bluuebunny/crossref_metadata_2025 huggingface dataset:
Inducible Nitric Oxide Synthase Mediates Delayed Myocardial Protection Induced by Activation of Adenosine A
1
Receptors
Authors: Zhao Tingcun , Xi Lei , Chelliah Jeya , Levasseur Joseph E. , Kukreja Rakesh C.
Published: June 2012

Background
—The mechanism of delayed preconditioning induced by activation of adenosine A
1
receptors (A
1
ARs) is not fully understood. We determined the role of inducible nitric oxide synthase (iNOS) in mediating adenosine-induced late cardioprotection using pharmacological inhibitors and iNOS gene–knockout mice.

Methods and Results
—Adult male mice were treated with saline or an A
1
AR agonist, 2-chloro-
N
6
-cyclopentyladenosine (CCPA). Twenty-four hours later, the hearts were perfused in Langendorff mode and subjected to 30 minutes of global ischemia followed by 30 minutes of reperfusion. 8-Cyclopentyl-1,3-dipropylxanthine (DPCPX; 0.1 mg/kg IP) and
S
-methylisothiourea (SMT; 3 mg/kg IP) were used to block A
1
ARs and iNOS, respectively. Infarct size (IS) was measured by triphenyltetrazolium chloride staining, and iNOS expression was measured by Western blots. Myocardial IS was reduced from 24.0±3.2% in the saline group to 12.2±2.5% in CCPA-treated mice (
P
<0.05). The infarct-reducing effect of CCPA was abrogated by DPCPX (29.3±3.4%) and SMT (32.3±2.6%) and was absent in mice with targeted ablation of iNOS (23.9±1.6%). CCPA produced improvement in postischemic end-diastolic pressure, developed pressure, and rate-pressure product, which was also blocked by DPCPX and SMT. Increased iNOS protein expression observed in CCPA-treated hearts was diminished by DPCPX.

Conclusions
—Selective activation of A
1
ARs produces delayed cardioprotection against ischemia/reperfusion injury in the mouse. Increased iNOS expression concomitant with the lack of protective effect of A
1
AR activation in iNOS gene–knockout mice suggests a direct cause-and-effect relationship of iNOS in adenosine-induced late cardioprotection.
Left Ventricular Electromechanical Mapping to Assess Efficacy of phVEGF
165
Gene Transfer for Therapeutic Angiogenesis in Chronic Myocardial Ischemia
Authors: Vale Peter R. , Losordo Douglas W. , Milliken Charles E. , Maysky Michael , Esakof Darryl D. , Symes James F. , Isner Jeffrey M.
Published: June 2012

Background
—NOGA left ventricular (LV) electromechanical mapping (EMM) can be used to distinguish among infarcted, ischemic, and normal myocardium. We investigated the use of percutaneous LV EMM to assess the efficacy of myocardial gene transfer (GTx) of naked plasmid DNA encoding for vascular endothelial growth factor (phVEGF
165
), administered during surgery by direct myocardial injection in patients with chronic myocardial ischemia.

Methods and Results
—A total of 13 consecutive patients (8 men, mean age 60.1±2.3 years) with chronic stable angina due to angiographically documented coronary artery disease, all of whom had failed conventional therapy (drugs, PTCA, and/or CABG), were treated with direct myocardial injection of phVEGF
165
via a minithoracotomy. Foci of ischemic myocardium were identified on LV EMM by preserved viability associated with an impairment in linear local shortening. Myocardial viability, defined by mean unipolar and bipolar voltage recordings ≥5 and ≥2 mV, respectively, did not change significantly after GTx. Analysis of linear local shortening in areas of myocardial ischemia, however, disclosed significant improvement after (15.26±0.98%) versus before (9.94±1.53%,
P
=0.004) phVEGF
165
GTx. The area of ischemic myocardium was consequently reduced from 6.45±1.37 cm
2
before GTx to 0.95±0.41 cm
2
after GTx (
P
=0.001). These findings corresponded to improved perfusion scores calculated from single-photon emission CT–sestamibi myocardial perfusion scans recorded at rest (7.4±2.1 before GTx versus 4.5±1.4 after GTx,
P
=0.009) and after pharmacological stress (12.8±2.7 before GTx versus 8.5±1.7 after GTx,
P
=0.047).

Conclusions
—The results of EMM constitute objective evidence that phVEGF
165
GTx augments perfusion of ischemic myocardium. These findings, together with reduction in the size of the defects documented at rest by serial single-photon emission CT–sestamibi imaging, suggest that phVEGF
165
GTx may successfully rescue foci of hibernating myocardium.
A Ca
2+
-Dependent Transgenic Model of Cardiac Hypertrophy
Authors: Muth James N. , Bodi Ilona , Lewis William , Varadi Gyula , Schwartz Arnold
Published: June 2012

Background
—Calcium imbalances have been implicated as an underlying mechanism of human cardiac dysfunction. The voltage-dependent calcium channel plays a critical role in calcium regulation in the heart. Thus, aberrant calcium signaling arising from this channel could initiate the calcium imbalances observed in heart failure. In the present study, we used a transgenic mouse with an increased number of L-type calcium channels to identify the role of an increased, sustained ingress of calcium as an initiator of hypertrophy.

Methods and Results
—Whole-heart histology and electrophysiology in isolated cardiomyocytes identified calcium-channel overexpression in the hearts of transgenic mice. Calcium-channel density was increased in 2-, 4-, and 8-month-old transgenic cardiomyocytes. Ventricular fibrosis, damage, and remodeling became more pronounced as the transgenic mice aged. Apoptosis was also present in transgenic hearts at 8 months of age. Increased protein kinase Cα activation was elevated before the development of hypertrophy and failure.

