bluuebunny/crossref_metadata_2025 huggingface dataset:
Endothelial Function in Deoxycorticosterone-NaCl Hypertension
Authors: Mäkynen Heikki , Kähönen Mika , Wu Xiumin , Arvola Pertti , Pörsti Ilkka
Published: June 2012

Background
Dietary calcium intake has been suggested to correlate inversely with blood pressure in humans and experimental animals. However, the effects of calcium supplementation on hypertensive disturbances of the endothelium have not been well characterized.

Methods and Results
Wistar-Kyoto rats were made hypertensive by deoxycorticosterone (DOC)-NaCl treatment, but a concurrent increase in chow calcium content from 1.1% to 2.5% markedly attenuated the rise in blood pressure. The function of isolated mesenteric arterial rings in vitro was investigated at the close of the 10-week study. In norepinephrine-precontracted rings, the relaxations to acetylcholine (ACh) and ADP, as well as to nitroprusside, 3-morpholinosydnonimine, and isoproterenol were attenuated in hypertensive rats on 1.1% calcium, but these responses were improved by calcium supplementation. In the presence of
N
G
-nitro-
l
-arginine methyl ester (L-NAME), the relaxations to ACh in hypertensive animals on normal calcium were practically absent, whereas in normotensive rats and calcium-supplemented hypertensive rats, distinct relaxations to higher concentrations of ACh were still present. These responses were reduced by 30% to 50% with apamin, a blocker of Ca
2+
-activated K
+
channels, and were further inhibited by blockade of ATP-dependent K
+
channels with glyburide. Interestingly, relaxations elicited by ACh and ADP during precontraction with 60 mmol/L KCl (preventing endothelium-dependent hyperpolarization) were not impaired in hypertensive animals. The contractile sensitivity of endothelium-intact arterial rings to 5-hydroxytryptamine and norepinephrine was higher in hypertensive rats on either normal or high-calcium diet, whereas the increase in contractile sensitivity caused by L-NAME corresponded in all groups.

Conclusions
High-calcium diet markedly opposed experimental DOC-NaCl hypertension, an effect associated with improved arterial relaxation, while abnormalities of vascular contractile properties remained unaffected. In particular, the hyperpolarization-related component of endothelium-dependent arterial relaxation, mediated via opening of arterial K
+
channels, could be augmented by calcium supplementation in DOC-NaCl hypertension.
Serum Markers of Collagen Type I Metabolism in Spontaneously Hypertensive Rats
Authors: Díez Javier , Panizo Angel , Gil María J. , Monreal Ignacio , Hernández Marta , Mindán Javier Pardo
Published: June 2012

Background
The assay of serum peptides of extracellular collagen synthesis and degradation could provide an indirect estimate of the rate of fibrillar turnover. This study was designed to investigate whether serum peptides of collagen type I synthesis and degradation are altered in spontaneously hypertensive rats (SHR) with left ventricular hypertrophy and whether these serum collagen-derived peptides are related to myocardial fibrosis.

Methods and Results
We measured serum levels of carboxy-terminal propeptide of procollagen type I (PIP) as a marker of collagen I synthesis and serum levels of the pyridinoline cross-linked telopeptide domain of collagen type I (CITP) as a marker of fibrillar collagen I degradation in ten 36-week-old normotensive Wistar-Kyoto (WKY) rats, ten 36-week-old SHR and, ten 16-week-old SHR treated with the angiotensin-converting enzyme inhibitor quinapril (10 mg/kg body wt per day, orally) for 20 weeks. PIP and CITP were determined by specific radioimmunoassays. Histomorphometric and immunohistochemical studies of the left ventricle were performed in all rats. In untreated SHR compared with WKY rats, we found a more extensive interstitial and perivascular fibrosis, an increased (
P
<.01) collagen volume fraction, a more marked deposition of collagen type I, an increased (
P
<.01) serum concentration of PIP, and a similar serum concentration of CITP. In quinapril-treated SHR compared with untreated SHR, we found an absence of left ventricular hypertrophy, a marked decrease of fibrosis, a lower (
P
<.01) collagen volume fraction, a diminished deposition of collagen type I, a decreased (
P
<.01) concentration of PIP, and a similar concentration of CITP. A direct correlation was found between the collagen volume fraction and serum PIP (
r
=.753,
P
<.05) in untreated SHR.

