bluuebunny/crossref_metadata_2025 huggingface dataset:
Selective Impairment of Vagally Mediated, Nitric Oxide–Dependent Coronary Vasodilation in Conscious Dogs After Pacing-Induced Heart Failure
Authors: Zhao Gong , Shen Weiqun , Xu Xiaobin , Ochoa Manuel , Bernstein Robert , Hintze Thomas H.
Published: June 2012

Background
Activation in conscious dogs of the carotid chemoreflex or cardiac receptors results in coronary vasodilation that is mediated by a vagal cholinergic mechanism. Our previous study showed that the coronary vasodilation following activation of carotid chemoreflex is also mediated by nitric oxide (NO). In addition, NO production is depressed after the development of heart failure. Therefore, we hypothesized that the coronary vasodilation after activation of reflexes that elicit efferent vagal coronary vasodilation would be blunted in conscious dogs after pacing-induced heart failure due to the disappearance of NO.

Methods and Results
Mongrel dogs were chronically instrumented using sterile techniques for measurements of systemic hemodynamics and left circumflex coronary blood flow (CBF). Without the heart rate controlled, intra-atrial injection of veratrine (4 μg/kg) caused bradycardia (−36±3 beats per minute). With the heart rate controlled, veratrine increased CBF in a dose-dependent manner: for example, 4 μg/kg of veratrine increased CBF by 54±5% from 38±4.9 mL/min (
P
<.05). The increases in CBF induced by veratrine were markedly blunted by nitro-
l
-arginine (NLA). Activation of carotid chemoreflex by nicotine increased CBF by 121±9% from 32±4 mL/min (
P
<.05) with the heart rate controlled and caused bradycardia (−32±5 beats per minute) without the heart rate controlled. After the development of heart failure, in response to activation of carotid chemoreflex or cardiac receptors the coronary vasodilation was almost abolished (CBF increased by only 23±8% or 11±3%,
P
<.05 compared with control). There still was a marked bradycardia after injections of nicotine or veratrine (−50±11 or −48±7 beats per minute).

Conclusions
Our results indicate that vagally mediated coronary vasodilation is selectively attenuated in conscious dogs after pacing-induced heart failure, whereas the vagally mediated bradycardia is preserved. Since muscarinic receptor–induced coronary vasodilation is mediated by NO, the disappearance of NO from blood vessels leads to a defect in the integrated neural regulation of coronary blood flow and myocardial function during heart failure.
Has Improvement in PTCA Intervention Affected Long-term Prognosis?
Authors: Detre Katherine , Yeh Wanlin , Kelsey Sheryl , Williams David , Desvigne-Nickens Patrice , Holmes David , Bourassa Martial , King Spencer , Faxon David , Kent Kenneth
Published: June 2012

Background
The NHLBI Percutaneous Transluminal Coronary Angioplasty (PTCA) Registry followed 1345 consecutive patients with first PTCA between 1977 and 1981 (registry 1) and 2136 consecutive patients with PTCA between 1985 and 1986 (registry 2). Changes in patient selection and in immediate and 1-year outcome are presented. This report extends to 5 years the comparison of the effects of early and more recent management with PTCA.

Methods and Results
Sixteen participating centers entered consecutive patients who had angioplasty for the first time between 1977 and 1981 and between 1985 and 1986. Patients with recent myocardial infarction (MI) were excluded. Vessel disease was defined according to the Coronary Artery Surgery Study. Successful dilatation required ≥20% reduction in luminal narrowing and <50% lumen diameter stenosis after intervention. Routine annual follow-up was conducted by telephone interview. The product-limit method was used to estimate freedom from untoward events, Cox regression analysis to model relative risk and adjusted relative risk of events between the two registries, and logistic regression when the exact time of outcome (such as recurrence of symptoms) was not known. Long-term event rates were computed by vessel disease for all patients and for the cohort of patients with initially successful PTCA. After adjustment for extent of disease, diabetes, prior bypass surgery (CABG), hypertension, age, and sex, the 5-year risk of death was similar in the two registry cohorts. However, rates of MI, CABG, and a combined outcome measure of death, MI, and/or CABG were significantly lower in the registry 2 cohort both for all patients and for patients who were initially treated successfully. Use of repeated PTCA was higher, and freedom from symptoms without adverse events was significantly better in the latter cohort.

Conclusions
Compared with registry 1, the management of the registry 2 cohort resulted in lower 5-year morbid event rates and reduced CABG operations. Mortality rates remained similar. When symptomatic status was considered in combination with events, a significantly better outcome was seen overall and in the initially successful cohort. In registry 2, repeated PTCA was used with much greater frequency early after the initial procedure.
An Antibody Against the Exosite of the Cloned Thrombin Receptor Inhibits Experimental Arterial Thrombosis in the African Green Monkey
Authors: Cook Jacquelynn J. , Sitko Gary R. , Bednar Bohumil , Condra Cindra , Mellott Michael J. , Feng Dong-Mei , Nutt Ruth F. , Shafer Jules A. , Gould Robert J. , Connolly Thomas M.
Published: June 2012

Background
Thrombin inhibitors have been shown to be efficacious in animal models of thrombosis and in initial human clinical trials. It is unknown if their efficacy is due to their prevention of thrombin-mediated fibrin formation or to an inhibitory effect on thrombin-stimulated platelet activation. Appropriate tools to address this question have not been available. Therefore, to evaluate the role of the platelet thrombin receptor in intravascular thrombus formation, a polyclonal antibody was raised against a peptide derived from the thrombin-binding exosite region of the cloned human thrombin receptor. This antibody serves as a selective inhibitor of the thrombin receptor for in vivo evaluation.

