bluuebunny/crossref_metadata_2025 huggingface dataset:
Effects of Growth Hormone Supplementation on Left Ventricular Morphology and Myocyte Function With the Development of Congestive Heart Failure
Authors: Houck Ward V. , Pan Lydia C. , Kribbs Scott B. , Clair Mark J. , McDaniel George M. , Krombach R. Stephen , Merritt William M. , Pirie Christine , Iannini Julie P. , Mukherjee Rupak , Spinale Francis G.
Published: June 2012

Background
—Release of growth hormone (GH), putatively through alterations in insulin growth factor-1 (IGF-1) levels, has been implicated to influence left ventricular (LV) myocardial structure and function. The objective of this study was to determine contributory mechanisms by which GH supplementation may influence LV function with the development of congestive heart failure (CHF).

Methods and Results
—Pigs were assigned to the following groups: (1) chronic pacing at 240 bpm for 3 weeks (n=10), (2) chronic pacing and GH supplementation (200 μg · kg
−1
· d
−1
, n=10), and (3) controls (n=8). GH treatment increased IGF-1 plasma levels by nearly 2.5-fold throughout the pacing protocol. In the untreated pacing CHF group, LV fractional shortening was reduced and peak wall stress increased. In the pacing CHF and GH groups, LV fractional shortening was higher and LV wall stress lower than untreated CHF values. Steady-state myocyte velocity of shortening was reduced with pacing CHF and was unchanged from CHF values with GH treatment. In the presence of 25 nmol/L isoproterenol, the change in myocyte shortening velocity was reduced in the untreated CHF group and increased in the GH-treated group. LV sarcoplasmic reticulum Ca
2+
-ATPase abundance was reduced with pacing CHF but was normalized with GH treatment.

Conclusions
—Short-term GH supplementation improved LV pump function in pacing CHF as a result of favorable effects on LV remodeling and contractile processes. Thus, GH supplementation may serve as a novel therapeutic modality in developing CHF.
Improvement of Impaired Myocardial Vasodilatation Due to Diffuse Coronary Atherosclerosis in Hypercholesterolemics After Lipid-Lowering Therapy
Authors: Yokoyama Ikuo , Momomura Shin-ichi , Ohtake Tohru , Yonekura Katsunori , Yang Weidong , Kobayakawa Naoshi , Aoyagi Teruhiko , Sugiura Seiryo , Yamada Nobuhiro , Ohtomo Kuni , Sasaki Yasuhito , Omata Masao , Yazaki Yoshio
Published: June 2012

Background
—Diminished myocardial vasodilatation (MVD) in hypercholesterolemics without overt coronary stenosis has been reported. However, whether the diminished MVD of angiographically normal coronary arteries in hypercholesterolemics can be reversed after lipid-lowering therapy is not known.

Methods and Results
—A total of 27 hypercholesterolemics and 16 age-matched controls were studied. All patients had >1 normal coronary artery, and those segments that were perfused by anatomically normal coronary arteries were studied. Myocardial blood flow (MBF) was measured during dipyridamole loading and at baseline using positron emission tomography and
13
N-ammonia, after which MVD was calculated before and after lipid-lowering therapy. Total cholesterol was significantly higher in hypercholesterolemics (263±33.8) than in controls (195±16.6), and it normalized after lipid-lowering therapy (197±19.9). Baseline MBF (ml · min
−1
· 100 g
−1
) was comparable among hypercholesterolemics (both before and after therapy) and controls. MBF during dipyridamole loading was significantly lower in hypercholesterolemics before therapy (189±75.4) than in controls (299±162,
P
<0.01). However, MBF during dipyridamole loading significantly increased after therapy (226±84.7;
P
<0.01). MVD significantly improved after therapy in hypercholesterolemics (2.77±1.35 after treatment [
P
<0.05] versus 2.02±0.68 before treatment [
P
<0.01]), but it remained significantly higher in controls (3.69±1.13,
P
<0.01). There was a significant relationship between the percent change of total cholesterol and the percent change of MVD before and after lipid-lowering therapy (
r
=−0.61,
P
<0.05).

Conclusions
—Diminished MVD of anatomically normal coronary arteries in hypercholesterolemics can be reversed after lipid-lowering therapy.
Cardiac Sympathetic Denervation After Transmyocardial Laser Revascularization
Authors: Al-Sheikh Thabet , Allen Keith B. , Straka Susan P. , Heimansohn David A. , Fain Richard L. , Hutchins Gary D. , Sawada Stephen G. , Zipes Douglas P. , Engelstein Erica D.
Published: June 2012

Background
—Transmyocardial laser revascularization (TMR) has been shown to improve refractory angina not amenable to conventional coronary interventions. However, the mechanism of action remains controversial, because improved myocardial perfusion has not been consistently demonstrated. We hypothesized that TMR relieves angina by causing myocardial sympathetic denervation.

Methods and Results
—PET imaging of resting and stress myocardial perfusion with [
13
N]ammonia (NH
3
) and of sympathetic innervation with [
11
C]hydroxyephedrine (HED) was performed before and after TMR in 8 patients with class IV angina ineligible for CABG or PTCA. A mean of 50±11 channels were created in the left ventricle (LV) with a holmium:YAG laser. A semiautomated program was used to determine NH
3
uptake and HED retention in the LV. Perfusion and innervation defects were defined as the percentage of LV with tracer uptake or retention >2 SD below normal mean values. All patients experienced improvement in their angina by 2.4±0.5 angina classes after surgery,
P
=0.008. Sympathetic innervation defects exceeded resting perfusion defects in all patients before TMR (34.6±27.3% for HED versus 9.4±10.8% for NH
3
,
P
=0.008). TMR did not significantly affect resting or stress myocardial perfusion but increased the extent of sympathetic denervation in 6 of 8 patients by 27.5±15.9%,
P
=0.03. In the remaining 2 patients, both sympathetic denervation and stress perfusion defects decreased after surgery.