Conclusions
These results suggest that tissue metabolism of collagen type I is abnormal in SHR and can be normalized by treatment with quinapril. On the basis of our findings, we propose that serum PIP may be a marker of collagen type I–dependent myocardial fibrosis in rats with genetic hypertension.
Reflex Control of Sympathetic Activity During Ventricular Tachycardia in Dogs
Authors: Smith Michael L. , Kinugawa Toru , Dibner-Dunlap Mark E.
Published: June 2012

Background
The determinants of hemodynamic outcome during ventricular tachycardia (VT) are not well understood. In the present study, we addressed the relative contributions of arterial and cardiopulmonary baroreflexes to the sympathetic and arterial pressure responses to VT or ventricular pacing (VP) in dogs with inducible VT.

Methods and Results
Responses of renal sympathetic nerve activity (RSNA), pulmonary capillary wedge pressure (PCWP), and mean arterial pressure (MAP) to induced VT or VP (220 to 280 beats per minute) were determined in 12 dogs with a healed anteroapical infarction and inducible VT and in 8 control dogs. The responses were determined with all reflexes intact, after selective denervation of either arterial or cardiopulmonary baroreflexes, and after combined denervation. Differences between intact and denervated conditions were used to assess the relative effects of each baroreflex. In the infarct group, responses during VT were comparable to those during VP. RSNA and PCWP increased significantly (
P
<.01), whereas MAP decreased significantly (
P
<.001) during VT or VP with baroreflexes intact in both groups. The increase in RSNA and the recovery of MAP during sustained VP were greater in the infarct group (
P
<.05); in addition, the increase in PCWP was greater in the infarct group (
P
<.05). Arterial baroreflex denervation abolished the increased RSNA and recovery of MAP during VP in both groups. After cardiopulmonary baroreflex denervation, the increase in RSNA was augmented in both groups (control group more than infarct group), but recovery of MAP was increased further only in the control group.

Conclusions
These results suggest that arterial baroreflex-mediated sympathoexcitation plays an important role in determining the hemodynamic outcome during VT, whereas cardiopulmonary baroreflexes play only a modest modulatory role.
Alteration in Energetics in Patients With Left Ventricular Dysfunction After Myocardial Infarction
Authors: Hayashi Yoshihiko , Takeuchi Motoshi , Takaoka Hideyuki , Hata Katsuya , Mori Masuki , Yokoyama Mitsuhiro
Published: June 2012

Background
Although the use of inotropic agents to treat congestive heart failure (CHF) in patients with coronary artery disease has yielded short-term hemodynamic improvement, long-term mortality has shown less improvement. The loss of cardiac muscle as a result of infarction not only decreases the pumping ability of the heart but also leads to some dramatic changes in myocardial energetics. However, little is known about the mechanoenergetics of the heart in patients with left ventricular (LV) dysfunction after myocardial infarction.

Methods and Results
The present study was designed to compare, by means of the V̇
o
2
-pressure-volume area relation (PVA, a measure of total mechanical energy) and E
max
(LV contractility index), the incremental oxygen cost of contractility measured as nonmechanical energy per unit increment in contractility in patients with various kinds of LV dysfunction. We assessed E
max
, V̇
o
2
, and PVA using conductance and Webster catheters under control conditions and during different rates of dobutamine infusion (3 and 6 μg·kg
−1
·min
−1
) in 30 patients with coronary artery disease. Patients were divided into three groups according to LV ejection fraction (EF): 10 without LV dysfunction (EF ≥60%), 10 with mild LV dysfunction (40%≤EF<60%), and 10 with severe LV dysfunction (EF <40%). Under control conditions, the V̇
o
2
-PVA relation was linear in each group. Contractile efficiency, the reciprocal of the slope of this relation, was comparable among the three groups. The oxygen cost of contractility in the severe LV dysfunction group was significantly greater than in the groups without and with mild LV dysfunction (0.022±0.014 versus 0.005±0.002 and 0.0012±0.005 mL O
2
· mL · mm Hg
−1
per beat,
P
<.05).