Methods and Results
The immune IgG (IgG 9600) inhibited thrombin-stimulated aggregation and secretion of human platelets. In contrast, it had no effect on platelet activation induced by other agonists including ADP, collagen, or the thrombin receptor–derived peptide SFLLR-NH
2
. IgG 9600 also inhibited thrombin-induced aggregation of African Green monkey (AGM) platelets. By Western blot analysis, the IgG identified a protein of ≈64 kD in homogenates of both human and AGM platelets. The effect of thrombin receptor blockade by this antibody on arterial thrombosis was evaluated in an in vivo model of platelet-dependent cyclic flow reductions (CFRs) in the carotid artery of the AGM. The intravenous administration of IgG 9600 (10 mg/kg) abolished CFRs in three monkeys and reduced CFR frequency by 50% in a fourth monkey. Ex vivo platelet aggregation in response to up to 100 nmol/L thrombin was completely inhibited during the 120-minute postbolus observation period in all four animals. There was a twofold increase in bleeding time, which was not statistically different from baseline, and ex vivo clotting time (APTT) was not changed. The glycoprotein IIb/IIIa receptor antagonist MK-0852 and the thrombin inhibitor recombinant hirudin also demonstrated inhibitory effects on CFRs at doses that did not significantly prolong template bleeding time. Control IgG had no effect on CFRs, ex vivo platelet aggregation, bleeding time, or APTT.

Conclusions
These results demonstrate that blockade of the platelet thrombin receptor can prevent arterial thrombosis in this animal model without significantly altering hemostatic parameters and suggest that the thrombin receptor is an attractive antithrombotic target.
Pharmacodynamics of Plasma Nitrate/Nitrite as an Indication of Nitric Oxide Formation in Conscious Dogs
Authors: Zeballos Guillermo A. , Bernstein Robert D. , Thompson Carl I. , Forfia Paul R. , Seyedi Nahid , Shen Weiqun , Kaminski Pawel M. , Wolin Michael S. , Hintze Thomas H.
Published: June 2012

Background
The present investigation was undertaken to better understand the production of nitric oxide (NO) in vivo as measured by alterations in plasma nitrite or nitrate in blood samples from studies in experimental animals or clinical studies in humans.

Methods and Results
Plasma samples were taken from the aorta, the coronary sinus, a peripheral vein in the leg (skeletal muscle), or the right ventricle (mixed venous) in chronically instrumented conscious dogs. Plasma nitrite was converted to NO gas in an argon environment by use of hydrochloric acid, and plasma nitrate was converted first to nitrite with nitrate reductase and then to NO gas with acid. Standard curves were constructed, and the amount of nitrite and nitrate in plasma was determined. The primary metabolite was nitrate, whereas nitrite was approximately 10% of the total and remained constant. In the resting dog, the only vascular bed with a positive arterial-venous nitrate difference, evidence for production of NO, was the heart. Nitrate infusion into quietly resting dogs resulted in increases in plasma nitrate up to 38±3.4 mmol/L, increases in systemic arterial pressure, and a marked diuresis. The plasma half-life was calculated as 3.8 hours. The volume of distribution was calculated as 0.215 L/kg, or equivalent to the extracellular volume.

Conclusions
These studies indicate that nitrate is a reliable measure of NO metabolism in vivo but that because of the long half-life, nitrate will accumulate in plasma once it is produced. Because of the large volume of distribution (21% of body weight versus the 4% of body weight usually attributed to plasma volume, the compartment in which nitrate is measured), simple measures of plasma nitrate underestimate by a factor of 4 to 6 the actual production of nitrate or NO by the body. In disease states, such as heart failure, in which renal function and extracellular volume are altered, caution should be exercised when increases in nitrate in plasma as an index of NO formation are evaluated.
Experimental Graft Coronary Artery Disease in a Murine Heterotopic Cardiac Transplant Model
Authors: Hirozane Toshiro , Matsumori Akira , Furukawa Yutaka , Sasayama Shigetake
Published: June 2012

Background
The development of immunosuppressive therapy has brought about a remarkable decrease in the risk of acute cardiac allograft rejection; however, the major cause of patient death or retransplantation after the first postoperative year is coronary artery disease (CAD) in the graft. The pathogenesis and management of CAD are still not clearly established.

Methods and Results
To make an animal model of CAD, we performed primary vascularized heterotopic cardiac transplantation using mice. Inbred strains, sharing major histocompatibility antigens but differing in minor antigens, were selected. DBA/2 mice (H-2
d
) served as donors and B10.D2 mice (H-2
d
) as recipients. Viability of the cardiac grafts was assessed by abdominal palpation. Eight of twelve cardiac allografts (67%) survived for 10 weeks after operation without any immunosuppressive therapy. Allografts rejected within 4 weeks showed acute rejection histologically, whereas allografts surviving more than 4 weeks displayed intimal hyperplasia in the coronary arteries, together with interstitial and perivascular fibrosis. The severity of intimal thickening in the graft coronary artery was then assessed by point counting. In allografts surviving for 70 days, intima comprised approximately 42% of the graft arterial wall, whereas in DBA/2 and B10.D2 syngeneic grafts, it comprised approximately 13%. A significant difference in percentage was observed between the intima area of allografts and that of syngrafts (
P
<.01, ANOVA). Long-term oral administration of cyclosporine at a dose of 40 mg/kg per day decreased the intima area to 34% (
P
<.05 versus nontreated allografts, ANOVA); however, this dose did not affect the incidence of arterial lesions.