Conclusions
—TMR causes decreased myocardial HED uptake in most patients without significant change in resting or stress myocardial perfusion, suggesting that the improvement in angina may be at least in part due to sympathetic denervation.
Relationship of Elevated
23
Na Magnetic Resonance Image Intensity to Infarct Size After Acute Reperfused Myocardial Infarction
Authors: Kim Raymond J. , Judd Robert M. , Chen Enn-Ling , Fieno David S. , Parrish Todd B. , Lima João A. C.
Published: June 2012

Background
—Elevated
23
Na MR image intensity after acute myocardial infarction has previously been shown to correspond to high tissue [Na
+
] and loss of myocardial viability. In this study, we explored the potential of in vivo
23
Na MRI to assess infarct size and investigated possible mechanisms for elevated
23
Na image intensity.

Methods and Results
—Thirteen dogs and 8 rabbits underwent in situ coronary artery occlusion and reperfusion and were imaged by
23
Na MRI. For anatomically matched left ventricular short-axis cross sections (n=46), infarct size measured by in vivo
23
Na MRI correlated well with triphenyltetrazolium chloride staining (
r
=0.87,
y
=0.92
x
+3.37,
P
<0.001). Elevated
23
Na image intensity was observed in infarcted myocardium (206±37% of remote in dogs,
P
<0.001; 215±58% in rabbits,
P
<0.002) but was not observed after severe but reversible ischemic injury (101±11% of baseline,
P
=NS). High-resolution ex vivo imaging revealed that regions of elevated
23
Na image intensity appeared to be identical to those of infarcted regions (
r
=0.97,
y
=0.92
x
+1.52,
P
<0.001). In infarcted regions, total tissue [Na
+
] was elevated (89±12 versus 37±9 mmol/L in control tissue, 156±60% increase,
P
<0.001) and was associated with increased intracellular sodium (254±68% of control,
P
<0.005) and an increased intracellular sodium/potassium ratio (868±512% of control,
P
<0.002). Morphometric analysis demonstrated only a minor increase in extracellular volume (17±8% versus 14±5%,
P
<0.05) in the infarcted territory.

Conclusions
—Elevated
23
Na MR image intensity in vivo measures infarct size after reperfused infarction in both a large and a small animal model. The mechanism of elevated
23
Na image intensity is probably intracellular sodium accumulation secondary to loss of myocyte ionic homeostasis.
Overexpression of Connective Tissue Growth Factor Gene Induces Apoptosis in Human Aortic Smooth Muscle Cells
Authors: Hishikawa Keiichi , Oemar Barry S. , Tanner Felix C. , Nakaki Toshio , Fujii Tomoko , Lüscher Thomas F.
Published: June 2012

Background
—Connective tissue growth factor (CTGF) is expressed at very high levels particularly in the shoulder of human atherosclerotic lesions but not in normal blood vessels. Thus, CTGF may be important in the regulation of vascular smooth muscle cell function in atherosclerosis, but its precise role remains elusive.

Methods and Results
—Full-length CTGF cDNA driven by a cytomegalovirus promoter was transiently transfected into cultured human aortic smooth muscle cells (HASCs). Northern and Western analysis demonstrated that CTGF was overexpressed in these cells 48 hours after transfection. The effects of CTGF overexpression on cell proliferation were evaluated by [
3
H]thymidine uptake and cell count in quiescent HASCs or those stimulated with platelet-derived growth factor (PDGF). Although mock transfection showed no effect, CTGF overexpression significantly inhibited cell proliferation in cells stimulated by PDGF. Moreover, CTGF overexpression, but not mock transfection, significantly increased apoptosis as assessed by DNA fragmentation associated with histone, TdT-mediated dUTP biotin nick end-labeling, and appearance of hypodiploid cells by flow cytometry.

Conclusions
—Our results for the first time demonstrate that CTGF can also act as a growth inhibitor in human aortic smooth muscle cells at least in part by inducing apoptosis. This may be important for the formation and composition of lesions and plaque stability in atherosclerosis.
Perturbation of the T-Cell Repertoire in Patients With Unstable Angina
Authors: Liuzzo Giovanna , Kopecky Stephen L. , Frye Robert L. , Fallon W. Michael O’ , Maseri Attilio , Goronzy Jorg J. , Weyand Cornelia M.
Published: June 2012

Background
—Monocytes are constitutively activated in unstable angina (UA), resulting in the production of IL-6 and the upregulation of acute phase proteins. Underlying mechanisms are not understood. To explore whether the production of the potent monocyte activator IFN-γ is altered in UA, we compared cytokine production by T lymphocytes in patients with UA (Braunwald’s class IIIB) and with stable angina (SA).

Methods and Results
—Peripheral blood lymphocytes were collected at the time of hospitalization and after 2 and 12 weeks. Cytokine-producing CD4
+
and CD8
+
T cells were quantified by 3-color flow cytometry after stimulation with phorbol myristate acetate and ionomycin. UA was associated with an increased number of CD4
+
and CD8
+
T cells producing IFN-γ, whereas patients with SA had higher frequencies of IL-2
+
and IL-4
+
CD4
+
T cells. Expansion of the IFN-γ
+
T-cell population in UA persisted for at least 3 months. Increased production of IFN-γ in UA could be attributed to the expansion of an unusual subset of T cells, CD4
+
CD28
null
T cells.

