bluuebunny/crossref_metadata_2025 huggingface dataset:
Nitrate Resistance In Platelets From Patients With Stable Angina Pectoris
Authors: Chirkov Yuliy Y. , Holmes Andrew S. , Chirkova Larissa P. , Horowitz John D.
Published: June 2012

Background
—Hemodynamic resistance to nitrates has been previously documented in congestive heart failure. In patients with stable angina pectoris (SAP), we have observed a similar phenomenon: decreased platelet response to disaggregating effects of nitroglycerin (NTG) and sodium nitroprusside (SNP).

Methods and Results
—In blood samples from normal subjects (n=32) and patients with SAP (n=56), we studied effects of NO donors (NTG and SNP) on ADP-induced platelet aggregation and on intraplatelet cGMP. NTG and SNP inhibited platelet aggregation in patients to lesser extents than in normal subjects (
P
<0.01). The cGMP-elevating efficacy of NTG and SNP was diminished in platelets from patients in comparison with those from normals (
P
<0.001). Inhibition of the anti-aggregatory effects of NTG and SNP by ODQ, a selective inhibitor of NO-stimulated guanylate cyclase, was significantly less pronounced in patients than in normal subjects. Content of O
2
−
was higher in blood samples from patients than in those from normal subjects (
P
<0.01). In blood samples from patients with SAP, but not in normal subjects, the O
2
−
scavenger superoxide dismutase (combined with catalase) suppressed platelet aggregation (
P
<0.01) and increased the extent of anti-aggregatory effect of SNP (
P
<0.01).

Conclusions
—In patients with SAP, platelets are less responsive to the anti-aggregating and cGMP-stimulating effects of NO donors; this may reflect both reduction in guanylate cyclase sensitivity to NO and inactivation of the released NO by O
2
−
. The implied impairment of anti-platelet efficacy of endogenous NO (in the form of EDRF) may contribute to platelet hyperaggregability associated with angina pectoris.
Progressive Loss of Myocardial ATP Due to a Loss of Total Purines During the Development of Heart Failure in Dogs
Authors: Shen Weiqun , Asai Kuniya , Uechi Masami , Mathier Michael A. , Shannon Richard P. , Vatner Stephen F. , Ingwall Joanne S.
Published: June 2012

Background
—Whether myocardial ATP content falls in heart failure is a long-standing and controversial issue. The mechanism(s) to explain any decrease in ATP content during heart failure have not been identified.

Methods and Results
—Cardiac dysfunction, heart failure, and a prolonged steady state of heart failure were induced by chronic right ventricular pacing for 1 to 2 weeks, 3 to 4 weeks, and 7 to 9 weeks in dogs. Cardiac function and myocardial O
2
consumption (MV̇
o
2
) were measured with the dogs in the conscious state. ATP, total purine, and creatine were measured in biopsy specimens obtained at each stage. ATP and the total purine pool progressively fell at rates of 0.12 and 0.15 nmol · mg protein
−1
· d
−1
, despite an increase in MV̇
o
2
. The rate of loss of creatine was 1.06 nmol · mg protein
−1
· d
−1
, 7 times faster than the depletion of total purine.

Conclusions
—(1) ATP contents progressively decreased during heart failure as a result of a loss of the total purine pool. The loss of purines may be due to inhibition of de novo purine synthesis. (2) Loss of creatine is an early marker of heart failure and may serve as a compensatory mechanism minimizing the reduction of the total purine pool in the failing heart.
Prevalence and Determinants of Valvulopathy in Patients Treated With Dexfenfluramine
Authors: Shively Bruce K. , Roldan Carlos A. , Gill Edward A. , Najarian Thomas , Loar Sonja Barton
Published: June 2012

Background
—Valve regurgitation has been associated with dexfenfluramine, but its prevalence and severity are uncertain. Additional factors that may contribute to valve regurgitation in patients exposed to this drug are poorly understood.

Methods and Results
—Echocardiography was performed on subjects recruited from 26 prescribing sites in 15 states. The total sample of 412 subjects included 172 dexfenfluramine patients and 172 unexposed controls matched for age, sex, and body mass index and 68 unmatched subjects meeting the same entry criteria (51 dexfenfluramine patients and 17 controls). Mean treatment duration was 6.9 months; mean interval from treatment discontinuation to echocardiogram was 8.5 months. Each echocardiogram was interpreted independently by 3 echocardiographers. FDA-grade regurgitation (at least mild aortic regurgitation or at least moderate mitral regurgitation) was significantly more frequent in dexfenfluramine patients (7.6% versus 2.1% for controls;
P
=0.01; odds ratio, 3.82). This difference was primarily due to more frequent mild aortic regurgitation in dexfenfluramine patients (6.3% versus 1.6% in controls;
P
<0.02; odds ratio, 4.15). No differences were found in sclerosis or mobility for either the aortic or mitral valve. Factors independently related to FDA-grade regurgitation or any grade of aortic regurgitation were older age, higher diastolic blood pressure at the time of echocardiography, and shorter time from drug discontinuation to echocardiogram.

Conclusions
—Dexfenfluramine use is associated with an increase in the prevalence of abnormal valve regurgitation. Age and blood pressure may also affect the prevalence of regurgitation. Dexfenfluramine-related valve regurgitation may regress after drug discontinuation.
Medial Localization of Mineralization-Regulating Proteins in Association With Mönckeberg’s Sclerosis
Authors: Shanahan Catherine M. , Cary Nathaniel R. B. , Salisbury Jon R. , Proudfoot Diane , Weissberg Peter L. , Edmonds Mike E.
Published: June 2012

Background
—Calcification of the media of peripheral arteries is referred to as Mönckeberg’s sclerosis (MS) and occurs commonly in aged and diabetic individuals. Its pathogenesis is unknown, but its presence predicts risk of cardiovascular events and leg amputation in diabetic patients. Several studies have documented expression of bone-associated genes in association with intimal atherosclerotic calcification, leading to the suggestion that vascular calcification may be a regulated process with similarities to developmental osteogenesis. Therefore, we examined gene expression in vessels with MS to determine whether there was evidence for a regulated calcification process in the vessel media.