Conclusions
—Transgenic mice developed hypertrophy and severe cardiomyopathy as a function of age, thus confirming that changes in channel density are sufficient to induce disease. The small, sustained increase in the ingress of Ca
2+
through the calcium channel elevated protein kinase Cα before the development of hypertrophy, suggesting that protein kinase Cα plays an important role in triggering hypertrophy.
Aldosterone Production Is Activated in Failing Ventricle in Humans
Authors: Mizuno Yuji , Yoshimura Michihiro , Yasue Hirofumi , Sakamoto Tomohiro , Ogawa Hisao , Kugiyama Kiyotaka , Harada Eisaku , Nakayama Masafumi , Nakamura Shota , Ito Teruhiko , Shimasaki Yukio , Saito Yoshihiko , Nakao Kazuwa
Published: June 2012

Background
—Recent reports have indicated that aldosterone is produced in extra-adrenal tissues in animals. The present study was designed to examine whether aldosterone is produced in human heart.

Methods and Results
—Plasma levels of aldosterone, BNP, and angiotensin-converting enzyme were measured in anterior interventricular vein (AIV), coronary sinus (CS), and aortic root (Ao), respectively, in 20 patients with left ventricular systolic dysfunction (LVSD), 25 patients with LV diastolic dysfunction (LVDD), and 23 control subjects. Aldosterone levels were significantly higher in AIV and CS than Ao in LVSD (98±10 versus 72±9 pg/mL,
P
<0.001, and 97±11 versus 72±9 pg/mL,
P
<0.001, respectively) and LVDD (87±10 versus 71±9 pg/mL,
P
<0.01, and 84±10 versus 71±9 pg/mL,
P
<0.01, respectively) groups, but no differences were observed in levels for these sites in the control group. Levels of ACE activity and BNP also were higher in AIV than Ao in both LV dysfunction groups. The difference in aldosterone levels between AIV and Ao and those in BNP and angiotensin-converting enzyme had a significant positive correlation with LVEDP and a significant negative correlation with LV ejection fraction in the LVSD group.

Conclusions
—Production of aldosterone, angiotensin-converting enzyme, and BNP are activated in failing human ventricle in proportion to severity.
Effects of Aging and Cardiac Denervation on Heart Rate Variability During Sleep
Authors: Crasset Vincent , Mezzetti Silvia , Antoine Martine , Linkowski Paul , Degaute Jean Paul , van de Borne Philippe
Published: June 2012

Background
—Cardiac vagal predominance increases the RR interval and RR high-frequency (HF) variability during non–rapid eye movement (non-REM) sleep (stages I through IV) in young subjects. Aging suppresses deep sleep, but effects of age-related changes in sleep architecture on RR are unknown. Whether mechanical effects of changes in the breathing pattern on the sinus node during sleep affect RR variability is unclear.

Methods and Results
—Polygraphic sleep recordings and RR and RR spectral profiles were determined in 8 young (22.5±3.3 years) and 8 older (55.0±7.3 years) healthy volunteers. HF oscillations in RR of 8 cardiac-denervated heart transplant recipients determined mechanical effects of respiration on the sinoatrial node during sleep. Transition from wakefulness to non-REM sleep increased the RR interval in young and older subjects and increased the HF variability of RR in the young (
P
<0.05) but not in the older subjects. Older subjects disclosed a faster RR (
P
<0.01) and a lower HF variability (
P
<0.05) during non-REM sleep than the young subjects. Aging did not affect light and REM sleep but decreased deep sleep (stage IV) from 39±23 to 6±6 minutes (
P
<0.001). Reduction in sleep stage IV with aging blunted the increase in RR and in RR HF variability during non-REM sleep (
r
>0.55,
P
<0.05). Transition from wakefulness to non-REM sleep doubled the markedly reduced HF variability of RR in the heart transplant recipients (
P
<0.05).

Conclusions
—Disappearance of deep sleep with aging impairs nocturnal increase in cardiac vagal activity. Mechanical effects of changes in breathing pattern during sleep favor increases in HF oscillations of the RR interval during non-REM sleep.
Genotype-Phenotype Correlation in the Long-QT Syndrome
Authors: Schwartz Peter J. , Priori Silvia G. , Spazzolini Carla , Moss Arthur J. , Vincent G. Michael , Napolitano Carlo , Denjoy Isabelle , Guicheney Pascale , Breithardt Günter , Keating Mark T. , Towbin Jeffrey A. , Beggs Alan H. , Brink Paul , Wilde Arthur A. M. , Toivonen Lauri , Zareba Wojciech , Robinson Jennifer L. , Timothy Katherine W. , Corfield Valerie , Wattanasirichaigoon Duangrurdee , Corbett Clive , Haverkamp Wilhelm , Schulze-Bahr Eric , Lehmann Michael H. , Schwartz Ketty , Coumel Philippe , Bloise Raffaella
Published: June 2012

Background
—The congenital long-QT syndrome (LQTS) is caused by mutations on several genes, all of which encode cardiac ion channels. The progressive understanding of the electrophysiological consequences of these mutations opens unforeseen possibilities for genotype-phenotype correlation studies. Preliminary observations suggested that the conditions (“triggers”) associated with cardiac events may in large part be gene specific.

Methods and Results
—We identified 670 LQTS patients of known genotype (LQT1, n=371; LQT2, n=234; LQT3, n=65) who had symptoms (syncope, cardiac arrest, sudden death) and examined whether 3 specific triggers (exercise, emotion, and sleep/rest without arousal) differed according to genotype. LQT1 patients experienced the majority of their events (62%) during exercise, and only 3% occurred during rest/sleep. These percentages were almost reversed among LQT2 and LQT3 patients, who were less likely to have events during exercise (13%) and more likely to have events during rest/sleep (29% and 39%). Lethal and nonlethal events followed the same pattern. Corrected QT interval did not differ among LQT1, LQT2, and LQT3 patients (498, 497, and 506 ms, respectively). The percent of patients who were free of recurrence with β-blocker therapy was higher and the death rate was lower among LQT1 patients (81% and 4%, respectively) than among LQT2 (59% and 4%, respectively) and LQT3 (50% and 17%, respectively) patients.

