bluuebunny/crossref_metadata_2025 huggingface dataset:
Long-Term Prognostic Value of Exercise Echocardiography Compared With Exercise
201
Tl, ECG, and Clinical Variables in Patients Evaluated for Coronary Artery Disease
Authors: Olmos Leopoldo I. , Dakik Habib , Gordon Richard , Dunn J. Kay , Verani Mario S. , Quiñones Miguel A. , Zoghbi William A.
Published: June 2012

Background
—The accuracy of exercise echocardiography and
201
Tl single photon emission computed tomography (SPECT) is similar in the diagnosis of coronary artery disease (CAD). However, comparative data on long-term prognosis are lacking.

Methods and Results
—Clinical variables and exercise, echocardiographic, and
201
Tl tomographic parameters were studied in 248 patients (age, 56±12 years [mean±SD]; 189 men) who underwent simultaneous treadmill exercise
201
Tl SPECT and echocardiography. Follow-up was obtained in 225 patients (91%) at a mean of 3.7±2.0 years. A total of 64 cardiac events occurred. With the use of stepwise logistic regression, 4 models simulating clinical stress testing scenarios were evaluated in the prediction of all cardiac events, ischemic events, and/or cardiac death. The best clinical models were exercise echocardiography with exercise ECG and exercise
201
Tl SPECT with exercise ECG. Both models were comparable in the prediction of cardiac events. For the exercise echocardiography model, exercise wall motion score index and induction of ischemia were the strongest predictors of events with ORs of 2.63 per unit increment (95% CI, 1.34 to 5.17;
P
=0.005) and 4.1 (95% CI, 1.32 to 12.79;
P
=0.015), respectively. For the model with exercise
201
Tl SPECT, the strongest predictor was ischemic perfusion defect (OR, 4.93; 95% CI, 1.72 to 14.08;
P
=0.003). The absence of ST changes during exercise decreased the risk of events. For the prediction of ischemic events and/or cardiac death, echocardiographic and
201
Tl parameters were the only predictive variables.

Conclusions
—In patients evaluated for CAD, exercise echocardiography and
201
Tl combined with ECG variables provide comparable prognostic information and can be used interchangeably for risk stratification.
Modulation by Dietary Salt of Verapamil Disposition in Humans
Authors: Darbar Dawood , Fromm Martin F. , Dell’Orto Simonetta , Kim Richard B. , Kroemer Heyo K. , Eichelbaum Michel , Roden Dan M.
Published: June 2012

Background
—The intestine is an increasingly well-recognized site of first-pass drug metabolism. In this study, we determined the influence of dietary salt on the steady-state disposition of verapamil, a drug that undergoes extensive first-pass metabolism.

Methods and Results
—Eight normal volunteers received 120 mg of racemic verapamil orally twice a day for 21 days. The disposition kinetics of verapamil enantiomers were determined after coadministration of intravenous deuterated verapamil with the morning oral dose on days 7, 14, and 21. Each study day was preceded by 7 days on a fixed-salt diet: in 5 subjects, the initial study was conducted during a low-salt (10 mEq/d) diet, the second study during a high-salt (400 mEq/d) diet, and the third during a low-salt diet, whereas in the other 3 subjects, the sequence of diets was reversed. Plasma concentrations of both unlabeled enantiomers (ie, from oral therapy) were significantly (
P
<0.05) lower during the high-salt phase (eg, mean area under the time-concentration curve [0 to 12 hours] for
S
-verapamil: 7765±2591 ng · min · mL
−1
[high salt] versus 12 514±3527 ng · min · mL
−1
[low salt],
P
<0.05). Peak plasma concentrations were significantly lower and the extent of PR interval prolongation significantly blunted with the high-salt diet. In contrast, data with labeled drug (ie, reflecting the intravenous route) were nearly identical for the 2 diets.

Conclusions
—These data indicate that a clinically important component of presystemic drug disposition occurs at the prehepatic (presumably intestinal) level and is sensitive to dietary salt.
Differential Effects of Angiotensin II on Cardiac Cell Proliferation and Intramyocardial Perivascular Fibrosis In Vivo
Authors: McEwan Pauline E. , Gray Gillian A. , Sherry Lorcan , Webb David J. , Kenyon Christopher J.
Published: June 2012

Background
—Growth effects of angiotensin II (Ang II) contribute to cardiac remodeling. Remodeling, in turn, may be influenced by proliferation of nonmyocytes. The aims of this study were to determine in vivo which cardiac cell types proliferate in response to Ang II, to evaluate whether proliferation is mediated by the Ang II AT
1
receptor, and to establish whether blood pressure affects cell proliferation by comparing proliferation in the normotensive right atrium and ventricle and pressure-overloaded left ventricle.

Methods and Results
—Groups of 8 Wistar rats were implanted with miniosmotic pumps releasing 5-bromo-2′-deoxyuridine (BrdU) as a cell proliferation marker for 2 weeks. Two groups received Ang II infusions via a second minipump and drinking water±losartan. Two groups received vehicle±losartan. Cell proliferation was assessed as the percentage of nuclei that incorporated BrdU. Ang II increased proliferation within medial vascular smooth muscle cells (VSMCs) and in associated adventitial/interstitial fibroblasts of intramyocardial coronary arterioles but decreased proliferation of myoendothelial cells. Despite increased blood pressure, proliferation in atria and ventricles was similar. Aldosterone levels were not significantly elevated, suggesting direct proliferative effects of Ang II. Losartan reduced Ang II–induced VSMC and adventitial fibroblast proliferation but had no effect on myoendothelial cell proliferation.