Conclusions
The histopathological features of DBA/2 allografts surviving for 10 weeks in B10.D2 recipient mice mimicked those in human CAD. Using this animal model, the beneficial effect of low-dose cyclosporine therapy on CAD was demonstrated, although this effect seemed to be limited. This DBA/2-B10.D2 mouse heterotopic cardiac transplant model provides valuable results for future studies of the disease.
SC-54684A: An Orally Active Inhibitor of Platelet Aggregation
Authors: Nicholson Nancy S. , Panzer-Knodle Susan G. , Salyers Anita K. , Taite Beatrice B. , Szalony James A. , Haas Neal F. , King Lucy W. , Zablocki Jeffery A. , Keller Bradley T. , Broschat Kay , Engleman V. Wayne , Herin Marc , Jacqmin Phillipe , Feigen Larry P.
Published: June 2012

Background
Intravenous therapy has been shown to be beneficial in the prevention of acute platelet-associated thrombotic events. However, orally active agents would be advantageous for chronic therapy. Fibrinogen receptor antagonists block the fibrinogen/platelet interaction and thus inhibit a step required for thrombus formation. To date, no orally active fibrinogen binding inhibitors have been characterized. SC-54684A, now in clinical trial, is the orally active prodrug of a potent and specific fibrinogen binding antagonist.

Methods and Results
We measured inhibition of
125
I-fibrinogen binding to activated platelets and inhibition of aggregation in platelet-rich plasma to selected agonists and showed IC
50
s of 1.0×10
−8
and 3 to 7×10
−8
mol/L, respectively. Specificity of the active moiety was determined by studying its effect on the binding of (1) neutrophils to interleukin (IL)-1β–stimulated endothelial cells, (2) endothelial cells to fibronectin, and (3) vitronectin to isolated vitronectin and fibrinogen receptors. No effect was observed on the binding neutrophils to IL-stimulated endothelial cells or endothelial cell binding to fibronectin. There was a fivefold separation between binding to isolated receptors of vitronectin and fibrinogen. Collagen-induced aggregation was inhibited by 80%, and bleeding time was increased ≈2.5-fold when the active moiety was infused to steady state at 0.2 μg/kg per minute in dogs. When the ester prodrug was given orally and the active moiety was given intravenously, the oral systemic activity was ≈20%. Pharmacokinetic analysis after intravenous infusion of the prodrug or active moiety showed that the prodrug was rapidly converted to the active moiety; the active moiety had a t

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of 6.5 hours. When the prodrug was administered both orally and intravenously, the systemic availability of the active moiety was 62%.

Conclusions
SC-54684A, an orally active antiplatelet drug now in clinical trial, is shown to be a potent, specific fibrinogen binding inhibitor that blocks platelet aggregation to a wide variety of known stimuli and has good bioavailability in animals.
Improved Defibrillation Threshold With a New Epicardial Carbon Electrode Compared With a Standard Epicardial Titanium Patch
Authors: Alt Eckhard U. , Fotuhi Parwis C. , Callihan Richard L. , Rollins Dennis L. , Mestre Edgar , Combs Marty P. , Smith William M. , Ideker Raymond E.
Published: June 2012

Background
Recent studies show that depending on the type of shock morphology used, 5% to 15% of patients requiring implantable defibrillators cannot be treated with a nonthoracotomy system. In these cases, an epicardial patch–based system becomes necessary. In this study, we investigated a newly developed epicardial carbon electrode as an alternative to a standard epicardial titanium patch.

Methods and Results
A tubular epicardial braided carbon electrode of 7F diameter and 14-cm length applied in a U-shape to the epicardium was compared with a standard left ventricular epicardial 15-cm
2
titanium mesh patch (CPI Inc). As cathode, a CPI endocardial lead, a Medtronic lead, or a carbon-platinum-iridium prototype electrode was used. Ventricular fibrillation was induced with a 60-Hz generator and allowed to continue for 10 seconds before a shock was given. Two different biphasic shock waveforms (3.2/2- and 6/6-millisecond) were delivered by the six electrode configurations. Eight dogs (weight, 24.5±1.3 kg) underwent an up-down defibrillation protocol. The order of testing the epicardial electrodes, the endocardial cathodes, and the waveform was randomized. With the epicardial carbon electrode, the mean defibrillation threshold (DFT) energy decreased 39% to 56% and the voltage decreased 24% to 35% compared with the titanium patch: from 8.3±2.5 to 4.9±3.6 J with the CPI lead and the 3.2/2-millisecond waveform, from 6.2±2.5 to 2.9±2.1 J with the carbon-platinum-iridium prototype, and from 6.4±3.4 J to 3.5±2.6 J with the Medtronic lead (
P
≤.05). The DFT determinations with the 6/6-millisecond biphasic waveform showed a similar trend with slightly higher values.

Conclusions
Compared with a titanium patch, the new braided epicardial electrode significantly decreases the defibrillation energy requirements. This effect can be maximized by using an endocardial carbon-platinum-iridium prototype as cathode and a short duration biphasic waveform.
Sympatholytic Action of Intravenous Amiodarone in the Rat Heart
Authors: Du Xiao-Jun , Esler Murray D. , Dart Anthony M.
Published: June 2012

Background
Amiodarone is a commonly used antiarrhythmic agent with complex pharmacological effects. Although ventricular arrhythmias can be suppressed soon after intravenous amiodarone, the mechanisms responsible for this action are unclear. We studied the effects of acute treatment with amiodarone on the metabolism and release of norepinephrine (NE) in intact rats and in perfused rat hearts.

