bluuebunny/crossref_metadata_2025 huggingface dataset:
Left Ventricular Diastolic Function in Normal Human Pregnancy
Authors: Mesa Andres , Jessurun Carlos , Hernandez Antonieta , Adam Karolina , Brown Dale , Vaughn William K. , Wilansky Susan
Published: June 2012

Background
—Little information is available about changes in left ventricular diastolic function during pregnancy. We used mitral inflow and pulmonary venous flow profiles to evaluate left ventricular diastolic function in 37 healthy pregnant women 26 to 41 years old (mean, 32 years).

Methods and Results
—Echocardiographic studies were performed at the end of each trimester. Eight subjects (control group) underwent similar testing 1 to 3.5 months (mean, 1.7 months) postpartum. During pregnancy, the cardiac output increased significantly as a result of an increased heart rate and, to a lesser degree, stroke volume. Significantly decreased systemic vascular resistance and increased left ventricular mass were also noted. Peak mitral flow velocity in early diastole (E) increased 13.3% during the first trimester and remained at the high end of normal throughout pregnancy. Peak A-wave velocity (A) increased maximally in the third trimester. Compared with control subjects, first-trimester subjects had a significantly increased E/A ratio. The ratio subsequently decreased, reflecting the augmented A-wave velocity. Pulmonary venous peak systolic forward flow velocity increased, peaking in the second trimester (nonsignificant), but returned to baseline levels postpartum. The pulmonary venous diastolic time-velocity integral decreased significantly from the first to the third trimester. Peak pulmonary venous reverse flow velocity at atrial contraction increased significantly, without being markedly changed in duration.

Conclusions
—Pregnancy, a chronic, natural volume-overload state, has important effects on hemodynamic and echocardiographic variables. Based on pulmonary venous flow and left ventricular inflow velocities, our results provide a standard reference concerning diastolic filling dynamics by trimester.
Genetic and Molecular Basis of Cardiac Arrhythmias: Impact on Clinical Management Parts I and II
Authors: Priori Silvia G. , Barhanin Jacques , Hauer Richard N. W. , Haverkamp Wilhelm , Jongsma Habo J. , Kleber André G. , McKenna William J. , Roden Dan M. , Rudy Yoram , Schwartz Ketty , Schwartz Peter J. , Towbin Jeffrey A. , Wilde Arthur M.
Published: June 2012

Abstract
—Genetic approaches have succeeded in defining the molecular basis of an increasing array of heart diseases, such as hypertrophic cardiomyopathy and the long-QT syndromes, associated with serious arrhythmias. Importantly, the way in which this new knowledge can be applied to managing patients and to the development of syndrome-specific antiarrhythmic strategies is evolving rapidly because of these recent advances. In addition, the extent to which new knowledge represents a purely research tool versus the extent to which it can be applied clinically is also evolving. The present article represents a consensus report of a meeting of the European Working Group on Arrhythmias. The current state of the art of the molecular and genetic basis of inherited arrhythmias is first reviewed, followed by practical advice on the role of genetic testing in these and other syndromes and the way in which new findings have influenced current understanding of the molecular and biophysical basis of arrhythmogenesis.
Effects of a Specific Endothelin-Converting Enzyme Inhibitor on Cardiac, Renal, and Neurohumoral Functions in Congestive Heart Failure
Authors: Wada Atsuyuki , Tsutamoto Takayoshi , Ohnishi Masato , Sawaki Masahide , Fukai Daisuke , Maeda Yukiharu , Kinoshita Masahiko
Published: June 2012

Background
—Endothelin (ET)-1 is generated from big ET-1 by endothelin-converting enzyme (ECE). Plasma big ET-1 and ET-1 levels are strongly related to survival in patents with congestive heart failure (CHF). Because selective enzymatic processing of ET-1 formation appears to be an important therapeutic target for CHF, we investigated the acute effects of a specific ECE inhibitor on cardiorenal and endocrine functions in CHF compared with those of a selective ETA receptor antagonist.

Methods and Results
—CHF was induced in beagle dogs by rapid right ventricular pacing (270 bpm, 14 days). Two incremental doses of a specific ECE inhibitor, FR901533, or a selective ETA receptor antagonist, FR139317 (1 and 3 mg/kg, n=8, respectively), were injected into dogs with CHF. FR901533 and FR139317 decreased mean arterial pressure and pulmonary capillary wedge pressure associated with reduction in systemic and pulmonary vascular resistance. These agents increased cardiac output but did not affect left ventricular fractional shortening. FR139317 exerted a greater depressor effect on mean arterial pressure than FR901533 (
P
<0.05). These agents decreased plasma atrial natriuretic peptide levels, but only FR901533 decreased plasma renin activity, angiotensin II, and aldosterone levels. Neither agent changed the plasma norepinephrine level despite the fall in blood pressure. These drugs increased the urinary water and sodium excretion rate associated with increases in the glomerular filtration rate and renal plasma flow, and the incremental magnitude induced by FR139317 was larger than that by FR901533 (
P
<0.05).

Conclusions
—An ETA receptor antagonist appeared to induce greater vasodilative effects on systemic and renal vasculature in CHF than an ECE inhibitor. However, the ECE inhibitor reduced the secretion of neurohumoral factors that are activated in proportion to the severity of CHF. Our acute complementary data may support the importance of the role of ECE in CHF and provide a rationale foundation for investigating the usefulness of long-term treatment with ECE inhibitors in CHF.
NPR-A–Deficient Mice Show Increased Susceptibility to Hypoxia-Induced Pulmonary Hypertension
Authors: Zhao Lan , Long Lu , Morrell Nicholas W. , Wilkins Martin R.
Published: June 2012

Background
—Mice in which the gene encoding NPR-A, a guanylyl cyclase–linked natriuretic peptide receptor, has been disrupted were used to examine the contribution of natriuretic peptides to maintaining pulmonary vascular homeostasis in normal- and low-oxygen environments.