Conclusions
—These results indicate direct, differential effects of Ang II on proliferation of atrial and ventricular nonmyocytes. VSMC and fibroblast proliferation is AT
1
receptor–dependent, whereas myoendothelial cells are controlled by an AT
1
-independent mechanism. The effects are independent of aldosterone and blood pressure and have important implications in renin-dependent hypertension and chronic cardiac failure when circulating Ang II is elevated.
Differential Effects of Quinaprilat and Enalaprilat on Endothelial Function of Conduit Arteries in Patients With Chronic Heart Failure
Authors: Hornig Burkhard , Arakawa Naoshi , Haussmann Daniel , Drexler Helmut
Published: June 2012

Background
—Chronic heart failure (CHF) is associated with endothelial dysfunction, including impaired flow-dependent (endothelium-mediated) dilation (FDD). We have previously shown that ACE inhibition improves endothelium-mediated vasodilation in healthy volunteers. The present study was designed to determine whether ACE inhibition improves the impaired FDD in patients with CHF. Because their affinity to tissue ACE may influence the ability of ACE inhibitors to affect endothelial function, we compared the effects of quinaprilat (high affinity to tissue ACE) and enalaprilat (low affinity to tissue ACE) on FDD in patients with CHF.

Methods and Results
—High-resolution ultrasound and Doppler were used to measure radial artery diameter and blood flow in patients with CHF. The effects of intra-arterial infusion of quinaprilat 1.6 μg/min (n=15) and enalaprilat 5 μg/min (n=15) were determined at rest and during reactive hyperemia (causing endothelium-mediated dilation) before and after
N
-monomethyl-
l
-arginine (L-NMMA) to inhibit endothelial synthesis of nitric oxide. Quinaprilat improved FDD by >40% (10.2±0.6% versus 6.9±0.6%;
P
<0.01), whereas enalaprilat had no effect. In particular, the part of FDD mediated by nitric oxide (ie, inhibited by L-NMMA) was increased by >100% with quinaprilat (5.6±0.5% versus 2.5±0.5%;
P
<0.01). Enalaprilat had no effect on FDD even when it was infused twice in the same dose (5 μg/min) and up to 30 μg/min. The effect of sodium nitroprusside on radial artery diameter and blood flow was similar in patients treated with quinaprilat, enalaprilat, and placebo.

Conclusions
—Quinaprilat improves FDD in patients with CHF as the result of increased availability of nitric oxide, whereas enalaprilat does not. This observation suggests that intrinsic differences exist between quinaprilat and enalaprilat that determine the ability to improve endothelium-mediated vasodilation, ie, their different affinity to tissue ACE.
In Vivo Evaluation of Fontan Pathway Flow Dynamics by Multidimensional Phase-Velocity Magnetic Resonance Imaging
Authors: Be’eri Eliezer , Maier Stephan E. , Landzberg Michael J. , Chung Taylor , Geva Tal
Published: June 2012

Background
—Hemodynamic efficiency of Fontan circulation is believed to be a major determinant of outcome. Prior research on flow dynamics in different modifications of Fontan circulation used in vitro models and computer-based simulation. This study was designed to compare in vivo flow dynamics in the systemic venous pathway between patients with atriopulmonary anastomosis (APA) and those with total cavopulmonary connection (TCPC).

Methods and Results
—Multidimensional phase-velocity magnetic resonance imaging (PV-MRI) studies were performed on 10 patients who had undergone a modified Fontan operation (5 with TCPC and 5 with APA) and were free of symptoms. The groups were comparable in terms of age and body surface area. The interval since surgery was longer for APA than for TCPC subjects. In each subject, the phase-velocity data sets were used to generate dynamic velocity-vector maps and to calculate quantitative flow indices describing the 3-dimensional blood-flow patterns throughout the cardiac cycle at the widest diameter of the Fontan pathway. Mean flow rate was comparable between groups. Velocity-vector maps showed areas of flow reversal, flow stagnation, and circular flow within APA but not TCPC pathways. Analysis of quantitative flow indices showed that compared with the APA group, flow velocities in the TCPC patients were significantly higher (mean velocity, 14±6 cm/s versus 5±3 cm/s;
P
=0.02), less variable (coefficient of variation, 19±2% versus 37±3.5%;
P
<0.0001), and more unidirectional (degree of unidirectionality, 89±7% versus 71±12%;
P
=0.03). APA pathways were significantly more dilated than were TCPC pathways (
P
<0.01) and showed a trend toward larger diameter with increased interval since surgery (
R
2
=0.6,
P
=0.09). Fontan pathway dilatation correlated with flow velocity variability (
R
2
=0.57,
P
=0.01) and inversely with flow unidirectionality (
R
2
=0.75,
P
=0.001).

Conclusions
—Blood flow patterns are more organized and uniform in TCPC than in APA pathways and are significantly influenced by pathway diameter. We speculate that TCPC may result in a more hemodynamically efficient circulation than APA because of differences in pathway dimension and uniformity.
Restoration of E2F Expression Rescues Vascular Endothelial Cells From Tumor Necrosis Factor-α–Induced Apoptosis
Authors: Spyridopoulos Ioakim , Principe Nicole , Krasinski Kevin L. , Xu Shu-hua , Kearney Marianne , Magner Meredith , Isner Jeffrey M. , Losordo Douglas W.
Published: June 2012

Background
—Normally, quiescent endothelial cells (EC) line the inner surface of arteries and protect against thrombosis and neointimal growth. A variety of noxious stimuli, including balloon angioplasty, may compromise EC integrity, thereby initiating proliferation and triggering the local release of cytokines, including tumor necrosis factor-α (TNF-α).