Conclusions
—Life-threatening arrhythmias in LQTS patients tend to occur under specific circumstances in a gene-specific manner. These data allow new insights into the mechanisms that relate the electrophysiological consequences of mutations on specific genes to clinical manifestations and offer the possibility of complementing traditional therapy with gene-specific approaches.
Catheter Ablation of Typical Atrial Flutter
Authors: Anselme Frédéric , Savouré Arnaud , Cribier Alain , Saoudi Nadir
Published: June 2012

Background
—Complete bidirectional isthmus conduction block (CBIB) was initially assessed by sequential detailed activation mapping at both sides of the ablation line during proximal coronary sinus and anteroinferior right atrium pacing. Mapping only the ablation line (“on-site” atrial potential analysis) was recently reported as a means of CBIB identification. The study was designed to compare these 2 techniques prospectively regarding the diagnosis of CBIB.

Methods and Results
—In 76 consecutive patients (mean age, 63.4±10.5 years), typical atrial flutter ablation was performed using either the activation mapping technique (group I) or on-site atrial potential analysis (group II). Criteria for CBIB using on-site atrial potential analysis was the recording of parallel, widely spaced double atrial potentials along the ablation line. The CBIB criterion was retrospectively searched using the alternative technique at the end of the procedure. In successful patients, the mean radiofrequency delivery duration was longer in group II (845±776 versus 534±363 s;
P
=0.03). On-site, clear-cut, widely spaced double atrial potentials and activation mapping suggesting CBIB were concomitantly observed in only 47 patients (54%), and ambiguous/atypical double potentials were recorded in 31 patients (39%).

Conclusions
—Although feasible, the on-site atrial potential analysis seemed to be inferior to the classic activation mapping technique, mainly because of the ambiguity of electrogram interpretation along the ablation line. However, when combined with the activation mapping technique, it provided additional information regarding isthmus conduction properties in some cases. Therefore, optimally, both methods should be used concomitantly.
Regression of Left Ventricular Hypertrophy After Nonsurgical Septal Reduction Therapy for Hypertrophic Obstructive Cardiomyopathy
Authors: Mazur Wojciech , Nagueh Sherif F. , Lakkis Nasser M. , Middleton Katherine J. , Killip Donna , Roberts Robert , Spencer William H.
Published: June 2012

Background
—Hypertrophic obstructive cardiomyopathy (HOCM) is characterized by left ventricular hypertrophy (LVH) in the absence of increased external load. Recently, nonsurgical septal reduction therapy (NSRT) with intracoronary ethanol has been introduced to treat severely symptomatic patients with outflow tract obstruction. Its long-term effects on LV mass, however, are unknown.

Methods and Results
—The LV size, function, and outflow tract gradient of 26 HOCM patients (53±15 years old) who underwent NSRT were assessed by echocardiography at baseline and 1 and 2 years after the procedure. LVH was evaluated by wall thickness of individual myocardial segments, planimetered myocardial area, and mass. The outflow gradient decreased from 36±6 mm Hg before NSRT to 0±3 mm Hg at 2 years (
P
<0.001), with patients experiencing symptomatic improvement (
P
<0.05). LV end-diastolic and end-systolic dimensions increased significantly at both 1 and 2 years (
P
<0.001). All parameters of LVH showed evidence of regression. LV mass decreased (301±78 g at baseline, 223±5 g at 1 year, and 190±58 g at 2 years;
P
<0.01), with the 2-year reduction in mass related to infarct size and the acute reduction in outflow tract gradient (
r
=0.48,
P
<0.05 and
r
=0.63,
P
<0.01, respectively).

Conclusions
—NSRT results in LV remodeling that is characterized by an increase in LV size and a decrease in the extent of LVH.
Bone Formation and Inflammation in Cardiac Valves
Authors: Mohler Emile R. , Gannon Francis , Reynolds Carol , Zimmerman Robert , Keane Martin G. , Kaplan Frederick S.
Published: June 2012

Background
—For nearly a century, the mechanical failure of calcified heart valves was attributed to a passive degenerative process. Recently, several case reports described bone formation in surgically excised heart valves and suggested an unexpected process of tissue repair.

Methods and Results
—We studied the prevalence and pathology of heterotopic ossification in 347 surgically excised heart valves (256 aortic, 91 mitral) in 324 consecutive patients (182 men, 142 women; mean age 68 years) who underwent cardiac valve replacement surgery between 1994 and 1998. The valves were examined microscopically to determine the prevalence and features of bone formation and remodeling. Two hundred eighty-eight valves (83%) had dystrophic calcification. Mature lamellar bone with hematopoietic elements and active bone remodeling were present in 36 valves (13%) with dystrophic calcification. Endochondral bone formation, similar to that seen in normal fracture repair, was identified in 4 valves. Microfractures were present in 92% of all valves with ossification. Neoangiogenesis was found in all valves with ossification. Bone morphogenetic proteins 2 and 4 (BMP 2/4), potent osteogenic morphogens, were expressed by myofibroblasts and preosteoblasts in areas adjacent to B- and T-lymphocyte infiltration in valves where ossification was identified. Mast cells were present in calcified and ossified valves and were especially prominent in atheromatous regions.

Conclusions
—Heterotopic ossification consisting of mature lamellar bone formation and active bone remodeling is a relatively common and unexpected finding in end-stage valvular heart disease and may be associated with repair of pathological microfractures in calcified cardiac valves.
Prognosis After Aortic Valve Replacement With a Bioprosthesis
Authors: Puvimanasinghe J. P. A. , Steyerberg E. W. , Takkenberg J. J. M. , Eijkemans M. J. C. , van Herwerden L. A , Bogers A. J. J. C. , Habbema J. D. F.
Published: June 2012

Background
—Bioprostheses are widely used as an aortic valve substitute, but knowledge about prognosis is still incomplete. The purpose of this study was to provide insight into the age-related life expectancy and actual risks of reoperation and valve-related events of patients after aortic valve replacement with a porcine bioprosthesis.