Methods and Results
—In situ hybridization, immunohistochemistry, and semiquantitative reverse-transcription polymerase chain reaction were used to examine the expression of mineralization-regulating proteins in human peripheral arteries with and without MS. MS occurred in direct apposition to medial vascular smooth muscle cells (VSMCs) in the absence of macrophages or lipid. These VSMCs expressed the smooth muscle–specific gene SM22α and high levels of matrix Gla protein but little osteopontin mRNA. Compared with normal vessels, vessels with MS globally expressed lower levels of matrix Gla protein and osteonectin, whereas alkaline phosphatase, bone sialoprotein, bone Gla protein, and collagen II, all indicators of osteogenesis/chondrogenesis, were upregulated. Furthermore, VSMCs derived from MS lesions exhibited osteoblastic properties and mineralized in vitro.

Conclusions
—These data indicate that medial calcification in MS lesions is an active process potentially orchestrated by phenotypically modified VSMCs.
Alterations of Heart Rate Variability After Radiofrequency Catheter Ablation of Focal Atrial Fibrillation Originating From Pulmonary Veins
Authors: Hsieh Ming-Hsiung , Chiou Chuen-Wang , Wen Zu-Chi , Wu Chieh-Hung , Tai Ching-Tai , Tsai Chin-Feng , Ding Yu-An , Chang Mau-Song , Chen Shih-Ann
Published: June 2012

Background
—Transient sinus bradycardia and hypotension have been reported as complications during radiofrequency (RF) ablation of focal atrial fibrillation (AF) originating from pulmonary veins (PVs). This study used heart rate variability (HRV) to evaluate the effects of focal PVs ablation on autonomic function.

Methods and Results
—Thirty-seven patients with paroxysmal AF were referred for ablation. The study group included 30 patients who underwent transseptal ablation of PVs, and the control group included 7 patients who underwent the transseptal procedure without ablation. The mean sinus rate and time-domain (standard deviation of RR intervals and root-mean-square of differences of adjacent RR intervals) and frequency-domain (low frequency, high frequency, and low-frequency/high-frequency ratio) analyses of HRV were obtained by use of 24-hour Holter monitoring before and 1 week, 1 month, and 6 months after ablation. All the triggering points of AF were from PVs, and they were successfully ablated. Severe bradycardia and hypotension were noted during ablation of PVs in 6 patients (group IA); 24 patients without the above complication belonged to group IB. Compared with preablation values, a significant increase in mean sinus rate and low-frequency/high-frequency ratio and a significant decrease in standard deviation of RR intervals, root-mean-square of differences of adjacent RR intervals, low frequency, and high frequency were noted in groups IA and IB patients 1 week after ablation. The changes in HR and HRV recovered spontaneously in the 2 subgroups by 1 month later. These parameters of HRV did not change in the control group after the transseptal procedure.

Conclusions
—Transient autonomic dysfunction with alterations in HR and HRV occurred after ablation of focal AF originating from PVs.
Restoration of Contractile Function in Isolated Cardiomyocytes From Failing Human Hearts by Gene Transfer of SERCA2a
Authors: Federica del Monte  , Harding Sian E. , Schmidt Ulrich , Matsui Takashi , Kang Zhao Bin , Dec G. William , Gwathmey Judith K. , Rosenzweig Anthony , Hajjar Roger J.
Published: June 2012

Background
—Failing human myocardium is characterized by abnormal relaxation, a deficient sarcoplasmic reticulum (SR) Ca
2+
uptake, and a negative frequency response, which have all been related to a deficiency in the SR Ca
2+
ATPase (SERCA2a) pump.

Methods and Results
—To test the hypothesis that an increase in SERCA2a could improve contractile function in cardiomyocytes, we overexpressed SERCA2a in human ventricular myocytes from 10 patients with end-stage heart failure and examined intracellular Ca
2+
handling and contractile function. Overexpression of SERCA2a resulted in an increase in both protein expression and pump activity and induced a faster contraction velocity (26.7±6.7% versus 16.6±2.7% shortening per second,
P
<0.005) and enhanced relaxation velocity (32.0±10.1% versus 15.1±2.4%,
P
<0.005). Diastolic Ca
2+
was decreased in failing cardiomyocytes overexpressing SERCA2a (270±26 versus 347±30 nmol/L,
P
<0.005), whereas systolic Ca
2+
was increased (601±38 versus 508±25 nmol/L,
P
<0.05). In addition, the frequency response was normalized in cardiomyocytes overexpressing SERCA2a.

Conclusions
—These results support the premise that gene-based therapies and targeting of specific pathways in human heart failure may offer a new modality for the treatment of this disease.
Threshold Values for Preserved Viability With a Noninvasive Measurement of Collateral Blood Flow During Acute Myocardial Infarction Treated by Direct Coronary Angioplasty
Authors: Christian Timothy F. , Berger Peter B. , O’Connor Michael K. , Hodge David O. , Gibbons Raymond J.
Published: June 2012

Background
—Quantitative measures of myocardial perfusion defect severity from acute
99m
Tc-sestamibi tomographic images (nadir) have correlated closely with collateral and residual antegrade blood flow during acute myocardial infarction. The purpose of this study was to determine whether a viability threshold could be identified from this measure in patients with acute myocardial infarction treated in a homogeneous manner with successful reperfusion therapy.