Methods and Results
—In vivo blockade of TNF-α using a soluble receptor molecule results in accelerated reendothelialization at sites of balloon angioplasty, suggesting an important physiological role of TNF-α in attenuating regrowth of endothelium after balloon angioplasty. Our studies reveal that TNF-α, an apoptosis-inducing cytokine, induces G1 cell-cycle arrest in proliferating EC. Quiescent EC are relatively immune to TNF-induced apoptosis versus proliferating EC, which display repression of the E2F transcription factor coincident with TNF-induced apoptosis and cell-cycle arrest. We also show that in this setting, E2F overexpression exerts a survival effect in proliferating EC and restores cell-cycle progression, in direct contrast to results of prior reports, which revealed that deregulated expression of E2F in normally cycling cells induces apoptosis.

Conclusions
—These data demonstrate that TNF-induced apoptosis is highly dependent on cell-cycle activity and that E2F can function as survival factor under certain conditions.
Coordinate Interaction Between ATP-Sensitive K
+
Channel and Na
+
,K
+
-ATPase Modulates Ischemic Preconditioning
Authors: Haruna Tetsuya , Horie Minoru , Kouchi Ichiro , Nawada Ryuzo , Tsuchiya Kunihiko , Akao Masaharu , Otani Hideo , Murakami Tomoyuki , Sasayama Shigetake
Published: June 2012

Background
—We reported that digoxin abolishes the infarct size (IS)-limiting effect of ischemic preconditioning (IPC). Because ATP-sensitive K
+
(K
ATP
) channels are involved in IPC, we studied whether Na
+
,K
+
-ATPase and K
ATP
channels functionally interact, thereby modulating IPC.

Methods and Results
—Rabbits received 30 minutes of coronary artery occlusion followed by 3 hours of reperfusion. IPC was elicited by 5 minutes of occlusion followed by 10 minutes of reperfusion. The IS, expressed as a percentage of the area at risk, was 40.2±2.8% in control and 39.8±5.0% in digoxin pretreatment rabbits. Both IPC and pretreatment with cromakalim, a K
ATP
channel opener, reduced IS to 11.8±1.8% and 13.4±2.6% (
P
<0.05 versus control). Digoxin abolished the reduction in IS induced by IPC (33.5±3.3%), whereas it did not change that induced by cromakalim (18.8±3.0%). In patch-clamp experiments, digoxin was found to inhibit the opening of K
ATP
channels in single ventricular myocytes in which ATP depletion had been induced by metabolic stress. In contrast, digoxin had little effect on the channel opening induced by cromakalim. Moreover, the inhibitory action of digoxin on channel activities was dependent on subsarcolemmal ATP concentration.

Conclusions
—The IS-limiting effect of IPC is modulated by an interaction between K
ATP
channels and Na
+
,K
+
-ATPase through subsarcolemmal ATP.
Neointimal Tissue Response at Sites of Coronary Stenting in Humans
Authors: Komatsu Ryushi , Ueda Makiko , Naruko Takahiko , Kojima Akiko , Becker Anton E.
Published: June 2012

Background
—Experimental animal studies have shown that coronary stenting induces neointimal proliferation. However, the histopathological events after coronary stenting in humans have not been studied systematically.

Methods and Results
—We investigated 11 stented coronary arteries (9 Palmaz-Schatz stents, 1 Wiktor stent, and 1 ACS Multi-Link stent) obtained from 11 patients who had died 2 days to 21 months after stenting. We focused on gross, histological, and immunohistochemical aspects of the repair processes. Two patients developed symptoms of restenosis. Serial sections were stained with antibodies against smooth muscle cells (SMCs), macrophages, and endothelial cells. At 9 and 12 days after stenting, the stent sites showed thrombus formation with early formation of neointima composed of abundant macrophages and α-actin–negative spindle cells. From 64 days on, all sites with stenting showed a distinct layer of neointima, albeit to varying degrees. In nonrestenotic lesions, neointimal thickening was markedly less than in restenotic lesions but without qualitative differences; the neointima contained macrophages but was composed predominantly of α-actin-positive SMCs.

Conclusions
—These observations strongly support the concept that neointimal proliferation in humans is a process of staged redifferentiation of SMCs, which may cause in-stent stenosis. Moreover, the exuberant neointimal proliferation with accumulation of macrophages and extensive neovascularization at sites of stent restenosis suggests a role for organization of mural thrombus.
Direct In Vivo Visualization of Intravascular Destruction of Microbubbles by Ultrasound and its Local Effects on Tissue
Authors: Skyba Danny M. , Price Richard J. , Linka Andre Z. , Skalak Thomas C. , Kaul Sanjiv
Published: June 2012

Background
—Our aim was to observe ultrasound-induced intravascular microbubble destruction in vivo and to characterize any resultant bioeffects.

Methods and Results
—Intravital microscopy was used to visualize the spinotrapezius muscle in 15 rats during ultrasound delivery. Microbubble destruction during ultrasound exposure caused rupture of ≤7-μm microvessels (mostly capillaries) and the production of nonviable cells in adjacent tissue. The number of microvessels ruptured and cells damaged correlated linearly (
P
<0.001) with the amount of ultrasound energy delivered.

Conclusions
—Microbubbles can be destroyed by ultrasound, resulting in a bioeffect that could be used for local drug delivery, angiogenesis, and vascular remodeling, or for tumor destruction.
Chlamydial Heat Shock Protein 60 Localizes in Human Atheroma and Regulates Macrophage Tumor Necrosis Factor-α and Matrix Metalloproteinase Expression
Authors: Kol Amir , Sukhova Galina K. , Lichtman Andrew H. , Libby Peter
Published: June 2012

Background
—Recent evidence has implicated
Chlamydia pneumoniae
in the aggravation of atherosclerosis. However, the mechanisms by which this agent affects atherogenesis remain poorly understood. Chlamydiae produce large amounts of heat shock protein 60 (HSP 60) during chronic, persistent infections, and
C pneumoniae
localizes predominantly within plaque macrophages. Several studies have furnished evidence that endogenous (human) HSP 60 may play a role in atherogenesis. We tested here the hypothesis that atheroma contains chlamydial HSP 60 and that this bacterial product might stimulate macrophage functions considered relevant to atherosclerosis and its complications, such as production of proinflammatory cytokines as tissue necrosis factor-α (TNF-α) and matrix-degrading metalloproteinases (MMPs).