Methods and Results
Experiments were performed in anesthetized rats and in perfused, innervated hearts with amiodarone administered intravascularly. NE release was induced by electrical stimulation of the sympathetic ganglion. Concentrations of NE and its intraneuronal metabolite dihydroxyphenylglycol (DHPG) in hearts, plasma, and coronary venous effluent were measured by high-performance liquid chromatography. Acute administration of amiodarone induced dose-dependent increases in DHPG concentrations in plasma (5 mg/kg, +48%; 15 mg/kg, +84%; and 50 mg/kg, +467%) and in coronary venous effluent (1 μmol/L, +37%; 3 μmol/L, +510%; and 10 μmol/L, +1100%) together with an unchanged basal overflow of NE. In perfused hearts, NE release evoked by nerve stimulation was inhibited by infusion of amiodarone (1 μmol/L, −16%; 3 μmol/L, −24%; and 10 μmol/L, −64%) or by intravenous amiodarone (50 mg/kg) given 1 hour before heart perfusion (−70%), and the extent of this suppression correlated well with levels of DHPG overflow present immediately before nerve stimulation. When given in vitro and in vivo, amiodarone also significantly reduced NE and increased DHPG content in the heart, leading to a raised DHPG/NE ratio. All these effects of amiodarone were similar to those found with reserpine but less potent. In contrast, oral amiodarone produced none of these effects.

Conclusions
Acute administration of amiodarone in perfused hearts or intact rats induces partial NE depletion in the heart by interfering with vesicular NE storage and enhancing intraneuronal NE metabolism, effects associated with an impaired NE release during sympathetic activation. Oral dosing with amiodarone has no such effect. Further study is required to test whether this novel sympatholytic effect of amiodarone contributes to its antiarrhythmic action after intravenous administration.
Sodium Pentobarbital Versus α-Chloralose Anesthesia
Authors: Rath Dipti P. , Little Charles M. , Zhang Huzeng , Jiang Zongchen , Abduljalil Amir M. , Zhu Hui , Tong Xiaoxin , Brown Charles , Hamlin Robert L. , Robitaille Pierre-Marie L.
Published: June 2012

Background
Transmural analyses of the creatine phosphate (CP)/ATP ratio in various lamina of the canine myocardium have previously revealed significant variations in the CP/ATP ratio, with the subendocardial layer displaying a decreased ratio relative to the subepicardial layer. Without exception, these results were obtained under sodium pentobarbital anesthesia. These findings have been interpreted to imply that the normal endocardium may be operating in the oxygen-limited domain or that there are transmurally varying set points for the regulation of oxidative phosphorylation.

Methods and Results
In this work, we examine the effect of the anesthetic regimen on the transmural CP/ATP ratio within the left ventricular wall of the canine myocardium using spatially localized
31
P-nuclear magnetic resonance (NMR) and an open-chest model. Two anesthetics were compared, α-chloralose and sodium pentobarbital. Under sodium pentobarbital, the CP/ATP ratio ranged from 1.92±0.06 to 2.51±0.08 from endocardium to epicardium, resulting in a transmural slope in the CP/ATP ratio of 0.149±0.047 (n=22). Under α-chloralose, CP/ATP ratios ranged from 2.18±0.05 to 2.32±0.06, with a transmural slope of 0.035±0.018 (n=38). Thus, the transmural slope in CP/ATP ratio was nearly four times greater with sodium pentobarbital than with α-chloralose, and the difference in these slopes was statistically significant (
P
=.029). No difference was observed in average CP/ATP obtained from the entire wall with either anesthetic.

Conclusions
These results demonstrate that the transmural trend in CP/ATP ratio previously reported in the myocardium is likely to be a direct reflection of the sodium pentobarbital anesthetic regimen, not truly reflecting the trend in the normal unanesthetized animal. Moreover, since the transmural variation in CP/ATP ratio was greatly reduced with α-chloralose, it appears unlikely that the endocardium in the normal unanesthetized heart is operating in the oxygen-limited domain. These results also point to the importance of the anesthetic regimen in biochemical analysis, indicate the necessity of increased caution in directly translating results obtained under anesthesia, and demonstrate the unique power of in vivo NMR to extract such subtle biochemical information.
Does PTCA in Acute Myocardial Infarction Affect Mortality and Reinfarction Rates?
Authors: Michels Karin B. , Yusuf Salim
Published: June 2012

Background
Percutaneous transluminal coronary angioplasty (PTCA) is often performed after acute myocardial infarction (AMI) either as an adjuvant to thrombolytic therapy or instead of thrombolysis. The effect of PTCA in AMI on mortality and reinfarction has remained unclear, with the available randomized trials indicating inconsistent results.