Methods and Results
—The study group consisted of 61 patients with acute myocardial infarction with a risk area of >6% LV treated with primary angioplasty between 120 and 240 minutes after symptom onset. All patients were injected with 20 to 30 mCi of
99m
Tc-sestamibi before primary angioplasty and imaged after the procedure. Acute myocardium at risk (MAR) and subsequent infarct size (IS) were quantified by a threshold program. Severity (nadir) from the acute image was the lowest ratio of minimal/maximum counts from 5 short-axis slices. Infarct location was anterior in 22 and inferior in 39 patients. MAR was 33±15% LV and IS was 13±15% LV: 23 patients had no infarction despite MAR similar to those with infarction. Receiver-operator characteristic curve analysis identified a nadir value of 0.26 as providing the best separation of patients with and without infarction (sensitivity, 74%; specificity, 74%). This nadir threshold varied by infarct location: anterior defect, 0.21; inferior defect, 0.31. The sensitivity and specificity for absent infarction for these values were anterior, 69% and 67%, and inferior, 88% and 84%, respectively.

Conclusions
—In a time frame in which the presence of residual blood flow is important, the severity of the acute
99m
Tc-sestamibi defect can be used to predict whether infarction will develop despite successful reperfusion.
Renal Response to Acute Neutral Endopeptidase Inhibition in Mild and Severe Experimental Heart Failure
Authors: Chen Horng H. , Schirger John A. , Chau William L. , Jougasaki Michihisa , Lisy Ondrej , Redfield Margaret M. , Barclay Paul T. , Burnett John C.
Published: June 2012

Background
—Neutral endopeptidase 24.11 (NEP) is a metalloprotease that is localized in the greatest abundance in the kidney and degrades natriuretic peptides, such as atrial natriuretic peptide (ANP). Mild congestive heart failure (CHF) is characterized by increases in circulating ANP without activation of the renin-angiotensin-aldosterone system (RAAS) or sodium retention. In contrast, severe CHF is characterized by sodium retention and coactivation of both ANP and the RAAS.

Methods and Results
—We defined the acute cardiorenal actions of the NEP inhibitor candoxatrilat (8 μg · kg
−1
· min
−1
) in 4 groups of anesthetized dogs (normal, n=8; mild CHF, n=6; severe CHF, n=5; and severe CHF with chronic AT
1
receptor antagonism, n=5). Mild CHF was produced by rapid ventricular pacing at 180 bpm for 10 days and severe CHF at 245 bpm for 10 days. In mild CHF, urinary sodium excretion and glomerular filtration rate were greatest in response to acute NEP inhibition compared with the response in either control animals or those with severe CHF. Furthermore, an increase in glomerular filtration rate was observed only in mild CHF in association with increases in renal blood flow and decreases in renal vascular resistance and distal tubular sodium reabsorption. Urinary ANP and cGMP excretion, markers for renal biological actions of ANP, were greatest in mild CHF. The renal actions observed in mild CHF were attenuated in severe CHF and not restored by chronic AT
1
receptor antagonism.

Conclusions
—The results of the present study demonstrate that acute NEP inhibition in mild CHF results in marked increases in renal hemodynamics and sodium excretion that exceed that observed in control animals and severe CHF. These studies underscore the potential therapeutic role for NEP inhibition to enhance renal function in mild CHF, an important phase of CHF that is marked by selective activation of endogenous ANP in the absence of an activated RAAS.
Heparin Blunts Endotoxin-Induced Coagulation Activation
Authors: Pernerstorfer T. , Hollenstein U. , Hansen J.-B. , Knechtelsdorfer M. , Stohlawetz P. , Graninger W. , Eichler H.-G. , Speiser W. , Jilma B.
Published: June 2012

Background
—Lipopolysaccharide (LPS) is a major trigger of sepsis-induced disseminated intravascular coagulation (DIC) via the tissue factor (TF)/factor VIIa–dependent pathway of coagulation. Experimental endotoxemia has been used repeatedly to explore this complex pathophysiology, but little is known about the effects of clinically used anticoagulants in this setting. Therefore, we compared with placebo the effects of unfractionated heparin (UFH) and low-molecular-weight heparin (LMWH) on LPS-induced coagulation.

Methods and Results
—In a randomized, double-blind, placebo-controlled trial, 30 healthy male volunteers received LPS 2 ng/kg IV followed by a bolus-primed continuous infusion of UFH, LMWH, or placebo. In the placebo group, activation of coagulation caused marked increases in plasma levels of prothrombin fragment F
1+2
(
P
<0.01) and polymerized soluble fibrin, termed thrombus precursor protein (TpP;
P
<0.01); TF-positive monocytes doubled in response to LPS, whereas levels of activated factor VII slightly decreased and levels of TF pathway inhibitor remained unchanged. UFH and LMWH markedly decreased activation of coagulation caused by LPS, as F
1+2
and TpP levels only slightly increased; TF expression on monocytes was also markedly reduced by UFH. TF pathway inhibitor values increased after either heparin infusion (
P
<0.01). Concomitantly, factor VIIa levels dropped by >50% at 50 minutes after initiation of either heparin infusion (
P
<0.01).

Conclusions
—This experimental model proved the anticoagulatory potency of UFH and LMWH in the initial phase of experimental LPS-induced coagulation. Successful inhibition of thrombin generation also translates into blunted activation of coagulation factors upstream and downstream of thrombin.
Comparative Effects of Tissue Plasminogen Activator, Streptokinase, and Staphylokinase on Cerebral Ischemic Infarction and Pulmonary Clot Lysis in Hamster Models
Authors: Nagai N. , Vanlinthout I. , Collen D.
Published: June 2012

Background
—The effects of alteplase (rtPA), streptokinase, and staphylokinase (rSak) on focal cerebral ischemia (FCI) and on pulmonary clot lysis (PCL) were studied in hamsters.