Conclusions
—Patients with UA are characterized by a perturbation of the functional T-cell repertoire with a bias toward IFN-γ production, suggesting that monocyte activation and acute phase responses are consequences of T-cell activation. IFN-γ is produced by CD4
+
CD28
null
T cells, which are expanded in UA and distinctly low in SA and controls. The emergence of CD4
+
CD28
null
T cells may result from persistent antigenic stimulation.
Long-Term Outcome of Patients With Intermediate-Risk Exercise Electrocardiograms Who Do Not Have Myocardial Perfusion Defects on Radionuclide Imaging
Authors: Gibbons Raymond J. , Hodge David O. , Berman Daniel S. , Akinboboye Olakunle O. , Heo Jaekyeong , Hachamovitch Rory , Bailey Kent R. , Iskandrian Ami E.
Published: June 2012

Background
—The appropriate management of patients with intermediate-risk Duke treadmill scores is not established. The purpose of this study was to determine the long-term risk of subsequent cardiovascular events in patients with an intermediate-risk treadmill score who do not have myocardial perfusion defects on radionuclide imaging.

Methods and Results
—The existing databases of the nuclear cardiology laboratories of 4 academic institutions were searched retrospectively. A total of 4649 patients were identified who had intermediate-risk Duke treadmill scores (−10 to 4), normal or near-normal exercise single photon-emission computed tomographic myocardial perfusion images using either thallium-201 or technetium-99m sestamibi, and no previous coronary revascularization. Follow-up was 95% complete. Cardiovascular survival was 99.8% at 1 year, 99.0% at 5 years, and 98.5% at 7 years. Cardiac survival free of myocardial infarction was similarly high at 96.6% at 7 years. Cardiac survival free of myocardial infarction or revascularization was 87.1% at 7 years. Near-normal scans and cardiac enlargement were independent predictors of time to cardiac death. Seven-year cardiac survival was still high at 97.0% in the 357 patients with near-normal scans and normal cardiac size and somewhat lower, at 89.0%, in the 167 patients with cardiac enlargement.

Conclusions
—Patients with an intermediate-risk treadmill score but with normal or near-normal exercise myocardial perfusion images and normal cardiac sizes are at low risk for subsequent cardiac death and can be safely managed medically until their symptoms warrant revascularization. The appropriate management of patients with cardiac enlargement will remain a matter of clinical judgment.
Improvement in Exercise Tolerance and Symptoms of Congestive Heart Failure During Treatment With Candesartan Cilexetil
Authors: Riegger G.A.J. , Bouzo H. , Petr P. , Münz J. , Spacek R. , Pethig H. , von Behren V. , George M. , Arens H.-J.
Published: June 2012

Background
—The renin-angiotensin system plays an important part in the pathogenesis of congestive heart failure (CHF). This study evaluated the effect of an angiotensin II type 1 receptor antagonist on exercise tolerance and symptoms of CHF.

Methods and Results
—In this multicenter, double-blind, parallel-group study, 844 patients with CHF were randomized to 12 weeks’ treatment with placebo (n=211) or candesartan cilexetil 4 mg (n=208), 8 mg (n=212), or 16 mg (n=213) after a 4-week placebo run-in period. Changes in exercise time, Dyspnea Fatigue Index score, NYHA functional class, and cardiothoracic ratio were determined. Candesartan cilexetil produced a dose-related improvement in exercise time. For the intention-to-treat population, the increase produced by candesartan cilexetil 16 mg was significantly greater than that produced by placebo (47.2 versus 30.8 seconds,
P
=0.0463). All doses of candesartan cilexetil significantly improved the Dyspnea Fatigue Index score relative to placebo. NYHA class improved more frequently in the candesartan cilexetil groups; the differences relative to placebo were not significant. The decrease in cardiothoracic ratio with candesartan 4 to 16 mg was small but statistically significant compared with placebo (all
P
<0.05). In all candesartan cilexetil groups, plasma renin activity and angiotensin II levels increased from baseline and aldosterone levels decreased in the 8- and 16-mg treatment groups. Candesartan cilexetil was well tolerated at all doses.

Conclusions
—In summary, treatment with candesartan cilexetil demonstrated significant improvements in exercise tolerance, cardiothoracic ratio, and symptoms and signs of CHF and was well tolerated.
Human Prostacyclin Synthase Gene and Hypertension
Authors: Iwai Naoharu , Katsuya Tomohiro , Ishikawa Kazuhiko , Mannami Toshifumi , Ogata Jun , Higaki Jitsuo , Ogihara Toshio , Tanabe Tadashi , Baba Shunroku
Published: June 2012

Background
—Prostacyclin (prostaglandin I
2
) is a strong vasodilator that inhibits the growth of vascular smooth muscle cells and is also the most potent endogenous inhibitor of platelet aggregation. Therefore, it has been considered to play an important roles in cardiovascular disease. On the basis of the hypothesis that variations of the prostacyclin synthase gene may also play an important role in human cardiovascular disease, we performed a screening for variations in the human prostacyclin synthase gene.

Methods and Results
—We have detected a repeat polymorphism in the promoter region of the human prostacyclin synthase gene. The number of 9-bp (CCGCCAGCC) repeats in the promoter region, which encodes a tandem repeat of Sp1 transcriptional binding sites, varied between 3 and 7 in Japanese subjects. Luciferase reporter analysis indicated that the alleles of 3 and 4 repeats (R3 and R4, respectively) had less promoter activity in cultured human umbilical vein endothelial cells. We then investigated the possible association of this repeat polymorphism with blood pressure in a large population-based sample (the Suita Study), which consisted of 4971 Japanese participants. Multivariate models indicated that participants with the R3R3, R3R4, or R4R4 genotype (SS genotype, n=80) had significantly higher systolic pressure (
P
=0.0133) and pulse pressure (
P
=0.0005). The odds ratio of hypertension (140/90 mm Hg) for the SS genotype was 1.942 (95% confidence interval 3.20 to 1.19,
P
=0.0084).