Methods and Results
—Surgical specimens of human carotid atherosclerotic arteries (n=19) and normal arterial wall samples (n=7, 2 carotid arteries and 5 aortas) were tested immunohistochemically for the presence of chlamydial HSP 60 and human HSP 60. Macrophage localization of these antigens was assessed by double immunostaining. Murine peritoneal macrophages, maintained in serum-free conditions for 48 hours after harvesting, were incubated with
C pneumoniae
, chlamydial HSP 60, human HSP 60, or
Escherichia coli
lipopolysaccharide (LPS). Culture supernatants, collected at 24 hours for concentration-dependence experiments and at up to 72 hours for time-dependence experiments, were analyzed for TNF-α by ELISA and for MMP by gelatin zymography. Atherosclerotic lesions showed immunoreactive chlamydial HSP 60 in 47% (9 of 19) of the cases and human HSP 60 in 89% (17 of 19) of the cases. Chlamydial HSP 60 colocalized with human HSP 60 within plaque macrophages in 77% (7 of 9) of the cases. Nonatherosclerotic samples contained neither HSP. Both
C pneumoniae
and recombinant chlamydial HSP 60 induced TNF-α production by mouse macrophages in a concentration- and time-dependent fashion.
E coli
LPS and human HSP 60 produced similar effects. Similarly,
C pneumoniae
and HSPs induced MMPs in a concentration- and time-dependent manner. Heat treatment abolished the effect of
C pneumoniae
and HSPs on both TNF-α and MMP production, but it did not alter the ability of
E coli
LPS to induce these functions.

Conclusions
—Chlamydial HSP 60 frequently colocalizes with human HSP 60 in plaque macrophages in human atherosclerotic lesions. Chlamydial and human HSP 60 induce TNF-α and MMP production by macrophages. Chlamydial HSP 60 might mediate the induction of these effects by
C pneumoniae
. Induction of such macrophage functions provides potential mechanisms by which chlamydial infections may promote atherogenesis and precipitate acute ischemic events.
Radiofrequency Catheter Ablation of Ventricular Tachycardia After Myocardial Infarction
Authors: Stevenson William G. , Friedman Peter L. , Kocovic Dusan , Sager Philip T. , Saxon Leslie A. , Pavri Behzad
Published: June 2012

Background
—Patients with ventricular tachycardia (VT) after myocardial infarction often have multiple morphologies of inducible VT, which complicates mapping and is viewed by some as a relative contraindication to ablation. Attempting to identify and target a single “clinical” VT is often limited by inability to obtain 12-lead ECGs of VTs that are terminated emergently or by defibrillators. This study assesses the feasibility of ablation in patients selected without regard to the presence of multiple VTs by targeting all VTs that allow mapping.

Methods and Results
—Radiofrequency catheter ablation targeting all inducible monomorphic VTs that allowed mapping was performed in 52 patients with prior myocardial infarction. Antiarrhythmic drug therapy had failed in 41 (79%) patients including amiodarone in 36 (69%) patients. An average of 3.6±2 morphologies of VT were induced per patient. More than 1 ablation session was required in 16 (31%) patients. Complications occurred in 5 (10%) patients, including 1 (2%) death caused by acute myocardial infarction. During follow-up 59% of patients continued to receive amiodarone; 23 (45%) had implantable defibrillators. During a mean follow-up of 18±15 months (range 0 to 51 months) 1 patient died suddenly, 2 died from uncontrollable VT, and 5 died from heart failure. Three-year survival rate was 70±10%, and rate for risk of VT recurrence was 33±7%.

Conclusions
—Radiofrequency catheter ablation controls VT that is sufficiently stable to allow mapping in 67% of patients despite failure of antiarrhythmic drug therapy and multiple inducible VTs. However, ablation was largely adjunctive to amiodarone and defibrillators in this referral population.
Vessel Dilator Enhances Sodium and Water Excretion and Has Beneficial Hemodynamic Effects in Persons With Congestive Heart Failure
Authors: Vesely David L. , Dietz John R. , Parks James R. , Baig Mohammad , McCormick Michael T. , Cintron Guillermo , Schocken Douglas D.
Published: June 2012

Background
—Vessel dilator, a 37–amino acid peptide hormone synthesized in the heart, enhances urine flow 4- to 12-fold and sodium excretion 3- to 6-fold in healthy humans. The present investigation was designed to determine whether vessel dilator might have similar beneficial effects in persons with congestive heart failure (CHF).

Methods and Results
—Vessel dilator (100 ng/kg body weight per minute) given intravenously for 60 minutes to NYHA class III CHF subjects increased urine flow 2- to 13-fold, which was still increased (
P
<0.001) 3 hours after its infusion was stopped. Vessel dilator enhanced sodium excretion 3- to 4-fold in CHF subjects (
P
<0.01), which was still significantly (
P
<0.01) elevated 3 hours after infusion. Vessel dilator decreased systemic vascular resistance 24%, pulmonary vascular resistance 25%, pulmonary capillary wedge pressure 33%, and central venous pressure 27% while increasing cardiac output 34%, cardiac index 35%, and stroke volume index 24% without significantly affecting heart rate or pulmonary artery pressure in the CHF subjects. The control CHF patients did not have any changes in the above parameters.