Methods and Results
—FCI was produced by ligation of the left middle cerebral artery (MCA) and common carotid artery (CCA) and a 10-minute occlusion of the right CCA. FCI was measured after 24 hours by 2,3,5-triphenyltetrazolium chloride staining.
125
I-fibrin–labeled plasma clots were injected via the jugular vein, and clot lysis was determined from residual radioactivity at 90 minutes. Study drugs were given intravenously over 60 minutes. FCI increased from 1.2 (0.27 to 2.3) mm
3
(median and 17th to 83rd percentile range, n=24) in controls to 19 to 27 mm
3
with thrombolytic agent, with maximal rates at 0.13±0.05 mg/kg rtPA, 0.23±0.09 mg/kg streptokinase, and 0.037±0.025 mg/kg rSak. PCL increased from 18±2% (mean±SEM, n=27) in controls to ≈85% with thrombolytics, with maximal rates at 0.12±0.03 mg/kg rtPA, 0.17±0.05 mg/kg streptokinase, and 0.018±0.002 mg/kg rSak. All agents caused maximal FCI and PCL rates at similar doses without α
2
-antiplasmin and fibrinogen depletion. Injection of 6 mg/kg human plasminogen combined with streptokinase caused a “systemic fibrinolytic state” with fibrinogen depletion. Maximal rates of FCI were obtained with 0.097±0.077 mg/kg streptokinase (
P
=0.26 versus streptokinase alone) and of PCL with 0.010±0.002 mg/kg (
P
=0.006 versus streptokinase alone).

Conclusions
—Thrombolytic agents cause similar dose-related extension of FCI after MCA ligation and PCL, irrespective of the agent or systemic plasmin generation.
Plasma α-Tocopherol and Coronary Endothelium-Dependent Vasodilator Function
Authors: Kinlay Scott , Fang James C. , Hikita Hiroyuki , Ho Ivan , Delagrange Danielle M. , Frei Balz , Suh Jung H. , Gerhard Marie , Creager Mark A. , Selwyn Andrew P. , Ganz Peter
Published: June 2012

Background
—In the presence of atherosclerosis, the coronary endothelial vasomotor response to acetylcholine is frequently abnormal but is variable between patients. We tested the hypothesis that the plasma concentration of α-tocopherol is associated with the preservation of nitric oxide–mediated endothelium-dependent vasomotion.

Methods and Results
—We studied 15 men and 6 women (mean age 61±10 years) at coronary angiography who were not taking vitamin supplements. Coronary endothelium-dependent and -independent vasomotion was assessed by intracoronary infusions of acetylcholine and nitroglycerin. The vasomotor responses were compared with the plasma concentration of α-tocopherol and the plasma α-tocopherol concentration relative to total lipid (total cholesterol plus triglycerides). The mean plasma α-tocopherol was 25.6±6.1 μmol/L, total cholesterol 193±27 mg/dL, triglycerides 115±66 mg/dL, and α-tocopherol to total lipid 4.2±0.9 μmol · L
−1
· (mmol/L)
−1
. The mean vasomotor response to acetylcholine was −1% (range −33% to 28%) and to nitroglycerin 22% (range 0% to 54%). Plasma α-tocopherol was significantly correlated with the acetylcholine response (
r
=0.49,
P
<0.05) but not the nitroglycerin response (
r
=0.13,
P
>0.05). The acetylcholine response remained significant after adjustment for other potential sources of oxidant stress (total cholesterol, diabetes mellitus, smoking, angina class) (
P
<0.01). The relative concentration of α-tocopherol to total lipid was not related to endothelial function (
r
=0.24,
P
=0.3, n=20).

Conclusions
—α-Tocopherol may preserve endothelial vasomotor function in patients with coronary atherosclerosis. This effect may be related primarily to the action of α-tocopherol in the vascular wall. Further studies that assess the impact of α-tocopherol supplementation as therapy of endothelial dysfunction are justified.
Long-Term Follow-Up After Percutaneous Transluminal Coronary Angioplasty Was Not Performed Based on Intravascular Ultrasound Findings
Authors: Abizaid Andrea S. , Mintz Gary S. , Mehran Roxana , Abizaid Alexandre , Lansky Alexandra J. , Pichard Augusto D. , Satler Lowell F. , Wu Hongsheng , Pappas Chrysoula , Kent Kenneth M. , Leon Martin B.
Published: June 2012

Background
—Angiography is limited in determining the anatomic severity of coronary artery stenoses. Clinical decision-making in patients with symptoms and intermediate lesions remains challenging.

Methods and Results
—The current analysis included 300 patients (357 intermediate native artery lesions) in whom intervention was deferred based on intravascular ultrasound (IVUS) findings. Standard clinical, angiographic, and IVUS parameters were collected. Patients were followed for >1 year. Events occurred in 24 patients (8%). They included 2 cardiac deaths, 4 myocardial infarctions, and 18 target-lesion revascularizations (TLR; 12 percutaneous transluminal coronary angiographies and 6 coronary artery bypass grafts; only 3 TLRs occurred within 6 months after the IVUS study). All significant univariate clinical, angiographic, and IVUS parameters (
P
<0.05) were tested in multivariate models. These included diabetes mellitus, IVUS lesion lumen area, maximum lumen diameter, minimum lumen diameter, plaque area, plaque burden, and area stenosis (AS). No angiographic measurement was significant at
P
<0.05. The only independent predictors of an event (death, myocardial infarction, or TLR) were IVUS minimum lumen area and AS. The only independent predictors of TLR were diabetes mellitus, IVUS minimum lumen area, and AS. In 248 lesions with a minimum lumen area ≥4.0 mm
2
, the event rate was only 4.4% and the TLR rate 2.8%.