Methods and Results
A systematic overview (meta-analysis) of the randomized trials was conducted to assess the effect of PTCA in AMI on mortality and reinfarction rates. Data from 7 trials in which primary PTCA was evaluated and 16 trials in which PTCA after thrombolysis was studied were included in this overview, comprising a total of 8496 patients. The trials represented different approaches to the timing of PTCA after AMI. The trials of PTCA after thrombolytic therapy were also categorized according to the different protocols with respect to the routine or elective character of PTCA in the invasive group. A reduction in short-term (6 week) mortality (odds ratio, 0.56; 95% CI, 0.33, 0.94) and in the combined outcome of short-term mortality and nonfatal reinfarction (odds ratio, 0.53; 95% CI, 0.35, 0.80) was observed in the trials comparing primary PTCA with thrombolytic therapy. In contrast, in trials in which an approach of thrombolysis and PTCA was compared with thrombolytic therapy alone, there was no important difference in early mortality, with an apparent reduction in mortality between 6 and 52 weeks. The lower mortality between 6 and 52 weeks among 6-week survivors seemed to be restricted to the subgroup of trials in which PTCA was used as a routine strategy (odds ratio, 0.58; 95% CI, 0.39, 0.87).

Conclusions
Although the analyses of the various categories of trials suggest that primary PTCA may be more beneficial than thrombolytic therapy in AMI, these data should be interpreted cautiously unless confirmed by larger studies. In contrast, the addition of various other strategies of PTCA to thrombolytic therapy does not convincingly indicate a clinically different outcome than if a more conservative strategy is followed, in which PTCA is used only if clinically indicated. Some specific strategies, however, such as rescue PTCA in high-risk patients with occluded arteries, may be of benefit.
Genetic Models of Human Vascular Disease
Authors: Dzau Victor J. , Gibbons Gary H. , Kobilka Brian K. , Lawn Richard M. , Pratt Richard E.
Published: June 2012

Abstract
The use of genetic models has greatly assisted investigations of the natural history, mechanisms, and potential therapy for human vascular disease. In the past, genetic models of vascular disease were obtained through serendipity and/or selective breeding to obtain inbred lines that express the phenotype of interest. This approach has yielded several valuable models of atherosclerosis and hypertension. In the past several years, the advent of molecular techniques has enabled investigators to produce additional novel genetic models of disease that have further enhanced the study of vascular biology and medicine. Transgenic techniques and the techniques of homologous recombination have allowed researchers to alter the genotype of an animal in a precise manner and to study the resultant change in phenotype. More recently, techniques of in vivo gene transfer have also accelerated and enhanced the development of novel models. The application of these methodologies has resulted in important breakthroughs in our understanding of the pathogenesis and treatment of vascular diseases. In this review, we compare and contrast these technologies along with examples of their use in the studies of vascular biology and medicine.
Soluble Interleukin-2 Receptor Levels in Patients With Dilated Cardiomyopathy
Authors: Limas Constantinos J. , Goldenberg Irvin F. , Limas Catherine
Published: June 2012

Background
There is evidence that autoimmunity plays an important role in the initiation and progression of myocardial injury in dilated cardiomyopathy. Abnormalities of both cellular and humoral immunity have been described in this disease. Soluble interleukin-2 receptor (sIL-2R) levels in the serum reflect activation of T lymphocytes in the periphery or in tissues. The present study explored the possibility that activation of cellular immunity is frequent in patients with idiopathic dilated cardiomyopathy and may have functional consequences.

Methods and Results
Serum sIL-2R levels were determined with an enzyme-linked immunosorbent assay in 50 dilated cardiomyopathy patients, 30 patients with ischemic heart disease, and 22 normal control subjects. In addition, the presence of anti–β-receptor and antimyosin antibodies was sought in the serum of cardiomyopathy patients. High sIL-2R levels (>1400 pg/mL) were found in 38% of the dilated cardiomyopathy patients but only 6% of the ischemic heart disease patients. The group of sIL-2R–positive patients was characterized by higher average age, a higher percentage of women, and more severe disease (lower ejection fraction, higher left ventricular filling pressures, and lower cardiac output). Although the prevalence of cardiac autoantibodies did not correlate with the presence of high sIL-2R levels, higher titers of autoantibodies were found predominantly in the sIL-2R–positive group.

Conclusions
T-lymphocyte activation, as reflected in elevated sIL-2R levels, is frequent in patients with dilated cardiomyopathy and is associated with more severe disease. Cellular and humoral immune activation may correlate with progression of the disease process.
Role of Cardiac β
2
-Receptors in Cardiac Responses to Exercise in Cardiac Transplant Patients
Authors: Leenen Frans H.H. , Davies Ross A. , Fourney Anne
Published: June 2012

Background
In healthy human hearts, β
2
-receptor–mediated chronotropic and inotropic responses contribute to the cardiac responses to β-agonists. A (patho)physiological relevance for β
2
-receptor–mediated responses has so far not been demonstrated, in part because β
1
-receptor–mediated responses to cardiac neuronally released norepinephrine can mask β
2
-receptor–mediated responses.

Methods and Results
In the present study, we evaluated the blood pressure and heart rate responses to bicycle exercise in cardiac transplant patients (n=7) compared with patients with essential hypertension (n=8) on placebo and two doses of the β
1
-selective β-blocker atenolol (25 and 50 mg/d) and the nonselective β-blocker nadolol (20 and 40 mg/d), each dose for 1 week using a double-blind, randomized, crossover design. Exercise was performed 3 hours after dosing, using a stepwise increase in load until exhaustion. Exercise performance was less in the transplant patients and significantly further (25%) decreased by nadolol. Exercise caused equivalent increases in plasma norepinephrine in the two groups, but more marked increases in plasma epinephrine in the transplant patients despite less exercise. In the essential hypertension patients, systolic blood pressure increased by 80 mm Hg on placebo and 60 mm Hg on either blocker. The increase in heart rate (by about 75 beats per minute) was inhibited by 10% and 20% by the lower and higher doses, respectively, similar for the two blockers. In contrast, in the transplant patients, systolic blood pressure increased by 60 mm Hg on placebo, but this increase was totally blocked by either blocker. The heart rate increase (by 50 beats per minute on placebo) was blunted (dose related) by either blocker but 50% more by nadolol versus atenolol.