Conclusions
These findings suggest that the alteration in mechanoenergetics in patients with severe LV dysfunction after myocardial infarction may result from the increased oxygen cost of excitation-contraction coupling rather than from a reduction in the efficiency of chemomechanical energy transduction.
Failure of Reflex Venoconstriction During Exercise in Patients With Vasovagal Syncope
Authors: Thomson Helen L. , Atherton John J. , Khafagi Frederick A. , Frenneaux Michael P.
Published: June 2012

Background
In this study, we tested two hypotheses. First, we tested the hypothesis that reflex constriction of the venous capacitance beds in patients with vasovagal syncope is impaired during both subhypotensive lower-body negative pressure. Second, we proposed that splenic venoconstriction may be impaired during exercise in patients with vasovagal syncope.

Methods and Results
We evaluated 25 patients with vasovagal syncope (age, 45.0±15.9 years; 12 men, 13 women) and 24 control subjects (age, 41.3±13.7 years; 16 men, 8 women). A nuclear technique was used to assess changes in forearm venous tone during lower-body negative pressure and in splenic venous volume during cycle exercise. Changes in forearm vascular resistance (FVR) during cycle exercise were assessed with a strain-gauge plethysmography technique. The percentage reduction in unstressed forearm vascular volume during lower-body negative pressure was similar in patients and control subjects (9.0±8.0% versus 9.7±5.9%,
P
=NS). During exercise, splenic venous volume decreased less in patients than in control subjects (15.8±21.7% versus 42.6±12.6%,
P
<.0001). FVR decreased by 2±32% in patients but increased 108±90% in control subjects (
P
<.0001). There was no relation between percentage change in splenic volume and percentage change in FVR during exercise in either patients or control subjects (
r
=−.06,
P
=NS and
r
=−.18,
P
=NS, respectively).

Conclusions
Patients with vasovagal syncope exhibit a failure of the normal increase in tone in the splenic capacitance bed and in forearm resistance vessels during dynamic exercise. Forearm venous tone increases normally during lower-body negative pressure.
Prediction of Successful Ablation Site of Concealed Posteroseptal Accessory Pathways by a Novel Algorithm Using Baseline Electrophysiological Parameters
Authors: Chiang Chern-En , Chen Shih-Ann , Tai Ching-Tai , Wu Tsu-Juey , Lee Shih-Huang , Cheng Chen-Chuan , Chiou Chuen-Wang , Ueng Kuo-Chang , Wen Zu-Chi , Chang Mau-Song
Published: June 2012

Background
Radiofrequency catheter ablation of concealed posteroseptal accessory pathways (APs) has been a relatively difficult task for electrophysiologists. Without a detailed mapping procedure, the left versus the right posteroseptal AP could not be distinguished. We investigated the electrophysiological characteristics of concealed posteroseptal APs and defined criteria from baseline parameters to predict the successful ablation site. Validity of the criteria was prospectively verified.

Methods and Results
Eighty-nine consecutive patients with a single concealed posteroseptal AP underwent successful radiofrequency catheter ablation. Of the initial 48 patients (group 1), the right posteroseptal area was first mapped. If no ideal electrogram could be obtained, or after several ineffective radiofrequency pulses, the left posteroseptal area was then mapped. Special attention was paid to the stability of the coronary sinus catheter with the most proximal electrode straddling the ostium, verified by coronary sinus venography, in all patients. Six patients (12.5%) had the earliest retrograde atrial activation at the middle electrode of the coronary sinus catheter, and successful ablation could only be achieved at the left posteroseptal area. For patients who presented with the earliest atrial activation at the proximal electrode, the presence of long RP′ tachycardia suggested a right endocardial approach, while the ΔVA (defined as the difference in the VA intervals between that recorded at the His bundle catheter and that at one of the electrode groups recording the earliest atrial activation) ≥25 ms during tachycardia suggested a left endocardial approach. The subsequent 41 patients (group 2) were randomized into two subgroups. The initial mapping site was guided by the algorithm in group 2B, while it was not in group 2A. The successful ablation site could be predicted accurately in 18 (90%) of the 20 patients in group 2B. The radiofrequency pulses, ablation time, and fluoroscopic time were markedly reduced in group 2B, mainly because of the omission of unnecessary mapping procedure in the right posteroseptal area in patients with “left atrio–left ventricular” fibers.