Conclusions
—Long-term follow-up after IVUS-guided deferred interventions in patients with de novo intermediate native artery lesions showed a low event rate. In patients with a minimum lumen area ≥4.0 mm
2
, the event rate was especially low. IVUS imaging is an acceptable alternative to physiological assessment in these patients.
Interactions Between Electronic Article Surveillance Systems and Implantable Cardioverter-Defibrillators
Authors: Groh William J. , Boschee Scott A. , Engelstein Erica D. , Miles William M. , Burton M. Erick , Foster Peter R. , Crevey Barry J. , Zipes Douglas P.
Published: June 2012

Background
—In patients with implantable cardioverter-defibrillators (ICDs). inappropriate shocks have been reported with exposure to electronic article surveillance systems. The risk to patients with ICDs of walking through or lingering near surveillance systems requires further investigation.

Methods and Results
—We evaluated the response in ICD function in 170 subjects during a 10- to 15-second midgate walk-through of and during extreme (2 minutes within 6 in of the gate) exposure to 3 common article surveillance systems. Complete testing was done in 169 subjects. During a 10- to 15-second (very slow) walk-through of the 3 surveillance systems, no interactions were observed that would negatively affect ICD function. During extreme exposure (169 subjects) and during extreme exposure and pacing via the ICD (126 subjects), interactions between the ICD and the article surveillance systems were observed in 19 subjects. In 7 subjects, this interaction was clinically relevant and would have likely (3 subjects) and possibly (4 subjects) resulted in ICD shocks. In 12 subjects, the interaction was minor.

Conclusions
—It is safe for a patient with an ICD to walk through electronic article surveillance systems. Lingering in a surveillance system may result in an inappropriate ICD shock.
Respiratory Muscles Performance Is Related to Oxygen Kinetics During Maximal Exercise and Early Recovery in Patients With Congestive Heart Failure
Authors: Nanas Serafim , Nanas John , Kassiotis Christos , Alexopoulos George , Samakovli Anastasia , Kanakakis John , Tsolakis Elias , Roussos Charis
Published: June 2012

Background
—Dyspnea and fatigue are the main causes of exercise limitation in chronic heart failure (CHF) patients, whose peak inspiratory (Pi
max
) and expiratory pressures (Pe
max
) are often reduced. The aim of this study was to examine the relationship between respiratory muscle performance and oxygen kinetics.

Methods and Results
—A total of 55 patients (NYHA class I to III) and 11 healthy subjects underwent cardiopulmonary exercise tests (CPET) on a treadmill. In 45 of the 55 patients (group I) and in healthy subjects (group II), pulmonary function tests, Pi
max
, and Pe
max
were measured before and 10 minutes after exercise, and oxygen kinetics were monitored throughout and during early recovery from CPET. The first degree slope of oxygen consumption (V̇
o
2
) decline during early recovery (V̇
o
2
/t-slope) and V̇
o
2
half-time (T
1/2
) were calculated. In 10 of the 55 CHF patients (group III), the measurements of Pi
max
were repeated 2, 5, and 10 minutes after CPET. A >10% reduction in Pi
max
after CPET (subgroup IA) was measured in 11 of 45 patients. In contrast, 34 of 45 CHF patients (subgroup IB) and all control subjects (group II) had Pi
max
>90% of baseline value after CPET. Subgroup IA patients had significantly lower peak V̇
o
2
(13.5±2.1 versus 17.8±5.6 mL · kg
−1
· min
−1
;
P
<0.001), lower anaerobic thresholds (10.1±2.4 versus 13.6±4.6 mL · kg
−1
· min
−1
;
P
=0.003) and lower V̇
o
2
/t-slopes (0.365±0.126 versus 0.519±0.227 L · min
−1
· min
−1
;
P
=0.008) than subgroup IB patients.

Conclusions
—The reduction of Pi
max
after exercise is associated with prolonged early recovery of oxygen kinetics, which may explain, in part, the role played by respiratory muscles in exercise intolerance in CHF patients.
Initial Experience With Larger Laser Sheaths for the Removal of Transvenous Pacemaker and Implantable Defibrillator Leads
Authors: Epstein Laurence M. , Byrd Charles L. , Wilkoff Bruce L. , Love Charles J. , Sellers T. Duncan , Hayes David L. , Reiser Christopher
Published: June 2012

Background
—In a previous randomized trial, the 12F laser sheath removed pacing leads via the implant vein more successfully than traditional mechanical tools alone. Two larger sizes of laser sheath, the 14F and 16F models, were developed to extract defibrillator leads and large-diameter pacing leads implanted for the chronic. These devices use pulsed ultraviolet laser light to core though fibrotic tissue grown over the lead body to free the lead from the vasculature. A mandatory prospective registry studied the safety and effectiveness profiles of the larger laser sheaths vis-à-vis the 12F laser sheath.

Methods and Results
—In this study, 863 patients underwent extraction of 1285 leads at 52 sites. Patients treated with the 14F device tended to have older leads than the 12F population; the 16F population, which comprised mostly defibrillator patients, were younger, had younger leads, and were more often male than the 12F population. Clinical success (extracting the entire lead or the lead body minus the distal electrode) was observed in 91% to 92% of cases for all device sizes. The overall complication rate was 3.6%, with 0.8% perioperative mortality. Incidence of complications was independent of laser sheath size.