Methods and Results
—Wild-type (+/+), heterozygous (+/−), and homozygous null mutants (−/−) were studied. The response of the pulmonary vasculature to atrial, B-type, and C-type natriuretic peptides (ANP, BNP, and CNP) during acute hypoxia was studied in isolated perfused lungs. Right ventricular systolic pressure (RVSP), RV weight, and pulmonary vascular remodeling were measured in each genotype exposed to normal air and after 7 and 21 days in a hypoxic atmosphere (10% O
2
). ANP and BNP (300 ng) reduced pulmonary artery pressure during acute hypoxia-induced pulmonary vasoconstriction in +/+ mice, but this effect was attenuated in +/− and absent in −/− mice. CNP (600 ng) had little effect in all 3 genotypes. RVSP and RV weight were similar in the 3 genotypes housed in a normal-O
2
environment. Seven and 21 days of hypoxia produced a pronounced and significantly greater increase in RVSP and RV weight in −/− mice compared with +/+ or +/− mice and more rapid muscularization of distal pulmonary arterioles.

Conclusions
—ANP and BNP do not contribute to maintaining normal pulmonary artery pressure but play an important role in attenuating the pulmonary vascular response to hypoxia. NPR-A mediates the vasorelaxant effect of ANP in pulmonary vasculature.
Vasoflux, a New Anticoagulant With a Novel Mechanism of Action
Authors: Weitz Jeffrey I. , Young Edward , Johnston Marilyn , Stafford Alan R. , Fredenburgh James C. , Hirsh Jack
Published: June 2012

Background
—Heparin and direct thrombin inhibitors, such as hirudin, have limitations in the treatment of acute coronary syndromes. Heparin does not inactivate fibrin-bound thrombin, whereas hirudin fails to block thrombin generation. In contrast, Vasoflux is a novel anticoagulant that inactivates fibrin-bound thrombin and attenuates factor Xa generation.

Methods and Results
—Vasoflux is prepared by depolymerization of heparin, restricting molecular size to between 3000 and 8000 Da, and reducing antithrombin affinity by periodate oxidation. Vasoflux catalyzes fibrin-bound thrombin inactivation by heparin cofactor II (HCII) and inhibits factor IXa activation of factor X independently of antithrombin and HCII. Compared with other anticoagulants in a thrombogenic extracorporeal circuit, Vasoflux maintains filter patency at concentrations that produce an activated clotting time (ACT) of 220 seconds. In contrast, to maintain filter patency, heparin, low-molecular-weight heparin (LMWH), and hirudin require concentrations that produced an ACT of 720, 415, and >1500 seconds, respectively, whereas dermatan sulfate was ineffective at concentrations that produced an ACT of 360 seconds.

Conclusions
—Vasoflux is more effective than heparin and LMWH because it inactivates fibrin-bound thrombin and is superior to hirudin and dermatan sulfate because it also blocks factor Xa generation.
Mechanism of Acceleration of Functional Reentry in the Ventricle
Authors: Uchida Takumi , Yashima Masaaki , Gotoh Masamichi , Qu Zhilin , Garfinkel Alan , Weiss James N. , Fishbein Michael C. , Mandel William J. , Chen Peng-Sheng , Karagueuzian Hrayr S.
Published: June 2012

Background
—The effect of effective refractory period (ERP) shortening on the vulnerability and characteristics of induced functional reentry in the ventricle remain poorly defined. We hypothesized that ERP shortening increases ventricular vulnerability to reentry and accelerates its rate, as is the case in the atrium.

Methods and Results
—The epicardial surfaces of 19 isolated and superfused canine right ventricular slices (4×4 cm and <2 mm thick) were mapped with 480 bipolar electrodes 1.6 mm apart. Vulnerability was tested during pacing at a cycle length (CL) of 600 ms and with a single premature stimulus of 5-ms duration at increasing current strength of 1 to 100 mA. Cromakalim (10 μmol/L), an ATP-sensitive potassium channel opener, caused a significant (
P
<0.001) shortening of the ERP but had no effect on conduction velocity. Cromakalim increased (
P
<0.01) the vulnerability (product of current and the stimulus coupling interval) for reentry induction. Reentry had a significantly shorter CL and lasted for a longer duration (
P
<0.001). The central core around which the wave front rotated became smaller, which caused shortening of the CL of reentry. A significant (
P
<0.001) linear correlation was found between core size and reentry CL. These effects of cromakalim were reversible. Two-dimensional simulation studies using the modified Luo-Rudy I model of cardiac action potential, in which the refractory period was variably shortened by a progressive increase of the time-independent potassium conductance, reproduced the experimental findings.

Conclusions
—ERP shortening by an ATP-sensitive potassium channel opener increases ventricular vulnerability to reentry and accelerates its rate by decreasing the core size around which the wave front rotates.
Early Contrast-Enhanced MRI Predicts Late Functional Recovery After Reperfused Myocardial Infarction
Authors: Rogers Walter J. , Kramer Christopher M. , Geskin Gennady , Hu Yong-Lin , Theobald Therese M. , Vido Diane A. , Petruolo Susan , Reichek Nathaniel
Published: June 2012

Background
—We have observed 3 abnormal patterns on contrast-enhanced MRI early after reperfused myocardial infarction (MI): (1) absence of normal first-pass signal enhancement (HYPO), (2) normal first pass signal followed by hyperenhanced signal on delayed images (HYPER), or (3) both absence of normal first-pass enhancement and delayed hyperenhancement (COMB). This study examines the association between these patterns in the first week after MI and late recovery of myocardial contractile function by use of magnetic resonance myocardial tissue tagging.