Conclusions
—Repeat polymorphism of the human prostacyclin synthase gene seems to be a risk factor for higher pulse pressure and is consequently a risk factor for systolic hypertension in the Japanese population.
Estrogen and Progesterone Reduce Lipid Accumulation in Human Monocyte-Derived Macrophages
Authors: McCrohon Jane A. , Nakhla Shirley , Jessup Wendy , Stanley Keith K. , Celermajer David S.
Published: June 2012

Background
—Males have an earlier onset and greater prevalence of clinical atherosclerosis than age-matched females, which is consistent with an atheroprotective effect of the female sex steroids, estrogen and progesterone. We therefore examined the effects of estrogen and progesterone on human foam cell formation, a key early event in atherogenesis.

Methods and Results
—Monocytes from healthy female and male donors were obtained from white cell concentrates and allowed to differentiate into macrophages over 10 days. These human monocyte-derived macrophages (MDMs) were exposed to either control (0.1% vol/vol ethanol) or estrogen or progesterone treatment on days 3 through 10. Lipid loading was achieved on days 8 through 10 by incubation with acetylated LDL. Lipid from the MDMs was then extracted for analysis of cholesteryl ester (CE) content. 17β-Estradiol at both physiological (2 nmol/L) and supraphysiological (20 and 200 nmol/L) concentrations produced a significant reduction in macrophage CE content (88±3%, 88±2%, and 85±4%, respectively;
P
<0.02 compared with control). Physiological and supraphysiological levels of progesterone (2, 10, and 200 nmol/L) produced an even more dramatic reduction in CE content (74±9%, 56±10%, and 65±8%, respectively;
P
<0.002 compared with control). This effect could be abrogated by coincubation with the progesterone receptor antagonist RU486. Neither estrogen nor progesterone produced a reduction in lipid loading in male-donor–derived MDMs. Detailed lipid trafficking studies demonstrated that both estrogen and progesterone altered macrophage uptake and/or processing of modified LDL.

Conclusions
—Physiological levels of estrogen and progesterone are associated with a female-sex–specific reduction in human macrophage lipid loading, which is consistent with an atheroprotective effect.
Dilated and Failing Cardiomyopathy in Bradykinin B
2
Receptor Knockout Mice
Authors: Emanueli Costanza , Maestri Roberta , Corradi Domenico , Marchione Roberta , Minasi Alessandra , Tozzi Maria Grazia , Salis Maria Bonaria , Straino Stefania , Capogrossi Maurizio C. , Olivetti Giorgio , Madeddu Paolo
Published: June 2012

Background
—The activation of B
2
receptors by kinins could exert cardioprotective effects in myocardial ischemia and heart failure.

Methods and Results
—To test whether the absence of bradykinin B
2
receptors may affect cardiac structure and function, we examined the developmental changes in blood pressure (BP), heart rate, and heart morphology of bradykinin B
2
receptor gene knockout (B
2
−/−
), heterozygous (B
2
+/−
), and wild-type (B
2
+/+
) mice. The BP of B
2
−/−
mice, which was still normal at 50 days of age, gradually increased, reaching a plateau at 6 months (136±3 versus 109±1 mm Hg in B
2
+/+
,
P
<0.01). In B
2
+/−
mice, BP elevation was delayed. At 40 days, the heart rate was higher (
P
<0.01) in B
2
−/−
and B
2
+/−
than in B
2
+/+
mice, whereas the left ventricular (LV) weight and chamber volume were similar among groups. Thereafter, the LV growth rate of B
2
−/−
and B
2
+/−
mice was accelerated, leading at 360 days to a LV weight–to–body weight ratio that was 9% and 17% higher, respectively, than that of B
2
+/+
mice. In B
2
−/−
mice, hypertrophy was associated with a marked chamber dilatation (42% larger than that of B
2
+/+
mice), an elevation in LV end-diastolic pressure (25±3 versus 5±1 mm Hg in B
2
+/+
mice,
P
<0.01), and reparative fibrosis.

Conclusions
—The disruption of the bradykinin B
2
receptor leads to hypertension, LV remodeling, and functional impairment, implying that kinins are essential for the functional and structural preservation of the heart.
Longitudinal Analysis of Fibroblast Growth Factor Expression After Transplantation and Association With Severity of Cardiac Allograft Vasculopathy
Authors: Miller Geraldine G. , Davis Stacy F. , Atkinson James B. , Chomsky Donald B. , Pedroso Pedro , Reddy V. Seenu , Drinkwater Davis C. , Zhao Xiao-Ming , Pierson Richard N.
Published: June 2012

Background
—Vascular smooth muscle cell growth factors are postulated to contribute to cardiac allograft vasculopathy (CAV). Few data quantitatively address the timing, location, or stimuli for growth factor expression and relationship to CAV.

Methods and Results
—Acidic fibroblast growth factor (aFGF) mRNA expression was determined in serial endomyocardial biopsies during the first year after transplantation. Patients with high levels of aFGF mRNA and elevations after the early posttransplant period had significantly more severe CAV than patients with low aFGF and no late elevations.

Conclusions
—Parenchymal aFGF expression varies between patients and in the same patient over time and correlates with development of CAV.
Creatine Kinase-MB Enzyme Elevation Following Successful Saphenous Vein Graft Intervention Is Associated With Late Mortality
Authors: Hong Mun K. , Mehran Roxana , Dangas George , Mintz Gary S. , Lansky Alexandra J. , Pichard Augusto D. , Kent Kenneth M. , Satler Lowell F. , Stone Gregg W. , Leon Martin B.
Published: June 2012

Background
—Although the risk for development of creatine kinase (CK-MB) elevation after saphenous vein graft (SVG) intervention is high, its prognostic significance remains unknown. This study evaluated the impact of periprocedural CK-MB elevation on late clinical events following successful SVG angioplasty.