Methods and Results
—We conducted a meta-analysis of 9 selected reports on stented porcine bioprostheses, including 5837 patients with a total follow-up of 31 874 patient-years. The annual rates of valve thrombosis, thromboembolism, hemorrhage, and nonstructural dysfunction were 0.03%, 0.87%, 0.38%, and 0.38%, respectively. The annual rate of endocarditis was estimated at 0.68% for >6 months of implantation and was 5 times as high during the first 6 months. Structural valve deterioration was described with a Weibull model that incorporated lower risks for older patients. These estimates were used to parameterize, calibrate, and validate a mathematical microsimulation model. The model was used to predict life expectancy and actual risks of reoperation and valve-related events after implantation for patients of different ages. For a 65-year-old male, these figures were 11.3 years, 28%, and 47%, respectively.

Conclusions
—The combination of meta-analysis with microsimulation enabled a detailed insight into the prognosis after aortic valve replacement with a bioprosthesis for patients of different ages. This information will be useful for patient counseling and clinical decision making. It also could serve as a baseline for the evaluation of newer valve types.
High-Energy Phosphate Metabolism and Creatine Kinase in Failing Hearts
Authors: Ye Yun , Gong Guangrong , Ochiai Koichi , Liu Jingbo , Zhang Jianyi
Published: June 2012

Background
—This study aimed to create a pig model of heart failure secondary to severe aortic stenosis and to examine the relationship between the alterations in myocardial high-energy phosphate (HEP) metabolism and protein expression of creatine kinase (CK) isoforms.

Methods and Results
—Sixteen pigs with left ventricular hypertrophy (LVH) secondary to ascending aortic banding and 10 normal pigs (N) were studied. Myocardial protein levels of CK isoforms (Western blot), HEP levels, and CK kinetics (
31
P MR spectroscopy) were measured under basal conditions. Nine of the 16 animals with LVH developed congestive heart failure (CHF), as evidenced by ascites (100 to 2000 mL). LV weight/body weight ratio (g/kg) was 2.18±0.15 in N hearts, 3.04±0.14 in hearts with LVH (
P
<0.01), and 4.23±0.36 in hearts with CHF (
P
<0.01 versus LVH). Right ventricle weight/body weight ratio and LV end-diastolic pressure were significantly higher in hearts with CHF (each
P
<0.01 versus N or LVH). Myocardial phosphocreatine/ATP ratios and the CK forward flux rates were decreased in LVH hearts, most severely in hearts with CHF. CK-M/β-actin ratios were 2.21±12 (N), 1.69±0.15 (LVH), and 1.39±0.27 (CHF,
P
<0.05 versus N). CK-mitochondria (CK-Mt)/β-actin ratios were 1.40±0.09 (N), 1.24±0.09 (LVH), and 1.02±0.08 (CHF,
P
<0.05 versus N or LVH). The severity of the reduction of CK flux rate was linearly related to the severity of the decrease of CK-Mt/β-actin (
r
=0.68,
P
<0.01).

Conclusions
—In this new model of heart failure/hypertrophy, the abnormal myocardial HEP metabolism is related to the decreased CK-Mt protein level, which in turn is related to the severity of the hypertrophy.
Direct Inhibition of Expressed Cardiac L- and T-Type Calcium Channels by IgG From Mothers Whose Children Have Congenital Heart Block
Authors: Xiao Guang-Qian , Hu Keli , Boutjdir Mohamed
Published: June 2012

Background
—Congenital heart block (CHB) is a disease that affects the offspring of mothers with autoimmune diseases. We recently reported that maternal sera containing antibodies against SSA/Ro and SSB/La ribonucleoproteins (positive IgG) inhibited L-type Ca current in isolated cardiac myocytes and induced sinus bradycardia in a murine model of CHB. The direct interaction of positive IgG with L-type Ca channel proteins and the possible inhibition of T-type Ca current that could account for the sinus bradycardia remain unknown.

Methods and Results
—The 2-electrode voltage-clamp technique was used to record currents via L-type (
I
Ba
-α
1C
or
I
Ba
-α
1C
+β
2a
+α
2
/δ) and T-type (
I
Ba
-α
1H
) Ca channels, Na channels (
I
Na
-hH1), and K channels (
I
Ks
-minK+KvLQT1) expressed in
Xenopus
oocytes. Positive IgG (350 μg/mL) inhibited
I
Ba
-α
1C
by 50.6±4.7% (
P
<0.01) and
I
Ba
-α
1C
+β
2a
+α
2
/δ by 50.9±4.2% (
P
<0.01);
I
Ba
-α
1H
was reduced by 18.9±1.0% (
P
<0.01). Immunoblot data show cross-reactivity of positive IgG with α
1C
subunit. Pretreatment of oocytes with atropine (1 μmol/L) or acetylcholine (10 μmol/L) did not affect the inhibitory effect of IgG on
I
Ba
-α
1C
and
I
Ba
-α
1C
+β
2a
+α
2
/δ (
P
<0.05). Positive IgG had no effect, however, on either
I
Na
-hH1 or
I
Ks
-minK+KvLQT1.

Conclusions
—Positive IgG inhibited expressed L-type
I
Ba
and cross-reacted with the α
1C
subunit in
Xenopus
oocytes, providing strong evidence that maternal antibodies interact directly with the pore-forming α
1
-subunit of Ca channels. In addition, we show for the first time that positive IgG also inhibited T-type
I
Ba
but not
I
Na
-hH1 or
I
Ks
-minK+KvLQT1. This could provide, in part, the ionic basis of sinus bradycardia reported in animal models of CHB and clinically in humans.
Regional Wall Motion and Abnormalities of Electrical Depolarization and Repolarization in Patients After Surgical Repair of Tetralogy of Fallot
Authors: Vogel Michael , Sponring Julia , Cullen Seamus , Deanfield John E. , Redington Andrew N.
Published: June 2012

Background
—Abnormal depolarization-repolarization in patients with repaired tetralogy of Fallot (TOF) is a risk factor for malignant ventricular tachycardia and sudden death. It is unclear whether ECG abnormalities are associated with abnormal regional right ventricular (RV) function.

