results
Eight of 76 asymptomatic patients with a coronary stenosis>25% and a positive dobutamine stress test were considered to have silent myocardial ischemia. All eight patients had>95% stenoses demonstrated by coronary angiography (CAG) just before PTCA. After PTCA, CAG showed that all of the coronary artery stenoses had been reduced to<50%. Additionally, intravascular ultrasonography (IVUS) performed in five patients before and after PTCA demonstrated adequate dilation of the coronary stenosis after PTCA. All eight patients underwent dobutamine stress TMS, BMS, and ELP 2 to 3 months after PTCA, which demonstrated no regions of myocardial ischemia. Approximately 6 months later, CAG was performed in all eight patients, and only one patient had developed restenosis.

Conclusions
PTCA effectively dilates stenotic coronary arteries in children with KD. Moreover, dobutamine stress TMS, BMS, and ELP are useful for detecting silent myocardial ischemia and estimating the effectiveness of PTCA. Furthermore, IVUS is useful for evaluating the severity of coronary artery lesions before and after PTCA in patients with KD.
Abundance and Location of the Small Heat Shock Proteins HSP25 and αB-Crystallin in Rat and Human Heart
Authors: Lutsch Gudrun , Vetter Roland , Offhauss Ulrike , Wieske Martin , Gröne Hermann-Josef , Klemenz Roman , Schimke Ingolf , Stahl Joachim , Benndorf Rainer
Published: June 2012

Background
In the heart, there are high constitutive levels of the two related small heat shock proteins, HSP25 and αB-crystallin. To gain insight into their functional role, we have analyzed abundance and location of both proteins in rat and human hearts at different stages of development and in diseased state.

Methods and Results
Immunoblotting analysis of rat ventricular tissue at fetal, neonatal, and adult stages reveals the level of HSP25 to decline strongly during development, whereas the level of αB-crystallin remains nearly constant. In parallel, the portion of phosphorylated isoforms of HSP25 decreases as shown by two-dimensional polyacrylamide gel electrophoresis. HSP25 is detected in cardiomyocytes and endothelial and vascular smooth muscle cells, whereas αB-crystallin is detected in cardiomyocytes only by immunofluorescence and immunoelectron microscopy. Both proteins colocalize in the I-band and M-line region of myofibrils in cardiomyocytes. In diseased and transplanted adult human hearts, HSP25 and αB-crystallin levels are considerably elevated compared with fetal hearts. In failing adult human hearts, phosphorylated isoforms of HSP25 predominate, and cardiomyocytes with a partial dislocation of HSP25 and αB-crystallin are observed.

Conclusions
Differential accumulation and location of HSP25 and αB-crystallin in heart tissue during development imply distinct functions of both proteins, which seem to be involved in organization of cytoskeletal structures. As judged by level, phosphorylation state, and location of both small heat shock proteins, diseased adult human hearts share features with fetal hearts.
In Utero Cardiac Gene Transfer via Intraplacental Delivery of Recombinant Adenovirus
Authors: Woo Y. Joseph , Raju G. Praveen , Swain Judith L. , Richmond Marc E. , Gardner Timothy J. , Balice-Gordon Rita J.
Published: June 2012

Background
The relationship among the maternal, placental, and uniquely shunted embryonic circulation was explored to provide access to the embryonic cardiovascular system in utero. Manipulation of gene expression in the developing heart would be particularly useful for studying the effects of altered gene expression on cardiac development and in the etiology of congenital cardiac anomalies.

Methods and Results
Dye studies demonstrated that intraplacental injection allows direct access to the embryonic cardiac and systemic circulation. To evaluate the efficacy of cardiac gene transfer using this approach, replication-deficient recombinant adenoviral vectors encoding luciferase or β-galactosidase as reporter genes were injected intraplacentally into embryonic day (E)12.5 murine embryos, an age at which the mass of the heart was observed to be large compared with other organs. Embryos were assayed for transgene expression at E15.5 and at birth. Survival rates at these times were similar among vector-injected and control groups. At E15.5 and at birth, luciferase activity within the heart was 9- and 23-fold higher, respectively, than in the remainder of the embryo, although levels of expression were generally lower at birth than during embryonic life. β-Galactosidase expression was observed within all regions of the embryonic heart and was localized to ≈15% of atrial and ventricular cells.

Conclusions
Intraplacental delivery of adenovirus at embryonic day 12.5 results in somatic gene transfer to the murine embryonic heart, which persists at least until birth. The combination of intraplacental injection to directly access the fetal coronary circulation and injection at E12.5 when the mass of the heart is large compared with other organs results in transgene expression in cardiac cells. Intraplacental injections early in embryonic life may thus be useful to study the effects of temporal manipulation of gene expression on cardiac development and disease.
Positive Chronotropic Actions of Parathyroid Hormone and Parathyroid Hormone–Related Peptide Are Associated With Increases in the Current,
I
f
, and the Slope of the Pacemaker Potential
Authors: Hara Motoki , Liu Yuan-Mou , Zhen LiCi , Cohen Ira S. , Yu Hangang , Danilo Peter , Ogino Kazuhide , Bilezikian John P. , Rosen Michael R.
Published: June 2012

Background
The classic calciotropic hormone parathyroid hormone (PTH) and its paracrine factor parathyroid hormone–related protein (PTHrP) both increase heart rate.