Methods and Results
—Seventeen patients (14 men) with a mean age of 53±12 years were studied after a reperfused first MI. Contrast-enhanced images were acquired immediately after bolus administration of gadolinium and 7±2 minutes later. Tagged images were acquired at weeks 1 and 7. Circumferential segment shortening (%S) was measured in regions displaying HYPER, COMB, or HYPO contrast patterns and in remote regions (REMOTE) at weeks 1 and 7. At week 1, %S was depressed in HYPER, COMB, and HYPO (9±8%, 7±6%, and 5±4%, respectively) and were less than REMOTE (18±6%,
P
<0.003). However, in HYPER, %S improved at week 7 from 9±8% to 18±5% (
P
<0.001 versus week 1). In contrast, HYPO did not improve significantly (5±4% to 6±3%,
P
=NS) and COMB tended to improve 7±6% to 11±6% (
P
=0.06).

Conclusions
—HYPER has partially reversible dysfunction and represents predominantly viable myocardium. COMB shows borderline improvement and likely contains an admixture of viable and necrotic myocardium. HYPO shows little functional improvement at 7 weeks, presumably because of irreversible myocardial damage.
Myocardial Protection Conferred by Electromagnetic Fields
Authors: DiCarlo A. L. , Farrell J. M. , Litovitz T. A.
Published: June 2012

Background
—It has been reported that electromagnetic (EM) fields induce stress proteins in vitro. These proteins have been shown to be important in recovery from ischemia/reperfusion. It was, therefore, hypothesized that EM fields could activate stress responses in vivo and protect myocardial tissue during anoxia.

Methods and Results
—Chick embryos were exposed to 4-, 6-, 8-, and 10-μT and 60-Hz EM fields for 20 minutes followed by a 1-hour rest period before placement in an anoxic chamber. Embryos were reoxygenated when survival of controls dropped to <40%, and final observations were made 30 minutes later. Data from 80 experiments (>500 EM field-exposed embryos) indicated that EM field protection was extremely significant (
P
<0.0001). Survival rates were 39.6% in controls and 68.7% in field-exposed embryos. In a second set of experiments, embryos were exposed for 20 minutes to several pretreatments: (1) hyperthermia (43°C), (2) 60-Hz, 8-μT EM fields, or (3) 60-Hz, 8-μT EM fields plus a random EM noise field (8 μT). Embryo survival was 37.7% (control), 57.6% (heated), 69% (60-Hz EM field only), and 41.5% (60-Hz EM field plus EM noise). To confirm that heating resulting from field exposures did not occur, thermocouples were placed into several eggs at the site of the embryo during exposure; no increase in temperature was noted.

Conclusions
—We conclude that athermal EM field exposures induce stress responses that protect chick embryo myocardium from anoxia damage. These results suggest that EM field exposures may be a useful, noninvasive means of minimizing myocardial damage during surgery, transplantation, or heart attack in humans.
Interleukin-1 Receptor Antagonist Gene Polymorphism and Coronary Artery Disease
Authors: Francis Sheila E. , Camp Nicola J. , Dewberry Rachael M. , Gunn Julian , Syrris Petros , Carter Nicholas D. , Jeffery Stephen , Kaski Juan Carlos , Cumberland David C. , Duff Gordon W. , Crossman David C.
Published: June 2012

Background
—Cytokine gene variations are contributory factors in inflammatory pathology. Allele frequencies of interleukin (IL)-1 cluster genes [IL-1A(-889), IL-1B(-511), IL-1B(+3953), IL-1RN Intron 2 VNTR] and tissue necrosis factor (TNF)-α gene [TNFA(-308)] were measured in healthy blood donors (healthy control subjects), patients with angiographically normal coronary arteries (patient control subjects), single-vessel coronary disease (SVD), and those with multivessel coronary disease (MVD).

Methods and Results
—Five hundred fifty-six patients attending for coronary angiography in Sheffield were studied: 130 patient control subjects, 98 SVD, and 328 MVD. Significant associations were tested in an independent population (London) of 350: 57 SVD, 191 MVD, and 102 control subjects. IL-1RN*2 frequency in Sheffield patient control subjects was the same as in 827 healthy control subjects. IL-1RN*2 was significantly overrepresented in Sheffield SVD patients (34% vs 23% in patient control subjects); IL-1RN*2 homozygotes in the SVD population (χ
2
carriage=8.490, 1
df
,
P
=0.0036). This effect was present though not quite significant in the London population (
P
=0.0603). A summary trend test of the IL-1RN SVD genotype data for Sheffield and London showed a significant association with *2 (
P
=0.0024). No significant effect of genotype at IL-1RN was observed in the Sheffield or London MVD populations. Genotype distribution analysis comparing the SVD and MVD populations at IL-1RN showed a highly significant trend (
P
=0.0007) with the use of pooled data. No significant associations were seen for the other polymorphisms.

Conclusions
—IL-1RN*2 was significantly associated with SVD. A difference in genetic association between SVD and MVD was also apparent.
Prognostic Value of Myocardial Perfusion Imaging in Patients With High Exercise Tolerance
Authors: Chatziioannou Sofia N. , Moore Warren H. , Ford Patrick V. , Fisher Ronald E. , Lee Vei-Vei , Alfaro-Franco Carina , Dhekne Ramesh D.
Published: June 2012

Background
—Although high exercise tolerance is associated with an excellent prognosis, the significance of abnormal myocardial perfusion imaging (MPI) in patients with high exercise tolerance has not been established. This study retrospectively compares the utility of MPI and exercise ECG (EECG) in these patients.