Conclusions
—These results indicate that vessel dilator has significant beneficial diuretic, natriuretic, and hemodynamic properties in humans with congestive heart failure.
Hyperinsulinemia Predicts Coronary Heart Disease Risk in Healthy Middle-aged Men
Authors: Pyörälä Marja , Miettinen Heikki , Laakso Markku , Pyörälä Kalevi
Published: June 2012

Background
—The Helsinki Policemen Study is one of the first prospective epidemiological studies demonstrating an association of hyperinsulinemia to the risk of coronary heart disease (CHD). The aim of the present study was to investigate the predictive value of hyperinsulinemia with regard to CHD risk during a 22-year follow-up of the Helsinki Policemen Study population.

Methods and Results
—The study was based on a cohort of 970 men who were 34 to 64 years of age and free of CHD, other cardiovascular disease, and diabetes. Risk factor measurements at baseline examination included an oral glucose tolerance test (OGTT) with blood glucose and plasma insulin measurements at 0, 1, and 2 hours. Area under the plasma insulin response curve (AUC insulin) during OGTT was used as a composite variable reflecting plasma insulin levels. During the 22-year follow-up, 164 men had a major CHD event (CHD death or nonfatal myocardial infarction). Age-adjusted hazard ratios for a major CHD event comparing men in the highest AUC insulin quintile with those in the combined 4 lower quintiles during 5-, 10-, 15-, and 22-year follow-up periods were 3.29 (95% CI, 1.56 to 6.91), 2.72 (95% CI, 1.67 to 4.42), 2.14 (95% CI, 1.43 to 3.21), and 1.61 (95% CI, 1.14 to 2.27), respectively. Further adjustment for other risk factors attenuated these hazard ratios to 2.36 (95% CI, 1.00 to 5.57), 2.29 (95% CI, 1.31 to 4.02), 1.76 (95% CI, 1.09 to 2.82), and 1.32 (95% CI, 0.89 to 1.97), respectively.

Conclusions
—Hyperinsulinemia predicted CHD risk in Helsinki policemen over the 22-year follow-up, and to a large extent independently of other CHD risk factors, but its predictive value diminished with lengthening follow-up time.
Nitric Oxide Synthase Is the Mediator of Late Preconditioning Against Myocardial Infarction in Conscious Rabbits
Authors: Takano Hitoshi , Manchikalapudi Srinivas , Tang Xian-Liang , Qiu Yumin , Rizvi Ali , Jadoon Asad K. , Zhang Qin , Bolli Roberto
Published: June 2012

Background
—Despite intense investigation, the effector of the infarct-limiting protection observed during the late phase of ischemic preconditioning (PC) remains unknown. The goal of this study was to test the hypothesis that late PC against myocardial infarction is mediated by the activity of nitric oxide synthase (NOS).

Methods and Results
—Conscious rabbits underwent a 30-minute coronary occlusion followed by 3 days of reperfusion. In group I (control group, n=10), infarct size (tetrazolium staining) averaged 56.8±5.3% of the risk region, which was decreased to 27.6±2.5% (
P
<0.05) in rabbits preconditioned 24 hours earlier with a sequence of six 4-minute occlusion/4-minute reperfusion cycles (group II, n=10). When preconditioned rabbits were given the nonselective NOS inhibitor
N
ω
-nitro-
l
-arginine (L-NA, 13 mg/kg IV [group III, n=8]) or the selective iNOS inhibitor aminoguanidine (AG, 150 mg/kg SC [group V, n=7]) before the 30-minute occlusion, the protective effect of late PC was completely abrogated; that is, infarct size (59.9±4.5% and 65.8±3.3%, respectively) was similar to that measured in the control group. Measurements of systolic wall thickening (sonomicrometry) demonstrated that L-NA and AG also abolished the improved recovery of myocardial function effected by late PC in group II. When rabbits were given L-NA or AG without prior PC (group IV [n=8] and group VI [n=6], respectively), infarct size did not differ from that observed in controls (53.8±4.3% and 59.8±4.3%, respectively), demonstrating that L-NA and AG do not increase the extent of cell death in nonpreconditioned myocardium.

Conclusions
—Taken together, these results indicate that in the conscious rabbit, the infarct-sparing effect of the late phase of ischemic PC is mediated by the activity of NOS and suggest that the specific isoform primarily responsible for this cardioprotective phenomenon is iNOS. Thus, NO appears to be a pivotal component of the pathophysiological cascade of late PC.
Four-Year Follow-up of Palmaz-Schatz Stent Revascularization as Treatment for Atherosclerotic Renal Artery Stenosis
Authors: Dorros Gerald , Jaff Michael , Mathiak Lynne , Dorros Isa I. , Lowe Adam , Murphy Kelly , He Thomas
Published: June 2012

Background
—Stent revascularization is perceived as superior to balloon angioplasty and surgical revascularization, but the paucity of stent publications precludes even historical comparison with surgical data.

Methods and Results
—Palmaz-Schatz stent revascularization of renal artery stenosis was successfully performed on 163 consecutive patients for poorly controlled hypertension or preservation of renal function. Of these, 145 were eligible for ≥6-month clinical follow-up of the effect of the procedure on renal function, blood pressure control, number of antihypertensive medications, and survival. At 4 years, systolic and diastolic blood pressures significantly decreased (from 166±26 to 148±22 mm Hg and from 86±14 to 80±11 mm Hg, respectively;
P
<0.05), and blood pressure control was more facile in approximately half of the patients. Creatinine decreased or remained stable in approximately two thirds of the patients. The cumulative probability of survival was 74±4% at 3 years, with few deaths related to end-stage renal disease. Survival was good in patients with normal (92±4%) baseline renal function, fair (74±7%) in those with mildly impaired renal function, and poor (52±7%) in patients with elevated baseline creatinine levels (≥2.0 mg/dL). The combination of impaired renal function and bilateral disease adversely affected survival.