Conclusions
The present study shows that cardiac β
2
-receptors contribute to a clear extent to the heart rate responses to endogenous circulating catecholamines in the absence of cardiac neuronally released norepinephrine. Nonselective β-blockade probably is less well tolerated in cardiac transplant patients compared with β
1
-selective blockade.
Left Ventricular Performance and Remodeling in Rabbits After Myocardial Infarction
Authors: Mahaffey Kenneth W. , Raya Thomas E. , Pennock Gregory D. , Morkin Eugene , Goldman Steven
Published: June 2012

Background
Because the rat postinfarction model differs from human heart failure with respect to the composition of myosin heavy chain (MHC) isoforms and other contractile proteins, alternative animal models are needed for the development of new treatments for human heart failure. The purpose of this study was threefold: (1) to test the feasibility of using the V
3
(β,β) rabbit postinfarction model for the study of heart failure by characterizing the effects of chronic coronary artery occlusion on the left ventricle; (2) to determine whether the thyroid hormone analogue 3,5-diiodothyropropionic acid (DITPA) produces improvements in left ventricular function; and (3) to determine the effects of myocardial infarction and treatment with DITPA on MHC protein isoforms.

Methods and Results
Male New Zealand White rabbits underwent proximal circumflex coronary artery ligation. After infarction, rabbits were treated with DITPA (3.75 mg/kg body wt) or placebo for 21 days and then underwent conscious and open-chest hemodynamic studies. In separate groups of rabbits, β- and α-MHC isoforms were separated, and relative proportions were measured using gradient sodium dodecyl sulfate–polyacrylamide gel electrophoresis and laser densitometry. Infarction resulted in increased left ventricular end-diastolic pressure and prolonged left ventricular relaxation (τ) (
P
=.001 for both variables). Postinfarction treatment with DITPA decreased left ventricular end-diastolic pressure and τ (
P
=.002 and
P
=.001, respectively) and increased maximum positive and negative dP/dt (
P
=.002 and
P
=.016, respectively). Infarcted rabbits treated with DITPA had no significant changes in heart rate or left ventricular systolic pressure compared with untreated rabbits with infarction. There were no significant differences in heart rate, positive dP/dt, peak systolic pressure, or τ between sham-operated rabbits and sham-operated rabbits treated with DITPA. Although infarction resulted in increased left ventricular diameter, there were no effects of DITPA on left ventricular remodeling. Neither myocardial infarction nor treatment with DITPA altered the ratio of MHC isoforms.

Conclusions
Rabbits that survive occlusion of the circumflex artery will develop myocardial dysfunction and left ventricular remodeling. Therapy with DITPA, a thyroid hormone analogue, produces improvement in ventricular performance and reduces end-diastolic pressure. The hemodynamic effects of DITPA were not associated with alterations of MHC isoforms. Whether DITPA represents the prototype of a previously undescribed class of agents for the treatment of heart failure will need to be determined by clinical trials.
Detection of Coronary Stenoses and Quantification of the Degree and Spatial Extent of Blood Flow Mismatch During Coronary Hyperemia With Myocardial Contrast Echocardiography
Authors: Ismail Suad , Jayaweera Ananda R. , Goodman Norman C. , Camarano Gustavo P. , Skyba Danny M. , Kaul Sanjiv
Published: June 2012

Background
We hypothesized that the degree and spatial extent of blood flow mismatch in beds supplied by stenoses that are not flow-limiting at rest can be quantified with myocardial contrast echocardiography (MCE) using left atrial (LA) and right atrial (RA) injections of contrast during pharmacologically induced coronary hyperemia.

Methods and Results
In 12 open-chest dogs, MCE was performed and myocardial blood flow (MBF) was measured by use of radiolabeled microspheres at baseline and during phenylephrine-induced coronary hyperemia. In the presence of this drug, stenoses were placed during different stages on the left anterior descending (LAD) and left circumflex (LCx) coronary arteries, and MCE and MBF assessments were performed. LA injections of 2 mL of 0.5 billion/mL microbubbles (mean diameter, 4.3 μm) were performed at each stage in all 12 dogs, and RA injections of 10 mL of 6 billion/mL microbubbles (mean diameter, 3.7 to 5.3 μm) were administered in 7 dogs. MCE images in which the contrast disparity between the LAD and LCx beds was maximal were digitally subtracted from precontrast images, and mean videointensities in these beds were measured after the dynamic range of gray-scale intensities was increased in the subtracted image and the image was color coded. The region showing hypoperfusion during LAD stenosis was planimetered and expressed as a percentage of the myocardial area in the short-axis slice. There was an excellent correlation between the LAD/LCx bed videointensity ratio and LAD/LCx bed MBF ratio (
y
=0.5
x
+0.44,
r
=.91,
P
<.001) during 57 LA injections. There was also an excellent correlation between the hypoperfused bed size on MCE during LA injection of contrast in the presence of LAD stenosis and the hypoperfused myocardium as determined by radiolabeled microspheres (
y
=0.8
x
+4.2,
r
=.90,
P
<.001, SEE=2.4, n=11). The anterior myocardium was opacified in 6 dogs receiving RA injections of contrast, and the hypoperfused area during LAD stenosis correlated closely with that determined by radiolabeled microspheres (
y
=0.86
x
+3.4,
r
=.93,
P
<.01).