Conclusions
—The 14F and 16F laser sheaths offer an extraction option for larger long-term transvenous pacemaker and defibrillator leads that is as safe and effective as the 12F laser sheath.
Reflex Control of Sympathetic Activity During Simulated Ventricular Tachycardia in Humans
Authors: Smith Michael L. , Joglar Jose A. , Wasmund Stephen L. , Carlson Mark D. , Welch Patrick J. , Hamdan Mohamed H. , Quan Kara , Page Richard L.
Published: June 2012

Background
—Ventricular tachyarrhythmias present a unique set of stimuli to arterial and cardiopulmonary baroreceptors by increasing cardiac filling pressures and decreasing arterial pressure. The net effect on the control of sympathetic nerve activity (SNA) in humans is unknown. The purpose of this study was to determine the relative roles of cardiopulmonary and arterial baroreceptors in controlling SNA and arterial pressure during ventricular pacing in humans.

Methods and Results
—Two experiments were performed in which SNA and hemodynamic responses to ventricular pacing were compared with nitroprusside infusion (NTP) in 12 patients and studied with and without head-up tilt or phenylephrine to normalize the stimuli to either the arterial or cardiopulmonary baroreceptors in 9 patients. In experiment 1, the slope of the relation between SNA and mean arterial pressure was greater during NTP (−4.7±1.4 U/mm Hg) than during ventricular pacing (−3.4±1.1 U/mm Hg). Comparison of NTP doses and ventricular pacing rates that produced comparable hypotension showed that SNA increased more during NTP (
P
=0.03). In experiment 2, normalization of arterial pressure during pacing resulted in SNA decreasing below baseline (
P
<0.05), whereas normalization of cardiac filling pressure resulted in a greater increase in SNA than pacing alone (212±35% versus 189±37%,
P
=0.04).

Conclusions
—These data demonstrate that in humans arterial baroreflex control predominates in mediating sympathoexcitation during ventricular tachyarrhythmias and that cardiopulmonary baroreceptors contribute significant inhibitory modulation.
In Vivo Inhibition of Elevated Myocardial β-Adrenergic Receptor Kinase Activity in Hybrid Transgenic Mice Restores Normal β-Adrenergic Signaling and Function
Authors: Akhter Shahab A. , Eckhart Andrea D. , Rockman Howard A. , Shotwell Kyle , Lefkowitz Robert J. , Koch Walter J.
Published: June 2012

Background
—The clinical syndrome of heart failure (HF) is characterized by an impaired cardiac β-adrenergic receptor (βAR) system, which is critical in the regulation of myocardial function. Expression of the βAR kinase (βARK1), which phosphorylates and uncouples βARs, is elevated in human HF; this likely contributes to the abnormal βAR responsiveness that occurs with β-agonist administration. We previously showed that transgenic mice with increased myocardial βARK1 expression had impaired cardiac function in vivo and that inhibiting endogenous βARK1 activity in the heart led to enhanced myocardial function.

Methods and Results
—We created hybrid transgenic mice with cardiac-specific concomitant overexpression of both βARK1 and an inhibitor of βARK1 activity to study the feasibility and functional consequences of the inhibition of elevated βARK1 activity similar to that present in human HF. Transgenic mice with myocardial overexpression of βARK1 (3 to 5-fold) have a blunted in vivo contractile response to isoproterenol when compared with non-transgenic control mice. In the hybrid transgenic mice, although myocardial βARK1 levels remained elevated due to transgene expression, in vitro βARK1 activity returned to control levels and the percentage of βARs in the high-affinity state increased to normal wild-type levels. Furthermore, the in vivo left ventricular contractile response to βAR stimulation was restored to normal in the hybrid double-transgenic mice.

Conclusions
—Novel hybrid transgenic mice can be created with concomitant cardiac-specific overexpression of 2 independent transgenes with opposing actions. Elevated myocardial βARK1 in transgenic mouse hearts (to levels seen in human HF) can be inhibited in vivo by a peptide that can prevent agonist-stimulated desensitization of cardiac βARs. This may represent a novel strategy to improve myocardial function in the setting of compromised heart function.
In Vivo Assessment of Stent Expansion and Recoil in Normal Porcine Coronary Arteries
Authors: Carrozza Joseph P. , Hosley Susanne E. , MD David J. Cohen , Baim Donald S.
Published: June 2012

Background
—Despite the routine use of high pressure, coronary stents generally fail to achieve a cross-sectional area (CSA) >60% to 80% of the nominal CSA of their dilating balloon. The extent to which incomplete balloon expansion and postdeflation stent recoil contribute to this failure has not been fully evaluated.

Methods and Results
—Thirty-two stents (8 Gianturco-Roubin II, 8 Palmaz-Schatz, 8 MultiLink, and 8 NIR) were deployed in nondiseased coronary arteries of 8 Yorkshire pigs. All stents were then expanded according to 1 of 3 balloon strategies: appropriately sized compliant balloons, oversized compliant balloons, or oversized noncompliant balloons. Continuous ultrasound imaging was performed during stepwise balloon inflation and deflation, with an 0.018-in imaging core positioned within the guidewire lumen of the balloon. In these normal arteries, balloon underexpansion relative to the nominal size was not observed. After balloon deflation, however, all stents showed significant recoil from their maximum inflated CSA. Recoil was significantly greater for the coil Gianturco-Roubin II stent (30% CSA) than for the 3 slotted-tube stent designs (15% to 17% CSA).