Methods and Results
—Seventy-four patients (37 patients <18 and 37 >18 years old) who had had TOF repair at 4.0 years old (0.1 to 47 years old) were examined when they were 18.7 years old (1.7 to 61.1 years old), as were 112 control subjects with normal hearts. Regional function was evaluated with tissue Doppler imaging of the RV and left ventricular (LV) free wall and the septum. Myocardial velocities were sampled continuously from base to apex. Synchronous ECG was analyzed for QRS, QT, and JT duration and QRS, QT, and JT dispersion. All 74 TOF patients had normal LV myocardial velocities. Forty-eight patients (24 patients <18 and 24 >18 years old) had reversed myocardial velocities in diastole in the RV free wall, which were associated with reversed systolic myocardial velocities in 22 and additional reverse diastolic myocardial velocities in the septum in 19. Those 48 patients had a longer QRS duration (151±31 versus 124±27 ms) and greater QRS (47±18 versus 29±12 ms), QT (73±27 versus 52±22 ms), and JT (96±31 versus 67±35 ms) dispersion. Compared with normal control subjects, all 74 TOF patients had decreased systolic and diastolic myocardial velocities and a longer isovolumic relaxation time.

Conclusions
—RV wall-motion abnormalities are a common finding late after TOF repair and are associated with repolarization-depolarization abnormalities. These data further underscore a likely mechanoelectrical interaction as an important part of the pathogenesis of RV disease in these patients.
Aspirin (5 mmol/L) Inhibits Leukocyte Attack and Triggered Reactive Cell Proliferation in a 3D Human Coronary In Vitro Model
Authors: Voisard Rainer , Fischer Robert , Oßwald Markus , Voglic Sami , Baur Regine , Susa Milorat , Koenig Wolfgang , Hombach Vinzenz
Published: June 2012

Background
—Leukocyte attack (LA) and the triggered reactive proliferation of smooth muscle cells (SMCs) are key events for the development of early atherosclerosis and restenosis. In the present study, we used a 3D human coronary in vitro model of LA (3DLA model) to examine the effect of high-dose aspirin on the adhesion and chemotaxis of leukocytes and the reactive proliferative response of SMCs.

Methods and Results
—For dose-finding, the effect of aspirin (1, 2, 5, and 10 mmol/L) on the tumor necrosis factor-α–induced upregulation of intercellular adhesion molecule-1 was analyzed in monocultures of human coronary endothelial cells (HCAEC) and the SMCs of the human coronary media (HCMSMC). In cytoflow and Northern blot experiments, the expression of intercellular adhesion molecule-1 was slightly reduced after incubation with 5 mmol/L aspirin, and strong inhibition was found after incubation with 10 mmol/L. In 3DLA models, HCAECs and HCMSMCs were cultured on both sides of a porous filter. For LA, human monocytes or CD4
+
lymphocytes were seeded on the HCAEC side of the 3DLA unit. A dose of 5 mmol/L aspirin inhibited the adherence of monocytes or CD4
+
lymphocytes by 50% (
P
<0.01) and the chemotaxis of monocytes by 90% (
P
<0.01). The reactive proliferative response of cocultured HCMSMCs after LA, as measured by the uptake of bromodeoxyuridine, was significantly reduced by 83% after selective monocyte attack (
P
<0.001) and by 42% after selective CD4
+
lymphocyte attack (
P
<0.05).

Conclusions
—A local concentration of 5 mmol/L aspirin should be accepted as the lowest rational concentration for the beneficial in vitro effects of high-dose aspirin to be reproduced in clinical studies.
Abnormalities of Hemorheological, Endothelial, and Platelet Function in Patients With Chronic Heart Failure in Sinus Rhythm
Authors: Gibbs Christopher R. , Blann Andrew D. , Watson Robert D. S. , Lip Gregory Y. H.
Published: June 2012

Background
—To investigate the hypothesis that abnormalities of hemorheological (fibrinogen, plasma viscosity), endothelial (von Willebrand factor [vWF]), and platelet (soluble P-selectin) function would exist in patients with chronic heart failure (CHF) who are in sinus rhythm, we conducted a cross-sectional study of 120 patients with stable CHF (median ejection fraction 30%). We also hypothesized that ACE inhibitors and β-blockers would beneficially affect the measured indices.

Methods and Results
—In the cross-sectional analysis, plasma viscosity (
P
=0.001), fibrinogen (
P
=0.02), vWF (
P
<0.0001), and soluble P-selectin (
P
<0.001) levels were elevated in patients with CHF compared with healthy controls. Women demonstrated greater abnormalities of hemorheological indices and vWF than males (all
P
<0.05). Plasma viscosity (
P
=0.009) and fibrinogen (
P
=0.0014) levels were higher in patients with more severe symptoms (New York Heart Association [NYHA] class III–IV), but there was no relationship with left ventricular ejection fraction. When ACE inhibitors were introduced, there was a reduction in fibrinogen (repeated-measures ANOVA,
P
=0.016) and vWF (
P
=0.006) levels compared with baseline. There were no significant changes in hemorheological, endothelial, or platelet markers after the introduction of β-blocker therapy, apart from a rise in mean platelet count (
P
<0.001).

Conclusions
—Abnormal levels of soluble P-selectin, vWF, and hemorheological indices may contribute to a hypercoagulable state in CHF, especially in female patients and in those with more severe NYHA class. Treatment with ACE inhibitors improved the prothrombotic state in CHF, whereas the addition of β-blockers did not. These positive effects of ACE inhibitors may offer an explanation for the observed reduction in ischemic events in clinical trials.
Bedside Multimarker Testing for Risk Stratification in Chest Pain Units
Authors: Newby L. Kristin , Storrow Alan B. , Gibler W. Brian , Garvey J. Lee , Tucker John F. , Kaplan Andrew L. , Schreiber Donald H. , Tuttle Robert H. , McNulty Steven E. , Ohman E. Magnus
Published: June 2012

Background
—Earlier, rapid evaluation in chest pain units may make patient care more efficient. A multimarker strategy (MMS) testing for several markers of myocardial necrosis with different time-to-positivity profiles also may offer clinical advantages.