Conclusions
By the algorithm based on baseline electrophysiological parameters, the successful ablation site could be accurately predicted in a majority of patients with concealed posteroseptal APs. Radiofrequency pulses, ablation time, and fluoroscopic time were markedly reduced.
C-Type Natriuretic Peptide
Authors: Davidson Neil C. , Barr Craig S. , Struthers Allan D.
Published: June 2012

Background
Atrial and B-type natriuretic peptide are both known to be antagonists of the renin-angiotensin system. C-type natriuretic peptide (CNP) is a new member of this family except that its principal source is the vascular endothelium. This study tested the hypothesis that CNP is a local inhibitor of vascular angiotensin-converting enzyme (ACE) activity.

Methods and Results
Vascular ACE activity was assessed by the differential vascular response to angiotensin I and angiotensin II. Healthy male volunteers were studied with the use of brachial artery infusions of angiotensin I and angiotensin II at two doses, with and without coinfusion of CNP at 500 pmol/min (n=8) and hydralazine at 10 μg/min (n=8) (as a nonspecific vasodilator control). CNP alone and hydralazine alone caused similar increases in forearm blood flow (CNP+, 93.0±14.8%; hydralazine+, 84.2±22.6%). CNP inhibited the vasoconstrictive effect of angiotensin I (reduction in overall effect with CNP, 56.8±12.9%;
P
<.001) but not that of angiotensin II. Hydralazine did not significantly inhibit the effect of either angiotensin I or angiotensin II.

Conclusions
This evidence of a differential effect of CNP on the vascular response to angiotensin I but not to angiotensin II suggests that CNP acts as a local endogenous regulator of vascular ACE activity in the human forearm resistance vessels.
Optical Coherence Tomography for Optical Biopsy
Authors: Brezinski Mark E. , Tearney Guillermo J. , Bouma Brett E. , Izatt Joseph A. , Hee Michael R. , Swanson Eric A. , Southern James F. , Fujimoto James G.
Published: June 2012

Background
Optical coherence tomography (OCT) is a recently developed medical diagnostic technology that uses back-reflected infrared light to perform in situ micron scale tomographic imaging. In this work, we investigate the ability of OCT to perform micron scale tomographic imaging of the internal microstructure of in vitro atherosclerotic plaques.

Methods and Results
Aorta and relevant nonvascular tissue were obtained at autopsy. Two-dimensional cross-sectional imaging of the exposed surface of the arterial segments was performed in vitro with OCT. A 1300-nm wavelength, superluminescent diode light source was used that allows an axial spatial resolution of 20 μm. The signal-to-noise ratio was 109 dB. Images were displayed in gray scale or false color. Imaging was performed over 1.5 mm into heavily calcified tissue, and a high contrast was noted between lipid- and water-based constituents, making OCT attractive for intracoronary imaging. The 20-μm axial resolution of OCT allowed small structural details such as the width of intimal caps and the presence of fissures to be determined. The extent of lipid collections, which had a low backscattering intensity, also were well documented.

Conclusions
OCT represents a promising new technology for imaging vascular microstructure with a level of resolution not previously achieved with the use of other imaging modalities. It does not require direct contact with the vessel wall and can be performed with a catheter integrated with a relatively inexpensive optical fiber. The high contrast among tissue constituents, high resolution, and ability to penetrate heavily calcified tissue make OCT an attractive new imaging technology for intracoronary diagnostics.
Intrinsic Myocyte Dysfunction and Tyrosine Kinase Pathway Activation Underlie the Impaired Wall Thickening of Adjacent Regions During Postinfarct Left Ventricular Remodeling
Authors: Melillo Guido , Lima João A.C. , Judd Robert M. , Goldschmidt-Clermont Pascal J. , Silverman Howard S.
Published: June 2012

Background
Left ventricular remodeling after infarction is accompanied by dysfunction of regions adjacent to the infarct. We hypothesized that myocyte contractile abnormalities and elongation greater than in remote regions underlie adjacent-region dysfunction in the remodeled ventricle. The activation of the tyrosine kinase pathway, which mediates in vitro hypertrophy by stretch and/or angiotensin, was also assessed in myocytes separately isolated from adjacent and remote regions.