Methods and Results
—We studied 1056 consecutive patients with successful (defined by angiographic success and absence of major complications) intervention of 1693 SVG lesions. These patients were grouped as normal CK-MB (n=556), minor CK-MB rise (CK-MB 1 to 5 times normal, n=339), and major CK-MB rise (CK-MB >5 times normal, n=161). There were no differences in major clinical events at 30-day follow-up among the 3 groups. However, 1-year mortality was 4.8%, 6.5%, and 11.7%, respectively,
P
<0.05 (ANOVA). Even within a population without any intraprocedure or in-hospital complications (n=727, 69% of the overall cohort), 1-year mortality remained significantly higher with CK-MB elevation: 2.4%, 5.5%, and 10.7%, respectively,
P
<0.05 (ANOVA). Multivariate analysis revealed major CK-MB elevation as the strongest independent predictor of late mortality (odds ratio 3.3, with 95% CI 1.7 to 6.2), followed by diabetes mellitus (odds ratio 2.6, with 95% CI 1.5 to 4.5).

Conclusions
—Major CK-MB elevation occurs after 15% of otherwise successful SVG interventions and is associated with increased late mortality.
Oscillatory Breathing Patterns During Wakefulness in Patients With Chronic Heart Failure
Authors: Ponikowski Piotr , Anker Stefan D. , Chua Tuan Peng , Francis Darrel , Banasiak Waldemar , Poole-Wilson Phillip A. , Coats Andrew J. S. , Piepoli Massimo
Published: June 2012

Background
—Oscillatory breathing patterns characterized by rises and falls in ventilation with apnea (Cheyne-Stokes respiration [CSR]) or without apnea (periodic breathing [PB]) commonly occur during the daytime in chronic heart failure (CHF). We have prospectively characterized patients with cyclical breathing in terms of clinical characteristics, indices of autonomic control, prognosis, and the role of peripheral chemosensitivity.

Methods and Results
—To determine cyclical breathing pattern, power spectral analysis was applied to 30-minute recordings of respiration in 74 stable CHF patients. Analyses of heart rate variability and baroreflex sensitivity were used to assess autonomic balance. Peripheral chemosensitivity was assessed with the transient hypoxia method. We also determined whether the suppression of peripheral chemoreceptor activity (hyperoxia or dihydrocodeine) would influence the respiratory pattern. Cyclical respiration was found in 49 (66%) patients (22 [30%] CSR, 27 [36%] PB) and was associated with more advanced CHF symptoms, impaired autonomic balance, and increased chemosensitivity (0.80 and 0.75 versus 0.34 L · min
−1
· %Sa
o
2
−1
,
P
<0.001, for CSR and PB versus normal breathing, respectively). Transient hyperoxia abolished oscillatory breathing in 7 of 8 patients. Dihydrocodeine administration decreased chemosensitivity by 42% (
P
=0.05), which correlated with improvement in respiratory pattern. Cyclical breathing predicted poor 2-year survival (relative risk 9.41,
P
<0.01, by Cox proportional hazards analysis), independent of peak oxygen consumption (
P
=0.04).

Conclusions
—An oscillatory breathing pattern during the daytime is a marker of impaired autonomic regulation and poor outcome. Augmented activity of peripheral chemoreceptors may be involved in the genesis of this respiratory pattern. Modulation of peripheral chemosensitivity can reduce or abolish abnormal respiratory patterns and may be an option in the management of CHF patients with oscillatory breathing.
Muscle and Skin Sympathetic Nerve Traffic During the “White-Coat” Effect
Authors: Grassi Guido , Turri Carlo , Vailati Sabrina , Dell’Oro Raffaella , Mancia Giuseppe
Published: June 2012

Background
—Sphygmomanometric blood pressure measurements induce an alerting reaction and thus an increase in the patient’s blood pressure and heart rate. Whether and to what extent this “white-coat” effect is accompanied by detectable changes in sympathetic nerve traffic has never been investigated.

Methods and Results
—In 10 mild untreated essential hypertensives (age 37.9±3.8 years, mean±SEM), we measured arterial blood pressure (by Finapres), heart rate (by ECG), and postganglionic muscle and skin sympathetic nerve activity via microneurography. Measurements were performed with the subject supine during (1) a 15-minute control period, (2) a 10-minute visit by a doctor unfamiliar to the patient who was in charge of measuring his or her blood pressure by sphygmomanometry, and (3) a 15-minute recovery period after the doctor’s departure. The entire procedure was performed twice at a 45-minute interval to obtain, in separate periods, muscle or skin sympathetic nerve traffic recordings, whose sequence was randomized. The doctor’s visit induced a sudden, marked, and prolonged pressor and tachycardic response, accompanied by a significant increase in skin sympathetic nerve traffic (+38.6±6.7%,
P
<0.01). In contrast, muscle sympathetic nerve traffic was significantly inhibited (−25.5±4.1%,
P
<0.01). All changes persisted throughout the doctor’s visit and, with the exception of skin sympathetic nerve traffic, showed a slow rate of disappearance after the doctor’s departure.

Conclusions
—Thus, the pressor and tachycardic responses to the alerting reaction that accompanies sphygmomanometric blood pressure measurement is characterized by a behavior of the adrenergic nervous system that causes muscle sympathoinhibition and skin sympathoexcitation.
Parasympathetic Control of Cardiac Sympathetic Activity
Authors: Azevedo Eduardo R. , Parker John D.
Published: June 2012

Background
—Muscarinic receptors on adrenergic nerve terminals attenuate norepinephrine release. The role of these receptors in the modulation of cardiac norepinephrine release in humans remains uncertain.