Methods and Results
We used standard electrophysiological techniques to study the effects of PTH and PTHrP on isolated rabbit sinus node, isolated canine Purkinje fibers, and disaggregated rabbit sinus node myocytes. Sinus node maximum diastolic potential, activation voltage, and amplitude were unchanged by PTH or PTHrP (
P
>.05). However, the slope of phase 4 and the automatic rate were increased at PTH and PTHrP ≥10 nmol/L (
P
<.05). Comparable results were seen in canine Purkinje fibers. We then used the perforated-patch technique to study the
I
f
pacemaker current in sinus node. PTH 12.5 nmol/L and PTHrP 12.5 to 18 nmol/L increased
I
f
at −65 mV by 68±41% (n=5) and 69±50% (n=5), respectively. Actions of both agents were reversible. The increase in
I
f
appeared to result from a change in maximal conductance and not a shift in the voltage dependence of activation.

Conclusions
These observations provide, for the first time, direct electrophysiological support for the chronotropic actions of PTH and PTHrP. They suggest that classic hormones and paracrine factors can have multiple functions and that in the case of PTH and PTHrP, a newly recognized action is to alter automaticity directly.
Effect of Angiotensin-Converting Enzyme Inhibition on Myocardial Fibrosis and Function in Hypertrophied and Failing Myocardium From the Spontaneously Hypertensive Rat
Authors: Brooks Wesley W. , Bing Oscar H. L. , Robinson Kathleen G. , Slawsky Mara T. , Chaletsky David M. , Conrad Chester H.
Published: June 2012

Background
After a period of stable hypertrophy, male spontaneously hypertensive rats (SHR) develop heart failure between 18 to 24 months of age, with depression of active myocardial function and increased passive stiffness. We tested the hypothesis that chronic ACE inhibition by captopril would prevent and possibly reverse impairment of myocardial function.

Methods and Results
Male SHR and normotensive Wistar-Kyoto rats (WKY) were assigned to no treatment or captopril treatment (2 g/L in drinking water) begun at ages 12, 18, and 21 months; animals were studied at 24 months of age, or earlier when evidence of heart failure was found in SHR (mean age, 19±2 months). In an additional group, captopril treatment was begun when SHR developed heart failure; surviving animals were studied at 24 months of age. In untreated SHR, relative to WKY, isometric stress development at L
max
, maximum rate of stress development, and shortening velocity were depressed, whereas passive stiffness was increased, in association with the development of myocardial fibrosis. In the SHR treated before cardiac dysfunction, captopril administration attenuated hypertrophy and prevented contractile dysfunction, fibrosis, and increased passive stiffness. Captopril treatment begun after cardiac function was impaired reduced left ventricular hypertrophy but did not restore intrinsic contractile function or reduce fibrosis or passive stiffness.

Conclusions
In the male SHR, early treatment with captopril was associated with the most marked attenuation of dysfunction relative to the untreated SHR. Treatment initiated after the onset of heart failure improved clinical signs of heart failure and decreased left ventricular hypertrophy in surviving animals but did not reverse the fibrosis and contractile dysfunction associated with heart failure.
Modulation of Growth Factor Action
Authors: Waltenberger Johannes
Published: June 2012

Abstract
Peptide growth factors are involved in fundamental cellular processes relevant for cardiovascular physiology and pathology, namely, atherogenesis and angiogenesis. The modulation of growth factor–related signals represents a novel strategy for the treatment of cardiac and vascular disease. Experimental modulation of growth factor action has already provided a better understanding of cardiovascular biology and pathophysiology. In turn, the development of specific and powerful molecular tools is setting the stage for the exploration of their clinical potentials. Current strategies include the use of recombinant proteins, specific inhibitors of protein-protein interactions, tyrosine kinase inhibitors, the generation and application of dominant-negative molecules, the development of antisense strategies, and a variety of different gene transfer approaches. Parallel avenues of research are heading toward the same goal, the specific suppression of potent pathogenic stimuli that induce and promote atherogenesis or the augmentation of beneficial ones such as induction of therapeutic angiogenesis. The successful application of one of these strategies seems to be in reach and will certainly be a milestone in molecular medicine.
Individual Recognition by Heart Rate Variability of Two Different Autonomic Profiles Related to Posture
Authors: Malliani Alberto , Pagani Massimo , Furlan Raffaello , Guzzetti Stefano , Lucini Daniela , Montano Nicola , Cerutti Sergio , Mela Giuseppe S.
Published: June 2012

Background
Power spectrum analysis of heart rate variability (HRV) can estimate the state of sympathovagal balance modulating sinus node activity. In view of the large distribution of spectral variables, a recognition of well-defined physiological conditions has never been attempted on an individual basis.