Methods and Results
—Of 388 consecutive patients who underwent exercise MPI and reached at least Bruce stage IV, 157 (40.5%) had abnormal results and 231 (59.5%) had normal results. Follow-up was performed at 18±2.7 months. Adverse events, including revascularization, myocardial infarction, and cardiac death, occurred in 40 patients. Nineteen patients had revascularization related to the MPI results or the patient’s condition at the time of MPI and were not included in further analysis. Seventeen patients (12.2%) with abnormal MPI and 4 (1.7%) with normal MPI had adverse cardiac events (
P
<0.001). Cox proportional-hazards regression analysis showed that MPI was an excellent predictor of cardiac events (global χ
2
=13.2;
P
<0.001; relative risk=8; 95% CI=3 to 23) but EECG had no predictive power (global χ
2
=0.05;
P
=0.8; relative risk=1; 95% CI=0.4 to 3.0). The addition of Duke’s treadmill score risk categories did not improve the predictive power of EECG (global χ
2
=0.17). The predictive power of the combination of EECG (including Duke score categories) and MPI was no better than that of MPI alone (global χ
2
=13.5).

Conclusions
—Unlike EECG, MPI is an excellent prognostic indicator for adverse cardiac events in patients with known or suspected CAD and high exercise tolerance.
In-Stent Neointimal Proliferation Correlates With the Amount of Residual Plaque Burden Outside the Stent
Authors: Prati Francesco , Di Mario Carlo , Moussa Issam , Reimers Bernhard , Mallus Maria Teresa , Parma Antonio , Lioy Ernesto , Colombo Antonio
Published: June 2012

Background
—The aim of this study was to evaluate the relationship between residual plaque burden after coronary stent implantation and the development of late in-stent neointimal proliferation.

Methods and Results
—Between January 1996 and May 1997, 50 patients underwent intravascular ultrasound (IVUS) interrogation at 6±1.2 months after coronary stent implantation in native coronary arteries. IVUS images were acquired with a motorized pullback, and cross-sectional measurements were performed within the stents at 1-mm intervals. The following measurements were obtained: (1) lumen area (LA), (2) stent area (SA), (3) area delimited by the external elastic membrane (EEMA), (4) percent neointimal area calculated as (SA−LA/SA)×100, and (5) percent residual plaque area calculated as (EEMA−SA)/EEMA×100. Volume measurements within the stented segments were calculated by applying Simpson’s rule. In the pooled data analysis of 876 cross sections, linear regression showed a significant positive correlation between percent residual plaque area and percent neointimal area (
r
=0.50,
y
= 45.03+0.29
x
,
P
<0.01). There was significant incremental increase in mean percent neointimal area for stepwise increase in percent residual plaque area. Mean percent neointimal area was 16.3±10.3% for lesions with a percent residual plaque area of <50% and 27.7±11% for lesions with a percent residual plaque area of ≥50% (
P
<0.001). The volumetric analysis showed that the percent residual plaque volume was significantly greater in restenotic lesions compared with nonrestenotic lesions (58.7±4.3% versus 51.4±5.7%, respectively;
P
<0.01).

Conclusions
—Late in-stent neointimal proliferation has a direct correlation with the amount of residual plaque burden after coronary stent implantation, supporting the hypothesis that plaque removal before stent implantation may reduce restenosis.
Origin of Contractile Dysfunction in Heart Failure
Authors: Pérez N. Gustavo , Hashimoto Katsuji , McCune Sylvia , Altschuld Ruth A. , Marbán Eduardo
Published: June 2012

Background
—Chronic congestive heart failure is a common, often lethal disorder of cardiac contractility. The fundamental pathophysiology of the contractile failure remains unclear, the focus being on abnormal Ca
2+
cycling despite emerging evidence for depressed myofilament function.

Methods and Results
—We measured intracellular Ca
2+
concentration ([Ca
2+
]
i
) and contractile force in intact ventricular muscle from SHHF rats with spontaneous heart failure and from age-matched controls. At physiological concentrations of extracellular Ca
2+
([Ca
2+
]
o
), [Ca
2+
]
i
transients were equal in amplitude in the 2 groups, but [Ca
2+
]
i
peaked later in SHHF muscles. Twitch force peaked slowly and was equivalent or modestly decreased in amplitude relative to controls. Steady-state analysis revealed a much greater (53%) depression of maximal Ca
2+
-activated force in SHHF muscles, which, had other factors been equal, would have produced an equivalent suppression of twitch force. Phase-plane analysis reveals that the slowing of Ca
2+
cycling prolongs the time available for Ca
2+
to activate the myofilaments in failing muscle, partially compensating for the marked dysfunction of the contractile machinery.

Conclusions
—Our results indicate that myofilament activation is severely blunted in heart failure, but concomitant changes in [Ca
2+
]
i
kinetics minimize the contractile depression. These results challenge prevailing concepts regarding the pathophysiology of heart failure: the myofilaments emerge as central players, whereas changes in Ca
2+
cycling are reinterpreted as compensatory rather than causative.
Tranilast Suppresses Vascular Chymase Expression and Neointima Formation in Balloon-Injured Dog Carotid Artery
Authors: Shiota Naotaka , Okunishi Hideki , Takai Shinji , Mikoshiba Imao , Sakonjo Hiroshi , Shibata Nobuo , Miyazaki Mizuo
Published: June 2012

Background
—Activation of vascular chymase plays a major role in myointimal hypertrophy after vascular injury by augmenting the production of angiotensin (ANG) II. Because chymase is synthesized mainly in mast cells, we assumed that the chymase-dependent ANG II formation could be downregulated by tranilast, a mast cell–stabilizing antiallergic agent. We have assessed inhibitory effects of tranilast on neointima formation after balloon injury in the carotid artery of dogs, which share a similar ANG II–forming chymase with humans, and further explored the pathophysiological significance of vascular chymase.