Methods and Results
—We prospectively compared bedside quantitative multimarker testing versus local laboratory results (LL) in 1005 patients in 6 chest pain units. Myoglobin, creatine kinase-MB, and troponin I were measured at 0, 3, 6, 9 to 12, and 16 to 24 hours after admission. Two MMS were defined: MMS-1 (all 3 markers) and MMS-2 (creatine kinase-MB and troponin I only). The primary assessment was to relate marker status with 30-day death or infarction. More patients were positive by 24 hours with MMS than with LL (MMS-1, 23.9%; MMS-2, 18.8%; LL, 8.8%;
P
=0.001, all comparisons), and they became positive sooner with MMS-1 (2.5 hours,
P
=0.023 versus LL) versus MMS-2 (2.8 hours,
P
=0.026 versus LL) or LL (3.4 hours). The relation between baseline MMS status and 30-day death or infarction was stronger (MMS-1: positive, 18.8% event rate versus negative, 3.0%,
P
=0.001; MMS-2: 21.9% versus 3.2%,
P
=0.001) than that for LL (13.6% versus 5.5%,
P
=0.038). MMS-1 discriminated 30-day death better (positive, 2.0% versus negative, 0.0%,
P
=0.007) than MMS-2 (positive, 1.8% versus negative, 0.2%;
P
=0.055) or LL (positive, 0.0% versus negative, 0.5%;
P
=1.000).

Conclusions
—Rapid multimarker analysis identifies positive patients earlier and provides better risk stratification for mortality than a local laboratory-based, single-marker approach.
Deterioration of Left Ventricular Chamber Performance After Bed Rest
Authors: Perhonen Merja A. , Zuckerman Julie H. , Levine Benjamin D.
Published: June 2012

Background
—Orthostatic intolerance after bed rest is characterized by hypovolemia and an excessive reduction in stroke volume (SV) in the upright position. We studied whether the reduction in SV is due to a specific adaptation of the heart to head-down tilt bed rest (HDTBR) or acute hypovolemia alone.

Methods and Results
—We constructed left ventricular (LV) pressure-volume curves from pulmonary capillary wedge pressure and LV end-diastolic volume and Starling curves from pulmonary capillary wedge pressure and SV during lower body negative pressure and saline loading in 7 men (25±2 years) before and after 2 weeks of −6° HDTBR and after the acute administration of intravenous furosemide. Both HDTBR and hypovolemia led to a similar reduction in plasma volume. However, baseline LV end-diastolic volume decreased by 20±4% after HDTBR and by 7±2% after hypovolemia (interaction
P
<0.001). Moreover, SV was reduced more and the Starling curve was steeper during orthostatic stress after HDTBR than after hypovolemia. The pressure-volume curve showed a leftward shift and the equilibrium volume of the left ventricle was decreased after HDTBR; however, after hypovolemia alone, the curve was identical, with no change in equilibrium volume. Lower body negative pressure tolerance was reduced after both conditions; it decreased by 27±7% (
P
<0.05) after HDTBR and by 18±8% (
P
<0.05) after hypovolemia.

Conclusions
—Chronic HDTBR leads to ventricular remodeling, which is not seen with equivalent degrees of acute hypovolemia. This remodeling leads to a greater decrease in SV during orthostatic stress after bed rest than hypovolemia alone, potentially contributing to orthostatic intolerance.
Saline-Cooled Versus Standard Radiofrequency Catheter Ablation for Infarct-Related Ventricular Tachycardias
Authors: Soejima Kyoko , Delacretaz Etienne , Suzuki Makoto , Brunckhorst Corinna B. , Maisel William H. , Friedman Peter L. , Stevenson William G.
Published: June 2012

Background
—Saline cooling of the electrode during radiofrequency (RF) ablation increases lesion size in animal models. If cooled RF also increases lesion size in human infarcts, it should facilitate the termination of ventricular tachycardia (VT).

Methods and Results
—In 66 patients with VT due to prior infarction, 366 ablation sites, which were classified by entrainment and isolated potentials followed by ablation during VT with either standard RF energy (247 sites) or cooled RF (119 sites), were retrospectively reviewed to compare the efficacy for terminating VT. RF energy was applied at 259 isthmus sites, 62 bystander sites, 28 inner loop sites, and 17 outer loop sites. Compared with standard RF, cooled RF terminated VT more frequently at isthmus sites where an isolated potential was present (89% versus 54%,
P
=0.003), isthmus sites without an isolated potential (36% versus 21%,
P
=0.04), and at inner loop sites (60% versus 22%,
P
=0.04). Termination rates were similarly low for cooled and standard RF at bystander sites (14% versus 9%,
P
=0.56) and outer loop sites (13% versus 11%,
P
=0.93).

Conclusions
—Greater efficacy of cooled RF for terminating VT is consistent with the production of a larger lesion in human infarctions, which should facilitate successful ablation.
Serum Vitamin C Concentration Is Low in Peripheral Arterial Disease and Is Associated With Inflammation and Severity of Atherosclerosis
Authors: Langlois Michel , Duprez Daniel , Delanghe Joris , De Buyzere Marc , Clement Denis L.
Published: June 2012

Background
—Peripheral arterial disease (PAD) is a severe atherosclerotic condition frequently accompanied by inflammation and oxidative stress. We hypothesized that vitamin C antioxidant levels might be low in PAD and are related to inflammation and disease severity.

Methods and Results
—We investigated vitamin C (
l
-ascorbic acid) levels in 85 PAD patients, 106 hypertensives without PAD, and 113 healthy subjects. Serum
l
-ascorbic acid concentrations were low among PAD patients (median, 27.8 μmol/L) despite comparable smoking status and dietary intake with the other groups (
P
<0.0001). Subclinical vitamin C deficiency (<11.4 μmol/L), confirmed by low serum alkaline phosphatase activity, was found in 14% of the PAD patients but not in the other groups. Serum C-reactive protein (CRP) concentrations were significantly higher in PAD patients (
P
<0.0001) and negatively correlated with
l
-ascorbic acid levels (
r
=−0.742,
P
<0.0001). In stepwise multivariate analysis, low
l
-ascorbic acid concentration in PAD patients was associated with high CRP level (
P
=0.0001), smoking (
P
=0.0009), and shorter absolute claudication distance on a standardized graded treadmill test (
P
=0.029).