Methods and Results
We considered 10 spectral variables extracted from short segments (200 to 500 cardiac cycles) of 350 ECG tracings recorded in normal subjects in both supine and upright positions (700 patterns). The tracings were first ordered consecutively and subsequently assigned alternatively to a training or to a test set (each consisting of 175 cases, providing 350 patterns considered to be independent). A forecasting linear method estimated a normalized activation index (ranging from −1 for supine to +1 for upright) that concentrated the information derived from spectral variables and that identified, in the test set, individual by individual, ≈84% of corresponding body postures.

Conclusions
The combined use of spectral methodology and forecasting analysis has revealed an information content embedded, per se, in a short series of RR intervals capable of recognizing, individual by individual, two different autonomic profiles related to posture.
Diastolic Ventricular Interaction
Authors: Atherton John J. , Thomson Helen L. , Moore Thomas D. , Wright Karen N. , Muehle Gerry W. F. , Fitzpatrick Loretta E. , Frenneaux Michael P.
Published: June 2012

Background
Baroreflex dysfunction is common in chronic heart failure and contributes to the associated sympathoexcitation. Baroreceptor activity normally decreases during volume unloading, causing an increase in sympathetic outflow and resulting in forearm vasoconstriction. Some heart failure patients develop attenuated vasoconstriction or paradoxical vasodilation. The mechanism for this is unknown. We have recently demonstrated diastolic ventricular interaction in some patients with chronic heart failure as evidenced by increases in left ventricular (LV) end-diastolic volume in association with decreases in right ventricular (RV) volume during volume unloading. We reasoned that such an increase in LV volume, by increasing LV mechanoreceptor activity, would decrease sympathetic outflow and could therefore explain the abnormal vascular responses seen in such patients.

Methods and Results
We assessed changes in forearm vascular resistance (FVR) during application of −20 and −30 mm Hg lower-body negative pressure (LBNP) in 24 patients with chronic heart failure and 16 control subjects. Changes in LV and RV end-diastolic volumes were assessed during −30 mm Hg LBNP in all heart failure patients. Diastolic ventricular interaction was demonstrated in 12 patients as evidenced by increases in LV end-diastolic volume in association with decreases in RV end-diastolic volume during LBNP. Changes in FVR during LBNP (−20 and −30 mm Hg) were markedly attenuated in these 12 patients (−1.6±11.2 and −0.9±12.5 U) compared with both the remaining patients (11.9±10.0 and 17.0±12.3 U) and the control subjects (16.5±9.5 and 23.1±13.9 U) (
P
<.01 for both comparisons at each level of LBNP). FVR decreased in 5 of these 12 patients during −30 mm Hg LBNP, a response seen in none of the remaining patients (
P
=.01).

Conclusions
Diastolic ventricular interaction in patients with chronic heart failure is associated with attenuated forearm vasoconstriction or paradoxical vasodilation during LBNP. This may explain the apparent derangement in baroreflex control of sympathetic outflow during acute volume unloading in heart failure.
Aqueous Oxygen
Authors: Spears J. Richard , Wang Bing , Wu Xiaojun , Prcevski Petar , Jiang Alice J. , Spanta Ali D. , Crilly Richard J. , Brereton Giles J.
Published: June 2012

Background
High levels of hyperoxemia may have utility in the treatment of regional tissue ischemia, but current methods for its implementation are impractical. A catheter-based method for infusion of O
2
, dissolved in a crystalloid solution at extremely high concentrations, ie, 1 to 3 mL O
2
/g (aqueous oxygen [AO]), into blood without bubble nucleation was recently developed for the potential hyperoxemic treatment of regional tissue ischemia.

Methods and Results
To test the hypotheses that hypoxemia is correctable and that hyperoxemia can be produced locally by AO infusion, normal saline equilibrated with O
2
at 3 MPa (30 bar; 1 mL O
2
/g) was delivered into arterial blood in two different animal models. In 15 New Zealand White rabbits with systemic hypoxemia, AO was infused into the midabdominal aorta at 1 g/min. Mean distal arterial P
o
2
increased to 236±113 and 593±114 mm Hg on 1-hour periods of air and O
2
breathing, respectively, from a baseline of 70±10 mm Hg (
P
<.01). In contrast, infusion of ordinary normal saline in a control group (n=7) had no effect on arterial P
o
2
. No differences between groups (
P
>.05) in temporal changes in blood counts and chemistries were identified. In 10 dogs, low coronary blood flow in the circumflex artery was delivered with a roller pump through the central channel of an occluding balloon catheter. Hypoxemic, normoxemic, and AO-induced hyperoxemic blood perfusates (mean P
o
2
, 52±4, 111±22, and 504±72 mm Hg, respectively) were infused for 3-minute periods in a randomized sequence. Short-axis two-dimensional echocardiography demonstrated a significant decrease (
P
<.05) in left ventricular ejection fraction compared with baseline physiological values with low-flow hypoxemic and normoxemic perfusion but not with low-flow hyperoxemic perfusion.

Conclusions
Intra-arterial AO infusion was effective in these models for regional correction of hypoxemia and production of hyperoxemia.