Conclusions
—In normal, compliant coronary arteries, stent recoil is the predominant mechanism by which stents fail to achieve the nominal CSA of their dilating balloon. The magnitude of this in vivo stent recoil is significantly greater than reported from bench testing and varies with stent design (coil versus slotted tube). Postdilatation strategies that result in controlled stent overexpansion are needed to overcome this recoil phenomenon and result in a final stent CSA that approximates the reference artery CSA.
Prognostication in 3-Vessel Coronary Artery Disease Based on Left Ventricular Ejection Fraction During Exercise
Authors: Supino Phyllis G. , Borer Jeffrey S. , Herrold Edmund M. , Hochreiter Clare
Published: June 2012

Background
—Previous data indicate that left ventricular ejection fraction (LVEF) provides prognostic information among patients with coronary artery disease (CAD), but the value of such testing specifically for defining benefits of coronary artery bypass grafting (CABG) may relate to severity of exercise-inducible ischemia measured noninvasively before surgery.

Methods and Results
—To determine the independent prognostic importance of preoperative ischemia severity for predicting outcomes of CABG among patients with extensive CAD, we monitored 167 stable patients with angiographically documented 3-vessel CAD (average follow-up of 9 years in event-free patients) who previously had undergone rest and exercise radionuclide cineangiography. Their course was correlated with data obtained during initial radionuclide testing, coronary arteriography, and clinical evaluation at study entry. Fifty-two patients received medical treatment only, and 115 underwent CABG (44 early [≤1 month after initial study]). Multivariate Cox model analysis indicated that change (Δ) in LVEF from rest to exercise during radionuclide study was the strongest independent predictor of major cardiac events (
P
=0.003) before surgery and also predicted magnitude of CABG benefit (
P
=0.04). Patients with ΔLVEF −8% or less derived significant survival-prolonging and event-reducing benefit from CABG performed ≤1 month after initial testing (
P
<0.02 for cardiac death and
P
=0.008 for cardiac events], early CABG versus medical-treatment-only patients); similar benefits were absent among patients with ΔLVEF more than −8%, and among those in whom CABG was deferred.

Conclusions
—Assessment of ischemia severity based on LVEF response to exercise enables effective prognostication among patients with 3-vessel CAD and defines the likelihood of life-prolonging and event-reducing benefits from CABG.
Intensity of Myocardial Expression of Inducible Nitric Oxide Synthase Influences the Clinical Course of Human Immunodeficiency Virus-Associated Cardiomyopathy
Authors: Barbaro Giuseppe , Di Lorenzo Gabriella , Soldini Maurizio , Giancaspro Giuseppe , Grisorio Benvenuto , Pellicelli Adriano , Barbarini Giorgio
Published: June 2012

Background
—Increased levels of tumor necrosis factor-α (TNF-α) and inducible nitric oxide synthase (iNOS) have been reported in patients with dilated cardiomyopathy. We investigated the myocardial expression of TNF-α and iNOS in patients with HIV-associated cardiomyopathy (HIV-DCM) compared with patients with idiopathic dilated cardiomyopathy (IDCM).

Methods and Results
—Endomyocardial biopsy specimens from 82 HIV-DCM and 80 IDCM patients were processed for determination of the immunostaining intensity of TNF-α and iNOS and for virological examination. Negative controls were derived from autopsy myocardium specimens from 32 HIV-negative patients without known heart disease. The mortality rate for congestive heart failure between groups according to the intensity of iNOS staining was also evaluated. The mean intensity of both TNF-α and iNOS staining was greater in patients with HIV-DCM (0.81 and 1.007, respectively) than in patients with IDCM (0.44 and 0.49, respectively) and controls (0.025 and 0.027, respectively). The staining intensity of both TNF-α and iNOS was inversely correlated with CD4 count. The staining intensity of iNOS was greater in HIV-DCM patients with HIV/coxsackievirus B3 (CVB3) or with HIV/cytomegalovirus coinfection than in IDCM patients showing infection with CVB3 and adenovirus alone. The staining intensity of iNOS correlated to mortality rate, because it was higher in HIV-DCM patients and, in particular, in those with an optical density unit >1.

Conclusions
—Cytokine activation seems to play a significant pathogenetic role in both HIV-DCM and IDCM. In HIV-DCM patients, the state of immunodeficiency may favor the selection of viral variants of increased pathogenicity, influencing the clinical course of cardiomyopathy by enhancement of the inflammatory process.
Effects of Chronic Heparin Administration on Coronary Vascular Adaptation to Hypertension and Ventricular Hypertrophy in Sheep
Authors: Flanagan Michael F. , Aoyagi Teruhiko , Arnold Lucy W. , Maute Christine , Fujii Alan M. , Currier Joseph , Bergau Dennis , Warren Henry B. , Rakusan Karel
Published: June 2012

Background
—Hypertension decreases myocardial perfusion capacity in adults for several reasons, including insufficient coronary angiogenesis with left ventricular (LV) hypertrophy, arteriolar hypertrophy, and altered vasomotion. Heparin influences growth factors that promote angiogenesis and vasodilation and inhibit arteriolar wall thickening.

Methods and Results
—Adult sheep were given heparin 200 U/kg body wt SC twice daily throughout 6 weeks of LV and coronary hypertension from a progressively constricted ascending aortic band (n=14). They were compared with untreated sheep with (n=13) and without (n=13) aortic stenosis. After 6 weeks, maximum myocardial perfusion was measured during adenosine infusion in the conscious state by the microsphere method. Sheep with aortic stenosis had less maximum coronary flow per gram, less conductance reserve, and thicker arteriolar walls in the LV and nonhypertrophied right ventricle. Capillary density decreased in the LV endomyocardium and remained unchanged in the right ventricle. Heparin-treated sheep had significant partial normalization of coronary conductance reserve and maximum perfusion in both ventricles and capillary density in the LV endomyocardium. Arteriolar wall thickness was unchanged. Compared with untreated sheep with aortic stenosis, in heparin-treated sheep LV FGF-2 protein increased 2-fold, whereas FGF-2 mRNA remained unchanged. VEGF mRNA and protein increased 3-fold and 1.4-fold, respectively, whereas TGF-β
1
mRNA declined 3-fold.