Methods and Results
—Either tranilast (50 mg/kg BID) or vehicle was orally administered to beagles for 2 weeks before and 4 weeks after balloon injury. Four weeks after the injury, remarkable neointima was formed in the carotid arteries of vehicle-treated dogs. Chymase mRNA levels and chymaselike activity of vehicle-treated injured arteries were increased 10.2- and 4.8-fold, respectively, those of uninjured arteries. Angiotensin-converting enzyme (ACE) activity was slightly increased in the injured arteries, whereas ACE mRNA levels were not. Tranilast treatment completely prevented the increase in chymaselike activity, reduced the chymase mRNA levels by 43%, and decreased the carotid intima/media ratio by 63%. In vehicle-treated injured arteries, mast cell count in the adventitia showed a great increase, which was completely prevented by the tranilast treatment. Vascular ACE activity and mRNA levels were unaffected by tranilast.

Conclusions
—Tranilast suppressed chymase gene expression, which was specifically activated in the injured arteries, and prevented neointima formation. Suppression of the chymase-dependent ANG II–forming pathway may contribute to the beneficial effects of tranilast.
Endogenous Nitric Oxide Synthase Inhibitor
Authors: Miyazaki Hiroshi , Matsuoka Hidehiro , Cooke John P. , Usui Michiaki , Ueda Seiji , Okuda Seiya , Imaizumi Tsutomu
Published: June 2012

Background
—Exposure to risk factors such as hypertension or hypercholesterolemia decreases the bioavailability of endothelium-derived nitric oxide (NO) and impairs endothelium-dependent vasodilation. Recently, a circulating endogenous NO synthase inhibitor, asymmetric dimethylarginine (ADMA), has been detected in human plasma. The purpose of this study was to examine the relationship between plasma ADMA and atherosclerosis in humans.

Methods and Results
—Subjects (n=116; age, 52±1 years; male:female ratio, 100:16) underwent a complete history and physical examination, determination of serum chemistries and ADMA levels, and duplex scanning of the carotid arteries. These individuals had no symptoms of coronary or peripheral artery disease and were taking no medications. Univariate and multivariate analyses revealed that plasma levels of ADMA were positively correlated with age (
P
<0.0001), mean arterial pressure (
P
<0.0001), and Σ glucose (an index of glucose tolerance) (
P
=0.0006). Most intriguingly, stepwise regression analysis revealed that plasma ADMA levels were significantly correlated to the intima-media thickness of the carotid artery (as measured by high-resolution ultrasonography).

Conclusions
—This study reveals that plasma ADMA levels are positively correlated with risk factors for atherosclerosis. Furthermore, plasma ADMA level is significantly correlated with carotid intima-media thickness. Our results suggest that this endogenous antagonist of NO synthase may be a marker of atherosclerosis.
Randomized, Controlled Trial of Long-Term Moderate Exercise Training in Chronic Heart Failure
Authors: Belardinelli Romualdo , Georgiou Demetrios , Cianci Giovanni , Purcaro Augusto
Published: June 2012

Background
—It is still a matter of debate whether exercise training (ET) is a beneficial treatment in chronic heart failure (CHF).

Methods and Results
—To determine whether long-term moderate ET improves functional capacity and quality of life in patients with CHF and whether these effects translate into a favorable outcome, 110 patients with stable CHF were initially recruited, and 99 (59±14 years of age; 88 men and 11 women) were randomized into 2 groups. One group (group T, n=50) underwent ET at 60% of peak V̇
o
2
, initially 3 times a week for 8 weeks, then twice a week for 1 year. Another group (group NT, n=49) did not exercise. At baseline and at months 2 and 14, all patients underwent a cardiopulmonary exercise test, while 74 patients (37 in group T and 37 in group NT) with ischemic heart disease underwent myocardial scintigraphy. Quality of life was assessed by questionnaire. Ninety-four patients completed the protocol (48 in group T and 46 in group NT). Changes were observed only in patients in group T. Both peak V̇
o
2
and thallium activity score improved at 2 months (18% and 24%, respectively;
P
<0.001 for both) and did not change further after 1 year. Quality of life also improved and paralleled peak V̇
o
2
. Exercise training was associated both with lower mortality (n=9 versus n=20 for those with training versus those without; relative risk (RR)=0.37; 95% CI, 0.17 to 0.84;
P
=0.01) and hospital readmission for heart failure (5 versus 14; RR=0.29; 95% CI, 0.11 to 0.88;
P
=0.02). Independent predictors of events were ventilatory threshold at baseline (β-coefficient=0.378) and posttraining thallium activity score (β-coefficient −0.165).

Conclusions
—Long-term moderate ET determines a sustained improvement in functional capacity and quality of life in patients with CHF. This benefit seems to translate into a favorable outcome.
Prenatal Features of Ductus Arteriosus Constriction and Restrictive Foramen Ovale in d-Transposition of the Great Arteries
Authors: Maeno Yasuki V. , Kamenir Steven A. , Sinclair Brian , van der Velde Mary E. , Smallhorn Jeffrey F. , Hornberger Lisa K.
Published: June 2012

Background
—Although most neonates with d-transposition of the great arteries (TGA) have an uncomplicated preoperative course, some with a restrictive foramen ovale (FO), ductus arteriosus (DA) constriction, or pulmonary hypertension may be severely hypoxemic and even die shortly after birth. Our goal was to determine whether prenatal echocardiography can identify these high-risk fetuses with TGA.