Conclusions
—Renal artery stent revascularization in the presence of normal or mildly impaired renal function had a beneficial effect on blood pressure control and a nondeleterious effect on renal function. Survival was adversely affected by renal dysfunction despite adequate revascularization. Early diagnosis and adequate revascularization before the onset of renal dysfunction could beneficially affect blood pressure control, preserve or prevent deterioration of renal function, and improve patient survival.
Regression of Cellular Hypertrophy After Left Ventricular Assist Device Support
Authors: Zafeiridis Andreas , Jeevanandam Valluvan , Houser Steven R. , Margulies Kenneth B.
Published: June 2012

Background
—Although multiple studies have shown that the left ventricular assist device (LVAD) improves distorted cardiac geometry, the pathological mechanisms of the “reverse remodeling” of the heart are unknown. Our goal was to determine the effects of LVAD support on cardiac myocyte size and shape.

Methods and Results
—Isolated myocytes were obtained at cardiac transplantation from 30 failing hearts (12 ischemic, 18 nonischemic) without LVAD support, 10 failing hearts that received LVAD support for 75±15 days, and 6 nonfailing hearts. Cardiac myocyte volume, length, width, and thickness were determined by use of previously validated techniques. Isolated myocytes from myopathic hearts exhibited increased volume, length, width, and length-to-thickness ratio compared with normal myocytes (
P
<0.05). However, there were no differences in any parameter between myocytes from ischemic and nonischemic cardiomyopathic hearts. Long-term LVAD support resulted in a 28% reduction in myocyte volume, 20% reduction in cell length, 20% reduction in cell width, and 32% reduction in cell length-to-thickness ratio (
P
<0.05). In contrast, LVAD support was associated with no change in cell thickness. These cellular changes were associated with reductions in left ventricular dilation and left ventricular mass measured echocardiographically in 6 of 10 LVAD-supported patients.

Conclusions
—These studies suggest that the regression of cellular hypertrophy is a major contributor to the “reverse remodeling” of the heart after LVAD implantation. The favorable alterations in geometry that occur in parallel fashion at both the organ and cellular levels may contribute to reduced wall stress and improved mechanical performance after LVAD support.
Cilostazol Has Beneficial Effects in Treatment of Intermittent Claudication
Authors: Dawson David L. , Cutler Bruce S. , Meissner Mark H. , Strandness D. Eugene
Published: June 2012

Background
—Cilostazol is a new phosphodiesterase inhibitor that suppresses platelet aggregation and also acts as a direct arterial vasodilator. This prospective, randomized, placebo-controlled, parallel-group clinical trial evaluated the efficacy of cilostazol for treatment of stable, moderately severe intermittent claudication.

Methods and Results
—Study inclusion criteria included age ≥40 years, initial claudication distance (ICD) on treadmill (12.5% incline, 3.2 km/h) between 30 and 200 m, and confirmation of diagnosis of chronic lower-extremity arterial occlusive disease. After stabilization and single-blind placebo lead-in, 81 subjects (62 male, 19 female) from 3 centers were randomized unequally (2:1) to 12 weeks of treatment with cilostazol 100 mg PO BID or placebo. Primary outcome measures included ICD and maximum distance walked (absolute claudication distance, or ACD). Secondary outcome measures included ankle pressures, subjective assessments of benefit by patients and physicians, and safety. Treatment and control groups were similar with respect to age, severity of symptoms, ankle pressures, and smoking status. Statistical analyses used intention-to-treat analyses for each of 77 subjects who had ≥1 treadmill test after initiation of therapy. Comparisons between groups were based on logarithms of ratios of ICD and ACD changes from baseline using ANOVA test at last treatment visit. The estimated treatment effect showed a 35% increase in ICD (
P
<0.01) and a 41% increase in ACD (
P
<0.01). There was no significant change in resting or postexercise ankle/brachial indexes. Patients’ and physicians’ subjective assessments corroborated the measured improvements in walking performance observed in the cilostazol-treated group.

Conclusions
—Cilostazol improved walking distances, significantly increasing ICD and ACD. The data suggest cilostazol is safe and well tolerated for the treatment of intermittent claudication.
Stem Cell Factor Induction Is Associated With Mast Cell Accumulation After Canine Myocardial Ischemia and Reperfusion
Authors: Frangogiannis Nikolaos G. , Perrard Jerry L. , Mendoza Leonardo H. , Burns Alan R. , Lindsey Merry L. , Ballantyne Christie M. , Michael Lloyd H. , Smith C. Wayne , Entman Mark L.
Published: June 2012

Background
—Myocardial infarction is associated with an intense inflammatory reaction leading to healing and scar formation. Because mast cells are a significant source of fibrogenic factors, we investigated mast cell accumulation and regulation of stem cell factor (SCF), a potent growth and tactic factor for mast cells, in the healing myocardium.

Methods and Results
—Using a canine model of myocardial ischemia and reperfusion, we demonstrated a striking increase of mast cell numbers during the healing phase of a myocardial infarction. Mast cell numbers started increasing after 72 hours of reperfusion, showing maximum accumulation in areas of collagen deposition (12.0±2.6-fold increase;
P
<0.01) and proliferating cell nuclear antigen (PCNA) expression. The majority of proliferating cells were identified as α-smooth muscle actin–positive myofibroblasts or factor VIII–positive endothelial cells. Mast cells did not appear to proliferate. Using a nuclease protection assay, we demonstrated induction of SCF mRNA within 72 hours of reperfusion. Immunohistochemical studies demonstrated that a subset of macrophages was the source of SCF immunoreactivity in the infarcted myocardium. SCF protein was not found in endothelial cells and myofibroblasts. Intravascular tryptase–positive, FITC-avidin–positive, CD11b-negative mast cell precursors were noted in the area of healing and in the cardiac lymph after 48 to 72 hours of reperfusion.