Methods and Results
—Twelve patients with normal left ventricular (LV) function and 18 with congestive heart failure (CHF) were studied. A radiotracer technique was used to measure cardiac norepinephrine spillover (CANESP) in response to intracoronary acetylcholine (ACh, 5×10
−5
Mol), and in response to intracoronary atropine (12 μg/min). ACh did not affect CANESP in the group of subjects with normal LV function, but it caused a significant reduction in those with CHF [197 (150 to 302) versus 168 (87 to 288) pmol/min,
P
<0.05]. Atropine caused a significant increase in CANESP in those with normal LV function [47 (27 to 51) versus 64 (38 to 139) pmol/min,
P
<0.05], but no change was observed in the CHF group.

Conclusions
—Therefore, in the setting of heart failure and sympathetic activation, muscarinic receptor stimulation decreases CANESP, an effect not observed in patients with preserved LV function. Blockade of muscarinic receptors with atropine increased CANESP in patients with normal LV function, suggesting that cardiac parasympathetic tone has inhibitory effects on cardiac sympathetic activity. This basal inhibition was not observed in CHF patients in response to atropine. The lack of basal parasympathetic inhibition of cardiac sympathetic activity may play a role in the pathogenesis of cardiac sympathetic activation in heart failure.
Can Coronary Blood Flow Velocity Pattern After Primary Percutaneous Transluminal Coronary Angiography Predict Recovery of Regional Left Ventricular Function in Patients With Acute Myocardial Infarction?
Authors: Kawamoto Takahiro , Yoshida Kiyoshi , Akasaka Takashi , Hozumi Takeshi , Takagi Tsutomu , Kaji Shuichiro , Ueda Yoshiaki
Published: June 2012

Background
—In the era of primary percutaneous transluminal coronary angioplasty (PTCA), it is important to judge whether myocardium within acute ischemic injury is viable. This study sought to investigate parameters derived from the coronary blood flow velocity spectrum immediately after primary PTCA in patients with acute myocardial infarction and to elucidate the clinical value of coronary blood flow measurement in predicting myocardial viability.

Methods and Results
—Using a Doppler guidewire, we measured coronary blood flow velocity after successful completion of primary PTCA in 23 consecutive patients with acute anterior myocardial infarction. Regional wall motion was analyzed to estimate anterior wall motion score index (A-WMSI) by echocardiography before PTCA and 1 month after the onset of symptoms. Average systolic peak velocity (ASV) and deceleration time of diastolic flow velocity (DDT) significantly correlated to 1-month A-WMSI (
r
=−0.54,
P
=0.007 and
r
=−0.62,
P
=0.002, respectively), and optimal cutoff values to predict viable myocardium (defined as 1-month A-WMSI ≤2.0) were 6.5 cm/s for ASV and 600 ms for DDT (sensitivity=0.79, specificity=0.89 and sensitivity=0.86, specificity=0.89, respectively). ASV and DDT also correlated weakly to the change in A-WMSI (
r
=0.46,
P
=0.03 and
r
=0.49,
P
=0.02, respectively).

Conclusions
—Low ASV and rapid DDT of coronary blood flow spectrum immediately after primary PTCA reflects a greater degree of microvascular damage in the risk area. Analysis of coronary blood flow spectrum immediately after primary PTCA by use of a Doppler guidewire is useful in predicting recovery of regional left ventricular function.
Effect of β-Blockers on Free Radical–Induced Cardiac Contractile Dysfunction
Authors: Flesch M. , Maack C. , Cremers B. , Bäumer A. T. , Südkamp M. , Böhm M.
Published: June 2012

Background
—We examined the effects of hydroxyl radicals (OH·) on human myocardial contractility and on sarcoplasmic reticulum Ca
2+
-ATPase (SERCA) activity and the effects of the β-receptor antagonists metoprolol, carvedilol, and its metabolite BM-910228.

Methods and Results
—Isometric force of contraction was determined in isolated human myocardium. H
2
O
2
1 mmol/L and Fe
3+
-nitrilotriacetic acid (Fe
3+
-NTA) 0.1 mmol/L used for generation of OH· induced a decrease in basal force of contraction and an increase in diastolic tension in atrial and left ventricular myocardial preparations. After challenge with OH·, the maximum positive inotropic response to Ca
2+
1.8 to 15 mmol/L was decreased by 60% and by 39%, respectively. The effects of OH· could be blocked by catalase. Carvedilol and its metabolite BM-910228 attenuated the OH·-induced impairment of the inotropic response to Ca
2+
in atrial myocardial preparations. Metoprolol had no significant effect. The stimulation frequency (0.5 to 3.0 Hz)–dependent increase in force of contraction and decrease in diastolic tension were abolished after exposure of atrial trabeculae to OH·. In parallel, SERCA activity was decreased by OH· concentration-dependently, as determined in myocardial membrane preparations. BM-910228 partially restored the force-frequency relationship and preserved SERCA activity.

Conclusions
—OH· radicals induce an impairment of contraction and relaxation and an attenuation of the force-frequency relationship in human myocardium accompanied by an inhibition of SERCA. Carvedilol and BM-910228 partly prevented OH·-induced contractile dysfunction. These observations could explain the improvement of ejection fraction in heart failure trials with carvedilol without a restoration of β-adrenergic receptor density.
Alterations in the Local Myocardial Motion Pattern in Patients Suffering From Pressure Overload Due to Aortic Stenosis
Authors: Stuber M. , Scheidegger M. B. , Fischer S. E. , Nagel E. , Steinemann F. , Hess O. M. , Boesiger P.
Published: June 2012

Background
—MR tissue tagging allows the noninvasive assessment of the locally and temporally resolved motion pattern of the left ventricle. Alterations in cardiac torsion and diastolic relaxation of the left ventricle were studied in patients with aortic stenosis and were compared with those of healthy control subjects and championship rowers with physiological volume-overload hypertrophy.