Methods and Results
—We reviewed the prenatal and postnatal echocardiograms and outcomes of 16 fetuses with TGA/intact ventricular septum or small ventricular septal defect. Of the 16 fetuses, 6 prenatally had an abnormal FO (fixed position, flat, and/or redundant septum primum). Five of the 6 had restrictive FO at birth. Five fetuses had DA narrowing at the pulmonary artery end in utero, and 6 had a small DA (diameter
z
score of <−2.0). Of 4 fetuses with the most diminutive DA, 2 also had an abnormal appearance of the FO, and both died immediately after birth. One other fetus had persistent pulmonary hypertension. Eight fetuses had abnormal Doppler flow pattern in the DA (continuous high-velocity flow, n=1; retrograde diastolic flow, n=7).

Conclusions
—Abnormal features of the FO, DA, or both are present in fetuses with TGA at high risk for postnatal hypoxemia. These features may result from the abnormal intrauterine hemodynamics in TGA. A combination of restrictive FO and DA constriction in TGA may be associated with early neonatal death.
Iron-Deficient Diet Reduces Atherosclerotic Lesions in ApoE-Deficient Mice
Authors: Lee Tzong-Shyuan , Shiao Ming-Shi , Pan Ching-Chien , Chau Lee-Young
Published: June 2012

Background
—Iron deposition is evident in human atherosclerotic lesions, suggesting that iron may play a role in the development of atherosclerosis. To test this idea, the correlation between the extent of iron deposition and the severity of atherosclerosis in apolipoprotein E (apoE)-deficient mice was investigated. Furthermore, the effect of a low-iron diet on the progression of atherosclerotic lesions in these animals was evaluated.

Methods and Results
—Iron deposition in tissues of apoE-deficient mice was examined by Perls’ staining method. The results clearly demonstrated that iron deposits are present in atherosclerotic lesions and tissue sections of heart and liver in an age-dependent manner. When the young mice received a low-iron diet for 3 months, the hematocrit, serum iron, hemoglobin, and cholesterol concentrations were not significantly altered compared with those of littermates placed on a chow diet. However, the serum ferritin level of animals in the iron-restricted group was 27% to 30% lower than that of the control group in either sex. Furthermore, the lipoproteins isolated from the iron-restricted group exhibited greater resistance to copper-induced oxidation. Histological examination revealed that atherosclerotic lesions developed in mice fed a low-iron diet were significantly smaller than those found in control littermates. Likewise, the iron deposition as well as tissue iron content was much less in aortic tissues of the iron-restricted animals. Circulating autoantibodies to oxidized LDL and immunostains for epitopes of malondialdehyde-modified LDL detected on lesions were also significantly lower in mice fed a low-iron diet.

Conclusions
—Iron deposition is closely associated with the progression of atherosclerosis in apoE-deficient mice. Restriction in dietary iron intake leads to significant inhibition of lesion formation in these animals. These results suggest that the beneficial effect of a low-iron diet may be mediated, at least in part, by the reduction of iron deposition as well as LDL oxidation in vascular lesions.
Digitalis
Authors: Hauptman Paul J. , Kelly Ralph A.
Published: June 2012

Abstract
—Cardiac glycosides have played a prominent role in the therapy of congestive heart failure since William Withering codified their use in his late 18th century monograph on the efficacy of the leaves of the common foxglove plant (
Digitalis purpurea
). Despite their widespread acceptance into medical practice in the ensuing 200 years, both the efficacy and the safety of this class of drugs continue to be a topic of debate. Moreover, despite the fact that the molecular target for the cardiac glycosides, the α-subunit of sarcolemmal Na
+
K
+
-ATPase (or sodium pump) found on most eukaryotic cell membranes, has been known for several decades, it remains controversial whether the sympatholytic or positive inotropic effects of these agents is the mechanism most relevant to relief of heart failure symptoms in humans with systolic ventricular dysfunction. Herein, we review the molecular and clinical pharmacology of this venerable class of drugs, as well as the manifestations of digitalis toxicity and their treatment. We also review in some detail recent clinical trials designed to examine the efficacy of these drugs in heart failure, with a focus on the Digoxin Investigation Group data set. Although, in our opinion, the data on balance warrant the continued use of these drugs for the treatment of symptoms of heart failure in patients already receiving contemporary multidrug therapy for this disease, the use of digitalis preparations will inevitably decline with the maturation of newer pharmacotherapies.
Cardiac output and peripheral resistance in strains of rats sensitive and resistant to NaCl hypertension.
Authors: Ganguli M , Tobian L , Iwai J
Published: June 2012