Conclusions
—Mast cells increase in number in areas of collagen deposition and PCNA expression after myocardial ischemia. The data provide evidence of mast cell precursor infiltration into the areas of cellular injury. SCF is induced in a subset of macrophages infiltrating the healing myocardium. We suggest an important role for SCF in promoting chemotaxis and growth of mast cell precursors in the healing heart.
Randomized, Double-Blind Crossover Study to Investigate the Effects of Amlodipine and Isosorbide Mononitrate on the Time Course and Severity of Exercise-Induced Myocardial Stunning
Authors: Rinaldi Christopher A. , Linka Andre Z. , Masani Navroz D. , Avery Philip G. , Jones Elizabeth , Saunders Helen , Hall Roger J. C.
Published: June 2012

Background
—Myocardial stunning may cause prolonged left ventricular dysfunction after exercise-induced ischemia that can be attenuated by calcium antagonists in animal models. To assess their effects in humans, we performed a randomized, double-blind crossover study comparing the calcium antagonist amlodipine (10 mg once daily) versus isosorbide mononitrate (ISMN, 50 mg once daily) on postexercise stunning.

Methods and Results
—Twenty-four men with chronic stable angina and normal left ventricular function underwent serial quantitative exercise stress echocardiography after 3 weeks on each treatment to assess the degree of postexercise stunning with simultaneous sestamibi single-photon emission computed tomography perfusion scans at peak stress to quantify the ischemic burden. Exercise time (
P
=1), maximum ST depression (
P
=0.48), and sestamibi single-photon emission computed tomography scores (
P
=0.17) were unchanged between treatments. Stunning occurred more often with ISMN than amlodipine (82% versus 48%). The global and segmental stress echocardiography parameters of stunning were attenuated in patients while taking amlodipine compared with ISMN. Shortening fractions and ejection fractions were less impaired 30 minutes after exercise in patients receiving amlodipine (3.5±1.4% versus 2.5±1.4%,
P
=0.014, and 59.7±5.4% versus 54.5±8%,
P
<0.001); similarly, the isovolumic relaxation period was less prolonged with amlodipine (93±15.5 versus 106.3±14.9 ms,
P
=0.018).

Conclusions
—Despite comparable levels of ischemia, amlodipine attenuated stunning when compared with ISMN. This beneficial effect may relate to a prevention of the calcium overload implicated in the pathogenesis of stunning.
Sympathetic Activity in Obese Subjects With and Without Obstructive Sleep Apnea
Authors: Narkiewicz Krzysztof , van de Borne Philippe J. H. , Cooley Ryan L. , Dyken Mark E. , Somers Virend K.
Published: June 2012

Background
—Obese humans are reported to have increased muscle sympathetic nerve activity (MSNA). Obstructive sleep apnea (OSA) may also be accompanied by increased MSNA. Because there is a high prevalence of OSA in obese humans, it is possible that high MSNA reported in obese subjects may in fact reflect the presence of OSA in these subjects. We tested the hypothesis that obesity, per se, in the absence of OSA, is not accompanied by increased MSNA.

Methods and Results
—We measured MSNA in 25 healthy normal-weight subjects and 30 healthy sedentary obese subjects. All subjects were screened by history and examination to exclude subjects with OSA or hypertension. OSA was further excluded by overnight polysomnographic studies. Despite careful screening, polysomnography revealed that 1 of 25 normal-weight subjects and 9 of 30 obese subjects had occult OSA (
P
=0.015). MSNA was similar in normal-weight subjects (41±3 bursts per 100 heartbeats) and obese subjects without sleep apnea (42±3 bursts per 100 heartbeats,
P
=0.99). MSNA in the 9 obese subjects with occult OSA was 61±8 bursts per 100 heartbeats, which was higher than MSNA in normal-weight subjects without sleep apnea (
P
=0.02) and higher than MSNA in obese subjects without sleep apnea (
P
=0.02).

Conclusions
—Obesity alone, in the absence of OSA, is not accompanied by increased sympathetic activity to muscle blood vessels.
Evidence That Macrophages in Atherosclerotic Lesions Contain Angiotensin II
Authors: Potter D. Dean , Sobey Christopher G. , Tompkins Pamela K. , Rossen James D. , Heistad Donald D.
Published: June 2012

Background
—We have reported that human mononuclear leukocytes contain large amounts of angiotensin II (Ang II). The goal of the present study was to test the hypothesis that Ang II is present in monocyte/macrophages in atherosclerotic lesions.

Methods and Results
—Segments of thoracic aorta and left circumflex coronary artery were obtained from 3 groups of cynomolgus monkeys: normal, atherosclerotic, and regression. Samples of human coronary arterial atherosclerotic lesions were obtained from directional atherectomy. Sections were stained for Ang II with 3 different polyclonal rabbit anti–human Ang II antisera. In aorta and coronary arteries from normal monkeys, there was no or minimal anti–Ang II staining in endothelial cells. All sections from atherosclerotic monkeys displayed discrete, localized regions of staining for Ang II in intima-media. Macrophages were present throughout the atherosclerotic intima-media, and anti–Ang II staining appeared to colocalize with macrophages. All human coronary atherectomy samples stained positive for Ang II and macrophages. Staining for both Ang II and macrophages was observed in vascular lesions from all 5 monkeys after regression of atherosclerosis, but staining was less extensive than in atherosclerotic blood vessels from monkeys.