Conclusions
—Vitamin C concentrations are lower in intermittent claudicant patients in association with higher CRP levels and severity of PAD. Future studies attempting to relate vitamin C levels to disease occurrence should include in their analysis an inflammatory marker such as CRP.
Cardiovascular Status of Carriers of the Apolipoprotein A-I
Milano
Mutant
Authors: Sirtori Cesare R. , Calabresi Laura , Franceschini Guido , Baldassarre Damiano , Amato Mauro , Johansson Jan , Salvetti Massimo , Monteduro Cristina , Zulli Roberto , Muiesan Maria L. , Agabiti-Rosei Enrico
Published: June 2012

Background
—Carriers of the apolipoprotein A-I
Milano
(apoA-I
M
) mutant present with very low plasma HDL cholesterol and moderate hypertriglyceridemia, apparently not leading to premature coronary heart disease. The objective of this study was to establish whether this high-risk lipid/lipoprotein profile is associated with structural changes in the carotid arteries and heart, indicative of preclinical atherosclerosis.

Methods and Results
—Twenty-one A-I
M
carriers were compared with age- and sex-matched control subjects from the same kindred and with 2 series of matched subjects with primary hypoalphalipoproteinemia (HA). Structural changes in the carotid arteries were defined as the intima-media thickness (IMT) measured by B-mode ultrasound. HA subjects, both recruited among patients attending our Lipid Clinic and blood donors, showed significant thickening of the carotids (average IMT, 0.86±0.25 and 0.88±0.29 mm, respectively) compared with control subjects (average IMT, 0.64±0.12 mm); the apoA-I
M
carriers instead showed normal arterial thickness (average IMT, 0.63±0.10 mm). Moreover, a significantly higher prevalence of atherosclerotic plaques was found in patients and blood donors with HA (both 57%) compared with apoA-I
M
carriers (33%) and control subjects (21%). Echocardiographic findings and maximal treadmill ECG did not differ significantly between apoA-I
M
carriers and control subjects, apart from a slight increase in left ventricular end-diastolic dimension in the carriers.

Conclusions
—Despite severe HA, carriers of the apoA-I
M
mutant do not show structural changes in the arteries and heart, in contrast to HA subjects, who are characterized by a marked increase in carotid IMT and increased prevalence of atherosclerotic plaques.
Elevated Levels of Oxidized Low Density Lipoprotein Show a Positive Relationship With the Severity of Acute Coronary Syndromes
Authors: Ehara Shoichi , Ueda Makiko , Naruko Takahiko , Haze Kazuo , Itoh Akira , Otsuka Masato , Komatsu Ryushi , Matsuo Toshihiko , Itabe Hiroyuki , Takano Tatsuya , Tsukamoto Yoshiaki , Yoshiyama Minoru , Takeuchi Kazuhide , Yoshikawa Junichi , Becker Anton E.
Published: June 2012

Background
—There is accumulating data that acute coronary syndromes relate to recent onset activation of inflammation affecting atherosclerotic plaques. Increased blood levels of oxidized low density lipoprotein (ox-LDL) could play a role in these circumstances.

Methods and Results
—Ox-LDL levels were measured in 135 patients with acute myocardial infarction (AMI; n=45), unstable angina pectoris (UAP; n=45), and stable angina pectoris (SAP; n=45) and in 46 control subjects using a sandwich ELISA method. In addition, 33 atherectomy specimens obtained from a different cohort of patients with SAP (n=10) and UAP (n=23) were studied immunohistochemically for ox-LDL. In AMI patients, ox-LDL levels were significantly higher than in patients with UAP (
P
<0.0005) or SAP (
P
<0.0001) or in controls (
P
<0.0001) (AMI, 1.95±1.42 ng/5 μg LDL protein; UAP, 1.19±0.74 ng/5 μg LDL protein; SAP, 0.89±0.48 ng/5 μg LDL protein; control, 0.58±0.23 ng/5 μg LDL protein). Serum levels of total, HDL, and LDL cholesterol did not differ among these patient groups. In the atherectomy specimens, the surface area containing ox-LDL–positive macrophages was significantly higher in patients with UAP than in those with SAP (
P
<0.0001).

Conclusions
—This study demonstrates that ox-LDL levels show a significant positive correlation with the severity of acute coronary syndromes and that the more severe lesions also contain a significantly higher percentage of ox-LDL–positive macrophages. These observations suggest that increased levels of ox-LDL relate to plaque instability in human coronary atherosclerotic lesions.
Relationship of Heart Rate Variability to Parasympathetic Effect
Authors: Goldberger Jeffrey J. , Challapalli Sridevi , Tung Roderick , Parker Michele A. , Kadish Alan H.
Published: June 2012

Background
—Baroreflex-mediated parasympathetic stimulation has variable effects on heart rate variability (HRV). We postulated that a quadratic function would describe the relationship between HRV and parasympathetic effect better than a linear function.

Methods and Results
—Twenty-nine normal volunteers (15 women; mean age 39±12 years) were studied after β-adrenergic blockade with intravenous propranolol. Five-minute ECG recordings were made during graded infusions of phenylephrine and nitroprusside to achieve baroreflex-mediated increases and decreases in parasympathetic effect, respectively. Time- and frequency-domain measures of HRV were calculated from the R-R interval tachograms. The R-R interval and the vagal-sympathetic effect (VSE=R-R interval/intrinsic R-R interval) were used as indices of parasympathetic effect. The data were fit to both quadratic and linear models. In each case, the quadratic model (with a negative coefficient for the squared term) was superior to the linear model. There was some evidence that age influenced the responsiveness of the HRV parameters with changing parasympathetic effect, although the regression analysis was significant only in the models for MSSD (
P
<0.03) and pNN50 (
P
<0.001).