Conclusions
Coronary stenoses, which are not flow limiting at rest, can be detected and the degree and spatial extent of blood flow mismatch during pharmacologically induced coronary hyperemia can be quantified with MCE using LA and RA injections of contrast. Thus, it is possible that the severity of coronary stenoses and the quantum of myocardium in jeopardy could be quantified in the future with MCE using venous injection of contrast.
Termination of Atrioventricular Nodal Reentrant Tachycardia by Premature Stimulation From Ablating Catheter
Authors: Sra Jasbir , Jazayeri Mohammad , Natale Andrea , Dhala Anwer , Blanck Zalmen , Deshpande Sanjay , Maglio Cheryl , Bremner Siobhan , Akhtar Masood
Published: June 2012

Background
Slow-pathway ablation is currently used more frequently to control atrioventricular nodal reentrant tachycardia (AVNRT). However, in patients with the common type of AVNRT, successful ablation of the slow pathway can be difficult and time-consuming. We tested a simple method to predict a site for slow-pathway ablation in patients with AVNRT of the common variety.

Methods and Results
Twenty patients with symptomatic common AVNRT (13 women and 7 men; mean age, 41±21 years) were included in the study. Once the AVNRT had a stable cycle length (±10 ms) for at least 20 cycles, single extrastimuli were delivered from the ablating catheter tip beginning with 20 ms less than the tachycardia cycle length and decrementing by 10 ms until tachycardia terminated or loss of capture occurred at the pacing site. The pacing protocol was performed systematically in a stepwise fashion at four adjacent sites starting from the posterior/inferior interatrial septum near the tricuspid annulus and moving progressively more anteriorly. The pacing protocol was then repeated in the same sequence, followed by delivery of radiofrequency current at each site to determine its effect at sites where AVNRT could not be terminated with a pacing protocol. AVNRT could be terminated in the anterograde direction from at least one site in 19 patients. Tachycardia could be terminated at two or more adjacent sites in 5 patients. The longest atrial coupling interval at the site of tachycardia termination was 67±27 ms (range, 30 to 130 ms) less than the AVNRT cycle length. Resetting of subsequent His bundle depolarization (H
2
), producing an H-H
2
interval prolongation of 26±24 ms (range, 10 to 80 ms), occurred in 17 patients before termination of the tachycardia. In 18 of the 19 patients, the slow pathway was successfully ablated at the site at which AVNRT was terminated at the longest atrial coupling interval.

Conclusions
Termination of tachycardia in the anterograde direction at the longest atrial coupling interval by extrastimuli delivered from the ablating catheter can be helpful for identification of an optimal site for slow-pathway ablation in patients with the common variety of AVNRT.
Effects of 15-Deoxyspergualin on Experimental Autoimmune Giant Cell Myocarditis of the Rat
Authors: Kodama Makoto , Zhang Shaosong , Hanawa Haruo , Saeki Makihiko , Inomata Takayuki , Suzuki Keisuke , Koyama Sen , Shibata Akira
Published: June 2012

Background
The benefits of immunosuppressive therapy for human myocarditis are controversial. The effects of a new immunosuppressant agent, 15-deoxyspergualin (DSG), on rats with experimental autoimmune myocarditis (EAM), an animal model of human giant cell myocarditis, were examined.

Methods and Results
Lewis rats were immunized with cardiac myosin in Freund’s complete adjuvant on day 0. In the first experiment, the effective doses of DSG required to prevent EAM were investigated. Rats were placed into one of five groups: the control group (A) was administered saline from days 1 to 10; group B, 0.3 mg/kg per day of DSG; group C, 1.0 mg/kg per day of DSG; group D, 3.0 mg/kg per day of DSG, and group E, 10.0 mg/kg per day of DSG. Rats were killed on day 28. The heart weight/body weight ratios of the rats of groups D and E were significantly lower than that of the control group. Macroscopic and microscopic scores for myocarditis decreased in groups D and E. In the next experiment, the effects of delayed administration of DSG in preventing autoimmune myocarditis were studied. Two groups of rats received 3.0 and 10.0 mg/kg per day of DSG from days 6 to 15, respectively. Two other groups of rats received the same doses of DSG from days 11 to 20. No preventive effect of delayed DSG treatment was observed. The effects of long-term, delayed initiation therapy then were evaluated. Rats were administered 10.0 mg/kg per day of DSG from days 6 to 25. The heart weight/body weight ratio and macroscopic and microscopic scores of the rats so treated significantly decreased compared with the controls.

Conclusions
It was demonstrated that DSG can prevent the development of cardiac myosin–induced autoimmune myocarditis.
Balloon Dilatation of Porcine Pulmonary Arteries Decreases Endothelium-Dependent Relaxations and Increases Vasoconstriction to Aggregating Platelets
Authors: Razzuk Susan J. , Zellers Thomas M.
Published: June 2012

Background
Balloon dilatation of muscular coronary arteries disrupts endothelium and smooth muscle and allows platelet aggregation and adherence and cell proliferation, which can lead to restenosis. Balloon dilatation of the more distensible pulmonary artery is commonly performed, but the extent of damage to endothelium and its effect on the release of endothelium-derived nitric oxide (EDNO) and prostacyclin has not been studied.