Conclusions
—These findings suggest that Ang II is present in atherosclerotic lesions in monkeys and humans, colocalizes with macrophages in intima-media of atherosclerotic vessels from monkeys, and decreases in lesions in monkeys with regression of atherosclerosis.
Physician Noncompliance With the 1993 National Cholesterol Education Program (NCEP-ATPII) Guidelines
Authors: Frolkis Joseph P. , Zyzanski Stephen J. , Schwartz Jonathan M. , Suhan Pamela S.
Published: June 2012

Background
—We sought to determine the frequency with which physicians follow National Cholesterol Education Program (NCEP-ATPII) guidelines in screening for cardiovascular risk factors and treating hyperlipidemia.

Methods and Results
—We conducted a retrospective chart review on randomly sampled charts of 225 patients admitted to the coronary care unit between January and June 1996. The main outcome measures were rates of physician screening for coronary heart disease risk factors; rates of counseling for cigarette cessation, diet, and exercise; and extent of use of NCEP algorithms for obtaining LDL cholesterol values and treating hypercholesterolemia. Screening rates for interns (who performed best) were: cigarette use (89%), known coronary heart disease (74%), hypertension (68%), hyperlipidemia (59%), family history (56%), diabetes (37%), postmenopausal hormone therapy (11%), and premature menopause (1%). Four percent of smokers were counseled to quit, 14% of patients were referred to dietitians, and 1% were encouraged to exercise. A full lipid panel was obtained in 50% of patients in whom it was indicated on the basis of NCEP criteria. Patients were more likely to receive lipid-lowering treatment if NCEP criteria indicated that they should, but 36% of hospitalized patients and 46% of patients who should have been treated on discharge were not.

Conclusions
—Physicians are poorly compliant with NCEP guidelines for risk factor assessment and counseling, even in patients at high risk for coronary heart disease. Physicians follow NCEP-ATPII algorithms for obtaining an LDL value, a key step in evaluating the need for treatment, only 50% of the time. NCEP criteria seem to influence the decision to initiate lipid-lowering therapy, but significant numbers of eligible patients remain untreated.
Mobilization of Antioxidant Vitamin Pools and Hemodynamic Function After Myocardial Infarction
Authors: Palace Vince P. , Hill Mike F. , Farahmand Firoozeh , Singal Pawan K.
Published: June 2012

Background
—Although most previous studies have attempted to correlate plasma concentrations of vitamins with specific cardiovascular end points, metabolic considerations suggest that changes in myocardial tissue and storage organs may be better indicators of myocardial oxidative stress.

Methods and Results
—Rats fed commercial chow or a diet enriched with vitamin E for 2 weeks were subjected to either a surgical myocardial infarction (MI) or a sham procedure. Rats were hemodynamically assessed 16 weeks after surgery, and their heart, liver, kidney, and plasma were analyzed for antioxidant vitamins E (tocopherol) and A (retinol and total retinyl esters). At 16 weeks, MI rats on a control diet showed depressed peak systolic and elevated diastolic pressures in both right and left ventricles compared with their sham controls. Plasma concentrations of vitamins E and A in MI rats were not different from sham controls fed the same diet. However, concentrations of vitamin E in left ventricle and liver and of vitamin A in liver (retinol) and kidney (retinyl esters) were decreased in rats with MI compared with the sham controls. Vitamin E supplementation improved hemodynamic function in rats with MI and increased plasma, myocardial, liver, and kidney concentrations of vitamin E. The vitamin E diet also prevented the loss of total retinyl esters from the kidney but not of retinol from the liver in MI rats.

Conclusions
—Dietary supplements of vitamin E can sustain better cardiac function subsequent to MI. Antioxidant vitamin levels in the myocardium or in storage organs and not in plasma may be better indicators of myocardial oxidative stress.
Recombinant Growth Hormone Therapy in Patients With Ischemic Cardiomyopathy
Authors: Genth-Zotz Sabine , Zotz Rainer , Geil Stefanie , Voigtländer Thomas , Meyer Jürgen , Darius Harald
Published: June 2012

Background
—We studied the effects of recombinant growth hormone (rhGH) on exercise capacity and cardiac function in patients with ischemic cardiomyopathy.

Methods and Results
—Seven patients (aged 55±9 years) with mild to moderate congestive heart failure (ejection fraction 31±4%) who were on standard therapy were included. The patients were studied at baseline, after 3 months of rhGH treatment, and 3 months after rhGH discontinuation. Cardiac function was assessed by exercise capacity, right heart catheterization at rest and after submaximal exercise, MRI, echocardiography, and Holter monitoring. When administered at a dose of 2 IU/d, rhGH doubled the serum concentration of insulin-like growth factor-I. rhGH improved clinical symptoms and exercise capacity significantly (New York Heart Association class 2.4±0.5 initially versus 1.4±0.5 at 3 months [mean±SD],
P
<0.05; V̇
o
2
max 13.6±3.8 versus 17.4±5.4 mL · kg
−1
· min
−1
,
P
<0.05). Additionally, pulmonary capillary wedge pressures at rest and after submaximal exercise were reduced significantly. Cardiac output increased, particularly at rest (5.0±1.1 versus 5.8±1.3 L/min;
P
<0.05). Posterior wall thickness was increased (1.08±0.1 versus 1.24±0.3 cm;
P
<0.05), and the end-diastolic and end-systolic volume indexes decreased significantly after rhGH treatment. There was no significant increase in left ventricular ejection fraction. The improvements were partially reversed 3 months after rhGH discontinuation.

Conclusions
—The administration of rhGH for 3 months in patients with ischemic cardiomyopathy results in significant improvement in hemodynamics and clinical function. The attenuation of left ventricular remodeling persisted 3 months after discontinuation of treatment.