Conclusions
—The relationship between HRV and parasympathetic effect is best described by a function in which there is an ascending limb where HRV increases as parasympathetic effect increases until it reaches a plateau level; HRV then decreases as parasympathetic effect increases. Because there is marked interindividual variation in this relationship, differences in HRV between individuals may reflect differences in this relationship and/or differences in autonomic effects.
Cholesterol Sulfate
Authors: Merten Michael , Dong Jing Fei , Lopez Jose A. , Thiagarajan Perumal
Published: June 2012

Background
—Cholesterol 3-sulfate is present on a variety of cells and in human LDL, and it has been found in atherosclerotic lesions of human aorta. Its precise biological role has not yet been described.

Methods and Results
—In this study, we investigated the interaction of platelets with cholesterol sulfate. Platelets adhered in a concentration-dependent and saturable manner to cholesterol sulfate but did not adhere to cholesterol, cholesterol acetate, estrone sulfate, or dehydroepiandrosterone sulfate, suggesting that the specificity of this interaction is determined not only by the cholesterol moiety but also by the sulfate group. This adhesion did not increase after platelet activation, and it was not cation-dependent. Soluble cholesterol sulfate inhibited adhesion in a concentration-dependent manner. However, antibodies against glycoprotein Ib, glycoprotein IIb/IIIa, CD36, P-selectin, von Willebrand factor, or thrombospondin had no significant effect on platelet adhesion to cholesterol sulfate. Perfusion of whole blood in a parallel-plate flow chamber resulted in the rapid and progressive adhesion of platelets to cholesterol sulfate but not to cholesterol acetate or estrone sulfate.

Conclusions
—Cholesterol sulfate supports platelet adhesion and may be one of the factors determining the prothrombotic potential of atherosclerotic lesions.
Sex Differences in Neurological Outcomes and Mortality After Cardiac Surgery
Authors: Hogue Charles W. , Barzilai Benico , Pieper Karen S. , Coombs Laura P. , DeLong Elizabeth R. , Kouchoukos Nicholas T. , Dávila-Román Victor G.
Published: June 2012

Background
—The purpose of this study was to evaluate whether women undergoing cardiac surgery are more likely to suffer neurological complications than men and whether these complications could explain, at least in part, their higher perioperative mortality.

Methods and Results
—The Society of Thoracic Surgery National Cardiac Surgery Database was examined for the years 1996 and 1997 to determine the frequency of new neurological events (stroke, transient ischemic attack, or coma) occurring after cardiac surgery. We reviewed clinical information on 416 347 patients (32% women) for whom complete neurological outcome data were available. New neurological events after surgery were higher for women than for men (3.8% versus 2.4%,
P
=0.001). For the whole group, the 30-day mortality was higher for women than for men (5.7% versus 3.5%,
P
=0.001), and among those patients who suffered a perioperative neurological event, mortality was also significantly higher for women than men (32% versus 28%,
P
=0.001). After adjustment for other risk factors (eg, age, history of hypertension and/or diabetes, duration of cardiopulmonary bypass, and other comorbid conditions) by multivariable logistic regression, female sex was independently associated with significantly higher risk of suffering new neurological events after cardiac surgery (OR 1.21, 95% CI 1.14 to 1.28,
P
=0.001).

Conclusions
—Women undergoing cardiac surgery are more likely than men to suffer new perioperative neurological events, and they have higher 30-day mortality when these complications occur. The higher incidence of perioperative neurological complications in women cannot be explained by currently known risk factors.
Randomized, Single-Blind, Placebo-Controlled Pilot Study of Catheter-Based Myocardial Gene Transfer for Therapeutic Angiogenesis Using Left Ventricular Electromechanical Mapping in Patients With Chronic Myocardial Ischemia
Authors: Vale Peter R. , Losordo Douglas W. , Milliken Charles E. , McDonald Maria C. , Gravelin Laura M. , Curry Cynthia M. , Esakof Darryl D. , Maysky Michael , Symes James F. , Isner Jeffrey M.
Published: June 2012

Background
—Catheter-based myocardial gene transfer (GTx) has not been previously tested in human subjects. Accordingly, we performed a pilot study to investigate the feasibility and safety of catheter-based myocardial GTx of naked plasmid DNA encoding vascular endothelial growth factor-2 (phVEGF-2) in patients with chronic myocardial ischemia.

Methods and Results
—A steerable, deflectable 8F catheter incorporating a 27-guage needle was advanced percutaneously to the left ventricular myocardium of 6 patients with chronic myocardial ischemia. Patients were randomized (1:1) to receive phVEGF-2 (total dose, 200 μg), which was administered as 6 injections into ischemic myocardium (total, 6.0 mL), or placebo (mock procedure). Injections were guided by NOGA left ventricular electromechanical mapping. Patients initially randomized to placebo became eligible for phVEGF-2 GTx if they had no clinical improvement 90 days after their initial procedure. Catheter injections (n=36) caused no changes in heart rate or blood pressure. No sustained ventricular arrhythmias, ECG evidence of infarction, or ventricular perforations were observed. phVEGF-2–transfected patients experienced reduced angina (before versus after GTx, 36.2±2.3 versus 3.5±1.2 episodes/week) and reduced nitroglycerin consumption (33.8±2.3 versus 4.1±1.5 tablets/week) for up to 360 days after GTx; reduced ischemia by electromechanical mapping (mean area of ischemia, 10.2±3.5 versus 2.8±1.6 cm
2
,
P
=0.04); and improved myocardial perfusion by SPECT-sestamibi scanning for up to 90 days after GTx when compared with images obtained after control procedure.

Conclusions
—This randomized trial of catheter-based phVEGF-2 myocardial GTx provides preliminary indications regarding the feasibility, safety, and potential efficacy of percutaneous myocardial GTx to human left ventricular myocardium.