Methods and Results
—Twelve aortic stenosis patients, 11 healthy control subjects with normal left ventricular function, and 11 world-championship rowers were investigated for systolic and diastolic heart wall motion on a basal and an apical level of the myocardium. Systolic torsion and untwisting during diastole were examined by use of a novel tagging technique (CSPAMM) that provides access to systolic and diastolic motion data. In the healthy heart, the left ventricle performs a systolic wringing motion, with a counterclockwise rotation at the apex and a clockwise rotation at the base. Apical untwisting precedes diastolic filling. In the athlete’s heart, torsion and untwisting remain unchanged compared with those of the control subjects. In aortic stenosis patients, torsion is significantly increased and diastolic apical untwisting is prolonged compared with those of control subjects or athletes.

Conclusions
—Torsional behavior as observed in pressure- and volume-overloaded hearts is consistent with current theoretical findings. A delayed diastolic untwisting in the pressure-overloaded hearts of the patients may contribute to a tendency toward diastolic dysfunction.
Interindividual Heterogeneity in the Hypoxic Regulation of VEGF
Authors: Schultz Aylit , Lavie Lena , Hochberg Irit , Beyar Rafael , Stone Tzachi , Skorecki Karl , Lavie Peretz , Roguin Ariel , Levy Andrew P.
Published: June 2012

Background
—The coronary artery collateral circulation may be beneficial in protecting against myocardial ischemia and necrosis. However, there is a tremendous interindividual variability in the degree of new collateral formation in patients with coronary artery disease. The basis for this interindividual heterogeneity is not understood. In this study we test the hypothesis that failure to generate collateral vessels is associated with a failure to appropriately induce with hypoxia or ischemia the angiogenic factor, vascular endothelial growth factor (VEGF).

Methods and Results
—We correlated the VEGF response to hypoxia in the monocytes harvested from patients with coronary artery disease with the presence of collaterals visualized during routine angiography. We found that there was a highly significant difference in the hypoxic induction of VEGF in patients with no collaterals compared with patients with some collaterals (mean fold induction 1.9±0.2 versus 3.2±0.3
, P
<0.0001). After subjecting the data to ANCOVA, using as covariates a number of factors that might influence the amount of collateral formation (ie, age, sex, diabetes, smoking, hypercholesterolemia), patients with no collaterals still have a significantly lower hypoxic induction of VEGF than patients with collaterals.

Conclusions
—This study provides evidence in support of the hypothesis that the ability to respond to progressive coronary artery stenosis is strongly associated with the ability to induce VEGF in response to hypoxia. The observed interindividual heterogeneity in this response may be due to environmental, epigenetic, or genetic causes. This interindividual heterogeneity may also help to explain the variable angiogenic responses seen in other conditions such as diabetic retinopathy and solid tumors.
Role of C3 Cleavage in Monocyte Activation During Extracorporeal Circulation
Authors: Rinder Christine S. , Rinder Henry M. , Johnson Kirk , Smith Michael , Lee David L. , Tracey Jayne , Polack Glenda , Higgins Paul , Yeh C. Grace , Smith MD Brian R.
Published: June 2012

Background
—We previously demonstrated that inhibiting formation of terminal complement components (C5a and C5b-9) prevents platelet and neutrophil (PMN) but not monocyte activation during simulated extracorporeal circulation (SECC). This study examined whether earlier complement inhibition during SECC, blocking C3a formation, would additionally prevent monocyte activation.

Methods and Results
—SECC was established by recirculating heparinized whole blood from human volunteers on a membrane oxygenator. CAB-2, a chimeric protein constructed from genes encoding the complement regulatory proteins CD46 and CD55, inactivates the C3/C5 convertases and blocks in vitro generation of C3a, C5a, and C5b-9. CAB-2 was used in 4 experiments at a final concentration of 300 μg/mL and 4 experiments at 30 μg/mL; 4 control runs used vehicle alone. Samples were assayed for C3a and C5b-9, monocyte activation (CD11b upregulation), PMN activation (CD11b upregulation and elastase release), and platelet activation (P-selectin expression and monocyte-platelet conjugate formation). CAB-2 at both doses significantly inhibited formation of C3a and C5b-9 during SECC. High-dose CAB-2 significantly blocked monocyte and PMN CD11b upregulation and PMN elastase release. CAB-2 also inhibited formation of platelet activation–dependent monocyte–platelet conjugates.

Conclusions
—Blockade of complement activation early in the common pathway inhibited monocyte CD11b upregulation during SECC, suggesting that early complement components contribute most to monocyte activation during SECC. As expected, PMN and platelet activation were blocked by terminal complement inhibition. This investigation further elucidates the relation between complement and blood cell activation during simulated cardiopulmonary bypass.
Mechanism of Procainamide-Induced Prevention of Spontaneous Wave Break During Ventricular Fibrillation
Authors: Kim Young-Hoon , Yashima Masaaki , Wu Tsu-Juey , Doshi Rahul , Chen Peng-Sheng , Karagueuzian Hrayr S.
Published: June 2012

Background
—Ventricular fibrillation (VF) is maintained by 2 mechanisms: first by reentry formation and second by spontaneous wave break or wave splitting. We hypothesized that spontaneous wave break results from a critical shortening of the action potential duration (APD) during VF and that its prevention by procainamide eliminates spontaneous wave break.