The interrelationship of blood pressure, cardiac output, and peripheral resistance was studied in Dahl "S" and "R" rats after 3 days on a high (8%) NaCl diet. Both "S" and "R" rats were normotensive when fed a normal (0.3%) NaCl diet. After 3 days of the high NaCl diet, the "R" rats remained normotensive (BP 112 mm Hg), while the "S" rats had an elevation of arterial pressure (BP 133 mm Hg) (p less than 0.001). The cardiac outputs of both "S" and "R" rats were similar on the low NaCl diet. After 3 days of high NaCl feeding, the cardiac output of the "R" rats rose 18% above the "R" control level (p less than 0.0001), while the peripheral resistance declined 14% below the "R" control level (p less than 0.005), and the blood pressure (BP) did not change, a pattern quite contrary to the concept of "whole-body" autoregulation. With a similar 3-day high NaCl feeding in "S" rats, cardiac output (p less than 0.005) and peripheral resistance (p less than 0.05) both increased 10%, while BP rose 20%. After 7 days of high NaCl feeding, the cardiac output of the "S" rats had returned to normal, while blood pressure and peripheral resistance both continued to be elevated. This pattern of response in "S" rats could be compatible with the concept of "whole-body" autoregulation. However, since both NaCl hypertension and Goldblatt hypertension can occur in settings in which "whole-body" autoregulation appears not be to causally related, one cannot be certain whether "whole-body" autoregulation is playing a causal role in the mechanism of NaCl-induced hypertension in "S" rats. It is a striking dichotomy that 3 days of high salt feeding produces vasoconstriction in "S" rats and vasodilation in "R" rats.
Changes in plasma norepinephrine, blood pressure and heart rate during physical activity in hypertensive man.
Authors: Watson R D , Hamilton C A , Reid J L , Littler W A
Published: June 2012

We have investigated the changes in plasma norepinephrine and blood pressure and heart rate during a range of physical activities in eight hypertensive subjects in order to determine whether changes in plasma norepinephrine reflect changes in sympathetic activity. Blood pressure was recorded over 24 hours from an intra-arterial cannula. Plasma norepinephrine, measured by a sensitive radioenzymatic method, increased progressively with increasing levels of physical activity. In each subject a statistically significant linear relationship was observed between the logarithm of plasma norepinephrine and systolic blood pressure. Analysis of variance showed that 66% of the variance of plasma norepinephrine was associated with changes in blood pressure and heart rate. These observations support the hypothesis that plasma norepinephrine reflects short-term changes in sympathetic activity. Use of the quantitative relationship described, in conjunction with measurements of norepinephrine metabolism, may help to determine the significance of increased levels of plasma norepinephrine observed in some hypertensive patients.
Sensitization of aortic baroreceptors by high salt diet in Dahl salt-resistant rats.
Authors: Ferrari A U , Mark A L
Published: June 2012

High salt diet alters neural cardiovascular control. This influence has been attributed to central neural or efferent mechanisms. To test the hypothesis that a high salt diet might alter afferent baroreceptor function, Dahl salt-resistant (DR) and salt-sensitive rats (DS) were fed a high or a low salt diet. Blood pressure was measured intra-arterially in unanesthetized animals. Aortic baroreceptor function was then evaluated during urethane anesthesia by recording multifiber aortic depressor nerve activity during a phenylephrine-induced blood pressure ramp. Mean arterial pressure in the conscious state was elevated (155 +/- 5 [SE]mm Hg) in DS fed a high salt diet but was normal in DS fed a low salt diet and in DR. Slopes of linear regressions relating aortic nerve discharge to mean arterial pressure were 71% higher in DR fed a high salt diet than in DR fed a low salt diet (p less than 0.025), indicating that high salt potentiated baroreceptor function in DR. In contrast, high salt diet produced no significant effects on baroreceptor function in DS. No salt-induced changes in dynamic or static aortic distensibility (assessed from pressure-volume curves of the in situ isolated arch) were detectable in either rat strain. Absence of salt-induced baroreceptor sensitization in DS was not due to the hypertensive state because the sensitization also failed to occur in separate groups of DS in which salt-induced hypertension had been prevented by chemical sympathectomy with 6-OH-dopamine.(ABSTRACT TRUNCATED AT 250 WORDS)
Central dopaminergic regulation of aldosterone secretion in sheep.
Authors: Huang B S , Malvin R L , Lee J , Grekin R J
Published: June 2012

Central dopaminergic mechanisms involved in the regulation of plasma aldosterone concentration were investigated in 16 conscious sheep following Na depletion with intramuscularly administered furosemide. Intracerebroventricular infusion of dopamine (20 micrograms/min) decreased plasma aldosterone significantly to 52 +/- 8% of basal level and increased plasma renin activity (PRA) significantly to 172 +/- 25% of basal level in this animal model. In addition, intracerebroventricular infusion of the dopamine antagonist metoclopramide (20 micrograms/min) in artificial cerebrospinal fluid vehicle significantly increased aldosterone levels to 144 +/- 14% of basal level and decreased PRA to 62 +/- 5% of basal value. Neither intracerebroventricular infusion of the vehicle nor intravenous infusions of metoclopramide or dopamine at the same doses changed aldosterone or PRA levels. Intracerebroventricular bolus injections of metoclopramide (20 micrograms/kg in 0.4 ml of vehicle) were also effective, increasing aldosterone levels to 266 +/- 22% of basal level and decreasing PRA to 70 +/- 12% of basal level. Intravenous bolus injections of the same dose of metoclopramide were ineffective. Dopamine was infused intracerebroventricularly into two uniadrenalectomized sheep with the remaining adrenal transplanted to the neck. Aldosterone levels were decreased to 49 +/- 10% of basal level, and PRA was increased to 157 +/- 10% of basal value. None of the infusions or injections changed arterial or intracranial pressure, or plasma K, Na, and cortisol levels. These data indicate that endogenous or exogenous dopamine may act on central dopamine receptors to decrease plasma aldosterone concentration by an unknown humoral mechanism. The known aldosterone regulators, plasma Na, K, angiotensin II, and adrenocorticotropic hormone, are not involved in the regulation.
Impaired endothelium-dependent relaxations in rabbits subjected to aortic coarctation hypertension.
Authors: Miller M J , Pinto A , Mullane K M
Published: June 2012