Conclusions
—Heparin administration during LV hypertension increases heparin-binding angiogenic factors FGF-2 and VEGF in the LV and ameliorates decreases in LV perfusion capacity and capillary density.
Staphylococcal α-Toxin Provokes Coronary Vasoconstriction and Loss in Myocardial Contractility in Perfused Rat Hearts
Authors: Sibelius Ulf , Grandel Ulrich , Buerke Michael , Mueller Doris , Kiss Ladislau , Kraemer Hans-Joachim , Braun-Dullaeus Ruediger , Haberbosch Werner , Seeger Werner , Grimminger Friedrich
Published: June 2012

Background
—Cardiac performance is severely depressed in septic shock. Endotoxin has been implicated as the causative agent in Gram-negative sepsis, but similar abnormalities are encountered in Gram-positive sepsis. We investigated the influence of the major exotoxin of
Staphylococcus aureus,
staphylococcal α-toxin, in isolated perfused rat hearts.

Methods and Results
—α-Toxin 0.25 to 1 μg/mL caused a dose-dependent increase in coronary perfusion pressure that more than doubled. In parallel, we noted a decrease in left ventricular developed pressure and the maximum rate of left ventricular pressure rise (dP/dt
max
), dropping to a minimum of <60% of control. These changes were accompanied by a liberation of thromboxane A
2
and prostacyclin into the coronary effluent. The release of creatine kinase, lactate dehydrogenase, potassium, and lactate did not surpass control heart values, and leukotrienes were also not detected. Indomethacin, acetylsalicylic acid, and the thromboxane receptor antagonist daltroban fully blocked the α-toxin–induced coronary vasoconstrictor response and the decrease in left ventricular developed pressure and dP/dt
max
, whereas the lipoxygenase inhibitor nordihydroguaiaretic acid, the platelet activating factor antagonist WEB 2086, and the α-adrenergic antagonist phentolamine were entirely ineffective. Inhibition of nitric oxide synthase even enhanced the α-toxin–induced increase in coronary perfusion pressure and the loss in myocardial performance.

Conclusions
—Purified staphylococcal α-toxin provokes coronary vasoconstriction and loss in myocardial contractility. The responses appear to be largely attributable to the generation of thromboxane and are even enhanced when the endogenous nitric oxide synthesis is blocked. Bacterial exotoxins, such as staphylococcal α-toxin, may thus be implicated in the loss of cardiac performance encountered in Gram-positive septic shock.
Influence of Postshock Epicardial Activation Patterns on Initiation of Ventricular Fibrillation by Upper Limit of Vulnerability Shocks
Authors: Chattipakorn Nipon , Rogers Jack M. , Ideker Raymond E.
Published: June 2012

Background
—Shocks of identical strength and timing sometimes induce ventricular fibrillation (VFI) and other times do not (NoVFI). To investigate this probabilistic behavior, a shock strength near the upper limit of vulnerability, ULV
50
, was delivered to yield equal numbers of VFI and NoVFI episodes.

Methods and Results
—In 6 pigs, a 504-electrode sock was pulled over the ventricles. ULV
50
was determined by scanning the T wave. S
1
pacing was from the right ventricular apex. Ten S
2
shocks of approximate ULV
50
strength were delivered at the same S
1
-S
2
coupling interval. Intercycle interval (ICI) and wave front conduction time (WCT) were determined for the first 5 postshock cycles. ICI and the WCT of cycle 1 were not different for VFI versus NoVFI episodes (
P
=0.3). Beginning at cycle 2, ICI was shorter and WCT was longer for VFI than NoVFI episodes (
P
<0.05).

Conclusions
—The first cycle after shocks of the same strength (ULV
50
) delivered at the same time has the same activation pattern regardless of shock outcome. During successive cycles, however, a progressive decrease in ICI and increase in WCT occur during VFI but not NoVFI episodes. These findings suggest shock outcome is (1) deterministic but exquisitely sensitive to differences in electrophysiological state at the time of the shock that are too small to detect or (2) probabilistic and not determined until after the first postshock cycle.
Inhibition of Neointima Formation After Experimental Coronary Artery Stenting
Authors: Alt Eckhard , Haehnel Iris , Beilharz Christine , Prietzel Klaus , Preter Daniel , Stemberger Axel , Fliedner Thilo , Erhardt Wolf , Schömig Albert
Published: June 2012

Background
—To minimize acute stent thrombosis and development of restenosis, stents coated with biodegradable and nonbiodegradable polymers have been proposed to serve as sustained-release drug carriers.

Methods and Results
—In both a sheep and a pig model, we examined the vascular response to standard and high-pressure implantation of coronary Palmaz-Schatz stents coated with a 10-μm layer of polylactic acid (MW 30 kDa) releasing recombinant polyethylene glycol (r-PEG)–hirudin and the prostacyclin analogue iloprost, both drugs with antithrombotic and potentially antiproliferative effects. Study observation time was 28 days. Between the corresponding stent groups, no differences were observed with regard to preplacement and postplacement implantation parameters. The morphometric analysis demonstrated that the coating was associated with a greater lumen diameter through a reduction in the mean restenosis area by 22.9% (
P
<0.02) in the standard-pressure model (sheep) and by 24.8% (
P
<0.02) in the overstretch pig model compared with uncoated control stents without inducing a local inflammatory response.

Conclusions
—The results from this study demonstrate beneficial effects of a polymeric stent coating with polylactic acid releasing r-PEG–hirudin and iloprost on the development of restenosis after coronary stent placement at 4 weeks, independent of the extent of vascular injury. Future studies are proposed to investigate the integration of other substances to further enhance the potential of the stent coating on reducing neointimal formation.