Methods and Results
—The endocardial surfaces of 7 isolated, perfused swine right ventricles were mapped with a 3.2×3.8 cm plaque with 477 bipolar electrodes. Activation pattern during VF was visualized dynamically while simultaneously recording epicardial action potentials with a glass microelectrode. APD restitution curves were constructed during VF (dynamic) and during S
1
S
2
protocols. At baseline, VF was maintained by 5.3±1 wavelets. Procainamide (PA) at 10 μg/mL decreased the number of wavelets to 3.5±1 (
P
<0.05). At baseline VF was maintained by spontaneous wave break and by new reentrant wave front formation. PA eliminated spontaneous wave break during VF while having no effect on reentry formation. PA increased the cycle length of the VF (148.5±41.2 ms vs 81±10 ms,
P
<0.01) and the core area of the reentry from 5.8 to 14.5 mm
2
(
P
<0.05). Dynamic APD restitution curve during VF showed that PA eliminated the initiation of activation with APDs shorter than 30 ms. The effects of PA on cellular properties and wave front dynamics were reversed during 60 minutes of drug-free perfusion.

Conclusions
—Critically short APDs during VF promote spontaneous wave break. Their elimination with PA, however, maintains VF by generating new reentrant wave front.
Decreased Sodium and Increased Transient Outward Potassium Currents in Iron-Loaded Cardiac Myocytes
Authors: Kuryshev Yuri A. , Brittenham Gary M. , Fujioka Hisashi , Kannan Perry , Shieh Char-Chang , Cohen Sidney A. , Brown Arthur M.
Published: June 2012

Background
—Patients with chronic iron overload may develop a cardiomyopathy manifested by ventricular arrhythmias and heart failure. We hypothesized that iron-loaded cardiomyocytes may have abnormal excitability.

Methods and Results
—We examined a new model of human iron overload, the Mongolian gerbil given repeated injections of iron dextran. In ventricular myocytes, we measured iron concentration and distribution, action potential, sodium and potassium currents, and sodium channel protein. We showed for the first time that (1) the iron content of gerbil ventricular cardiomyocytes was increased to amounts similar to those of patients with iron-induced cardiomyopathy; (2) the overshoot and duration of the cardiac action potential decreased; (3) sodium current was reduced, steady-state inactivation was enhanced, and single-channel currents were unchanged; and (4) transient outward potassium current was increased, but inwardly rectifying potassium current was unchanged. Neonatal rat cardiomyocytes incubated with iron for 1 to 3 days showed similar changes, and levels of cardiac sodium channel proteins were unchanged.

Conclusions
—Abnormal excitability and heterogeneous cardiac iron deposition may cause the arrhythmogenesis of human siderotic heart disease.
Splice-Site Mutations in Atherosclerosis Candidate Genes
Authors: von Kodolitsch Yskert , Pyeritz Reed E. , Rogan Peter K.
Published: June 2012

Background
—Nucleotide variants in several genes for lipid and methionine metabolism influence the risk of premature atherosclerosis. Ten percent of single nucleotide substitutions in these genes involve mRNA splice sites. The effects of some of these changes on splicing and on phenotypic severity are not inherently obvious.

Methods and Results
—Using an information theory-based model, we measured the individual information content (R
i
, in bits) of splice sites adjacent to 289 mutations (including 31 splice-site mutations) in the atherosclerosis candidate genes
APOAII
,
APOB
,
APOCII
,
APOE
,
CBS
,
CETP
,
LCAT
,
LIPA
,
LDLR,
and
LPL
. The predictions of information analysis were then corroborated by published mRNA analyses. The R
i
values of mutant sites were consistent with either complete (n=17) or partial (n=8) inactivation of these sites. Seven mutations were predicted to activate cryptic splice sites. Predicted inactive mutant sites were associated with either “average” or “severe” dyslipidemia and commensurate reductions in protein levels or activity, whereas mutations expected to exhibit residual splicing had average or “mild” effects on lipid and protein expression.

Conclusions
—Information analysis of splice-junction variants in atherosclerosis candidate genes distinguishes inactive from leaky splice sites and identifies activated cryptic sites. Predicted changes in splicing were related to phenotypic severity.
Inhibition of Neointima Hyperplasia of Mouse Vein Grafts by Locally Applied Suramin
Authors: Hu Yanhua , Zou Yiping , Dietrich Hermann , Wick Georg , Xu Qingbo
Published: June 2012

Background
—Saphenous vein grafts are widely used for aortocoronary bypass surgery as treatment for severe atherosclerosis and often are complicated by subsequent occlusion of the graft vessel.

Methods and Results
—We described a mouse model of venous bypass graft arteriosclerosis that can be effectively retarded by locally applied suramin, a growth factor receptor antagonist. Mouse isogeneic vessels of the vena cava veins pretreated with suramin were grafted end to end into the carotid arteries and enveloped with a mixture of suramin (1 mmol/L) and pluronic-127 gel. In the untreated group, vessel wall thickening was observed as early as 1 week after surgery and progressed to 4-fold and 10-fold the original thickness in grafted veins at 4 and 8 weeks, respectively. Pluronic-127 gel alone did not influence neointima formation. Suramin treatment reduced the neointima hyperplasia 50% to 70% compared with untreated controls. Immunohistochemical studies demonstrated that a significant proliferation of vascular smooth muscle cells (SMCs) constituted neointimal lesions between 4 and 8 weeks. The majority of SMCs expressed platelet-derived growth factor (PDGF) receptors-α and -β, which were significantly reduced by suramin treatment. In vitro studies indicated that suramin completely blocked PDGF receptor activation or phosphorylation stimulated by PDGF-AB, inhibited activation of mitogen-activated protein kinase (ERK) kinases (MEK1/2) and ERK1/2, and abrogated transcription factor AP-1 DNA-binding activity.

Conclusions
—Suramin inhibited SMC migration and proliferation in vivo and in vitro by blocking PDGF-initiated PDGF receptor and MAPK-AP-1 signaling. These findings indicate that locally applied suramin is effective in a mouse model of venous bypass graft arteriosclerosis.