Rabbits were rendered hypertensive by suprarenal coarctation of the abdominal aorta. Seven days later, endothelium-dependent and endothelium-independent vascular relaxations were examined in vascular rings taken from hypertensive (thoracic aorta, carotid artery) and normotensive (abdominal aorta) regions. Relaxation of phenylephrine-contracted rings in response to endothelium-dependent agonists (acetylcholine, A23187) was impaired, compared with that in sham-operated and intact controls, in regions exposed to the elevated blood pressure (i.e., above the coarctation). Responses to acetylcholine and A23187 in the abdominal aorta, below the coarctation, were not altered. The diminished endothelium-dependent responses in the thoracic aorta were not affected by pretreatment with the cyclooxygenase inhibitor indomethacin. In contrast to acetylcholine and A23187, responses to the endothelium-independent agonist nitroprusside were not attenuated in vessels from hypertensive regions, indicating that the defect occurred in the endothelium. The EC50 for acetylcholine-induced relaxations of thoracic aorta correlated significantly with mean arterial pressure above the coarctation, indicating that the extent to which endothelium-dependent relaxation is impaired is in proportion to the degree of blood pressure elevation. This study suggests that the diminished relaxations by endothelium-dependent agonists is a local response to the elevation of blood pressure and is not due to a circulating factor.
Effect of advancing age on cardiopulmonary baroreceptor function in hypertensive men.
Authors: Sowers J R , Mohanty P K
Published: June 2012

Blood pressure, heart rate, forearm vascular resistance, and hormonal responses to graded lower body negative pressure were investigated in 15 hypertensive men younger than 55 years of age (mean age, 44 +/- 2 years) and 13 comparably hypertensive men older than 55 years of age (mean age, 63 +/- 2 years). Baseline forearm vascular resistance was greater in the elderly group compared with the younger hypertensive men. However, forearm vascular resistance responses to selective unloading of low pressure cardiopulmonary baroreceptors were similar in the two groups. This finding suggests that normal vascular responses to the unloading of cardiopulmonary baroreceptors are preserved in subjects with advancing age and mild to moderate hypertension. Baseline plasma norepinephrine levels, as well as norepinephrine responses to lower body negative pressure, were comparable in the two groups. This finding suggests that, unlike normotensive subjects, essential hypertensive subjects do not have an age-related increase in sympathetic nervous system activity.
Inhibition of hypertension and salt intake by oral taurine treatment in hypertensive rats.
Authors: Abe M , Shibata K , Matsuda T , Furukawa T
Published: June 2012

Effects of oral treatment with taurine on fluid intakes produced by renin were assessed in spontaneously hypertensive rats of the Okamoto strain (SHR). Renin injected into the preoptic area increased water intake and evoked salt (2.7% NaCl solution) intake, and angiotensin II injected into this area increased water intake, but not salt intake, in both SHR and control normotensive Wistar-Kyoto rats (WKY). The salt intake elicited by renin, but not water intake produced by renin or angiotensin II, was potentiated in SHR. These effects of renin and angiotensin II on fluid intakes were antagonized by previous administration of taurine or gamma-aminobutyric acid into the cerebral ventricles in both strains. When SHR received water containing 3% taurine from 32 to 105 days of age, development of hypertension was inhibited. Renin administered into the preoptic area at 105 days of age caused an increase in salt intake, but the increase was markedly inhibited by the oral administration of taurine as well. These results show that salt appetite produced by centrally administered renin is exaggerated in SHR and that development of hypertension as well as renin-induced salt appetite in SHR is inhibited by dietary taurine.
Does so-called streptozocin hypertension exist in rats?
Authors: Kusaka M , Kishi K , Sokabe H
Published: June 2012

Although the existence of so-called streptozocin hypertension seems well established, some reports have indicated that no rise in blood pressure (BP) occurred after streptozocin treatments. To ascertain the streptozocin-induced BP response, normotensive Wistar-Kyoto rats (WKY) and spontaneously hypertensive rats (SHR) were treated with streptozocin, 40 to 45 and 35 mg/kg i.v., respectively, and BP was determined directly and indirectly every week for 3 to 4 weeks. Direct mean BP was determined without anesthesia or restraint through a cannula inserted into the rat's abdominal aorta. Indirect BP was determined at the tail without anesthesia after prewarming the rat in a holder. Compared with control values, indirect BP increased significantly in diabetic WKY 2 weeks after streptozocin treatment. In contrast, direct BP of these rats decreased, compared with control values. Indirect BP of diabetic SHR was as high as that of the controls, whereas direct BP of diabetic SHR decreased significantly 1 week after the treatment and thereafter, compared with control values. These discrepancies between the direct and indirect BP values may be caused by severe emaciation of diabetic rats. Extra pressure in the cuff may be necessary to occlude the bloodstream. These results indicate that under these conditions the value of BP obtained by the direct measurement is more reliable than that by the indirect one; therefore, we concluded that so-called streptozocin hypertension does not exist.
Assessment of baroreceptor reflex sensitivity by means of spectral analysis.
Authors: Robbe H W , Mulder L J , Rüddel H , Langewitz W A , Veldman J B , Mulder G
Published: June 2012

A method of determining baroreceptor reflex sensitivity is proposed that is based on spectral analysis of systolic pressure values and RR interval times, namely, the modulus (or gain) in the mid frequency band (0.07-0.14 Hz) between these two signals. Results using this method were highly correlated (0.94; n = 8) with results of the phenylephrine method. In addition, compared with the values for the preceding rest period, the modulus decreased during mental challenge, as might be expected from the literature.