Methods and Results
We dilated distal pulmonary arteries of intact ex vivo porcine lungs (n=20; balloon-dilated [BD] group) using similar-sized adjacent vessels as controls with (E+ group) and without (E− group) endothelium. Isolated rings were studied in vitro. Aggregating platelets caused constrictions of quiescent rings from the BD (27.4±8% of constriction to 80 mmol/L KCl) and E− groups (24±5%), which were inhibited by pyrilamine, a histamine blocker (11±4%;
P
<.05), and an intact endothelium (8±5%;
P
<.05). Constrictions to histamine and KCl were similar in the BD and E− groups. In rings with increased tone, platelets caused endothelium-dependent relaxations in the E+ group (70±6% relaxation), which were significantly (
P
<.05) inhibited in the BD group (20±7%), by
l
-nitro-arginine (EDNO blocker, 17±7%) and in the E− group (21±9%). Balloon dilatation markedly reduced endothelium-dependent relaxations to 5-hydroxytryptamine, thrombin, acetylcholine, and the calcium ionophore A23187, but relaxations to sodium nitroprusside were unaffected.

Conclusions
Despite the distensibility of the pulmonary artery, balloon dilatation significantly damages the pulmonary endothelium, decreases EDNO production, impairs vasodilation, and favors platelet-induced vasoconstriction.
Direct Measurements of Endothelium-Derived Nitric Oxide Release by Stimulation of Endothelin Receptors in Rat Kidney and Its Alteration in Salt-Induced Hypertension
Authors: Hirata Yasunobu , Hayakawa Hiroshi , Suzuki Etsu , Kimura Kenjiro , Kikuchi Kazuya , Nagano Tetsuo , Hirobe Masaaki , Omata Masao
Published: June 2012

Background
Stimulation of endothelin subtype B (ET
B
) receptors has been proposed to induce release of endothelium-derived nitric oxide (EDNO).

Methods and Results
To obtain direct evidence of its release and its alteration in deoxycorticosterone acetate (DOCA)-salt hypertension, EDNO released from renal vessels by ET stimulation was assayed by a highly sensitive chemiluminescence method. Kidneys were isolated from DOCA-salt and control rats, and renal perfusion pressure (RPP) and EDNO (by hydrogen peroxide–luminol chemiluminescence) in the perfusate were monitored simultaneously during perfusion of ET-1, ET-3, an ET
A
receptor antagonist (BQ-123), and an ET
B
receptor agonist (BQ-3020). In control rats, ET-1 and ET-3 dose-dependently increased both RPP and NO release. Although the vasoconstricting effects of ET-1 were greater, their NO-releasing effects were comparable. The increase in NO release by ETs was inhibited by
N
G
-monomethyl-
l
-arginine. After 10
−6
mol/L BQ-123 treatment, ET-1 decreased RPP and increased NO release in control kidneys. DOCA-salt rats responded to these agents with much less NO release. BQ-3020 at up to 10
−10
mol/L caused vasodilation (RPP, 10
−11
mol/L, −5.4±1.7%,
P
<.01) associated with increased NO release in control kidneys (+9.0±2.7 fmol · min
−1
· g
−1
kidney wt,
P
<.01). However, in DOCA-salt kidneys, BQ-3020 caused renal vasoconstriction (RPP, +5.4±2.4%,
P
<.01 versus control) and a much smaller NO release (+1.1±0.4 fmol · min
−1
· g
−1
kidney wt,
P
<.01 versus control). Northern blot analysis revealed that renal ET
B
mRNA was significantly decreased in DOCA-salt rat kidneys compared with controls (0.36±0.13 versus 1.00±0.23,
P
<.05).

Conclusions
These results suggest that ET-1 and ET-3 release EDNO via ET
B
receptors in renal vessels. ET
B
-mediated NO release was reduced in DOCA-salt rats, which may modulate renal function and thus blood pressure regulation in DOCA-salt hypertensive rats.
Noninvasive Determination of Infarct Artery Patency By Cine Magnetic Resonance Angiography
Authors: Hundley W. Gregory , Clarke Geoffrey D. , Landau Charles , Lange Richard A. , Willard John E. , Hillis L. David , Peshock Ronald M.
Published: June 2012

Background
In survivors of myocardial infarction, restoration of antegrade flow in the infarct artery reduces morbidity and mortality. At present, coronary artery patency must be assessed invasively with contrast angiography. A noninvasive method of evaluating infarct artery patency would be useful in managing survivors of infarction. This study was performed to determine whether magnetic resonance (MR) imaging could reliably assess infarct artery patency in this patient population.

Methods and Results
Eighteen survivors of myocardial infarction (11 men and 7 women, aged 35 to 74 years) who were consecutively referred for cardiac catheterization underwent contrast coronary angiography and cine MR coronary angiography. Sequential overlapping images of the infarct artery were acquired with cine MR during 15- to 20-second periods of breath-holding. In each study, proximal, middle, and distal segments of infarct arteries were classified as having antegrade, collateral, or no flow. The infarct artery was the left anterior descending in 10 patients, the right anterior descending in 7, and the circumflex in 1. When compared with the results of contrast angiography, MR imaging correctly identified the presence or absence of antegrade flow in the infarct artery of all 18 patients. In addition, cine MR coronary angiography with presaturating pulses correctly established the presence or absence of collateral filling of the distal portion of occluded arteries in 6 of 7 subjects.

Conclusions
In survivors of myocardial infarction, cine MR coronary angiography can reliably determine the patency and direction of flow in the infarct artery.