Methods and Results
ECG-gated magnetic resonance imaging short-axis images were acquired 2 weeks after coronary ligation in rats. After the rats were killed, myocytes were isolated from animals with large (n=7) and small (n=7) infarcts and from 4 sham-operated controls. Regional wall thickening was correlated with local myocyte function and morphology. Cytochemistry for tyrosine-phosphorylated proteins was performed in myocytes from the same regions. Remodeled ventricles were dilated relative to controls by 93.7%, and wall thickening in adjacent regions was less than in remote regions (27.8±6.11% versus 54.0±10.1%,
P
<.01). In large infarcts, cell extent and velocity of shortening were reduced in adjacent cells versus controls by 47% and 44%, respectively (
P
<.05). Myocyte shortening was reduced in adjacent versus remote regions (
P
<.06), and cell dysfunction correlated with impaired wall thickening (
r
=.72,
P
<.05). Myocytes in adjacent regions were longer than in remote regions (150.3±1.89 versus 143.1±1.76 μm,
P
<.05) and also showed 88% more membrane-related phosphotyrosine clusters (
P
<.05).

Conclusions
After infarction, impaired wall thickening in adjacent regions is accompanied by greater myocyte dysfunction and elongation than in remote regions. These abnormalities are associated with regional differences in the tyrosine kinase pathway activation, indicating a potential intracellular mechanism for postinfarct myocardial remodeling.
Contribution of Glycogen to Aerobic Myocardial Glucose Utilization
Authors: Henning Sarah L. , Wambolt Richard B. , Schönekess Brett O. , Lopaschuk Gary D. , Allard Michael F.
Published: June 2012

Background
We determined glycogen turnover and the contribution of glycogen as a source of glucose for aerobic myocardial glycolysis and glucose oxidation in parallel series of isolated, working rat hearts subjected to pulse-chase perfusions.

Methods and Results
Myocardial glycogen of isolated, working rat hearts was radiolabeled, after 30 minutes of substrate-free glycogen depletion, by perfusion for 60 minutes with buffer designed to stimulate resynthesis of glycogen (1.2 mmol/L palmitate, 11 mmol/L [U-
14
C]- or [5-
3
H]-glucose, 0.5 mmol/L lactate, and 100 μU/mL insulin). Rates of glucose oxidation (
14
CO
2
production) and glycolysis (
3
H
2
O production) were then measured by perfusing the hearts for 40 minutes with buffer designed to simulate physiological conditions (0.4 mmol/L palmitate, 0.5 mmol/L lactate, 11 mmol/L [5-
3
H]- or [U-
14
C]-glucose, 100 μU/mL insulin) containing radiolabeled glucose different from that used during resynthesis. During the chase perfusion, rates of glycolysis and glucose oxidation from exogenous glucose were significantly greater than those from endogenous glycogen. Nevertheless, glycogen contributed significantly to myocardial energy production (41% of the overall ATP produced from glucose), and a significantly greater fraction of the glucose from glycogen that passed through glycolysis was oxidized (>50%) compared with the fraction oxidized from exogenous glucose (<20%,
P
<.05). Myocardial glycogen was simultaneously synthesized and degraded (ie, glycogen turnover) during the chase perfusion, despite net glycogenolysis. Furthermore, enrichment of labeled glucose in glycogen at the end of the chase perfusion, when corrected for newly synthesized glycogen, did not differ from that at the end of the labeling period.

Conclusions
Thus, glycogen contributes significantly to aerobic myocardial glucose use under these experimental conditions, and the glucose derived from glycogen is oxidized preferentially compared with exogenous glucose. Additionally, substantial myocardial glycogen turnover occurs, and the manner in which glycogen is degraded does not fit the ordered hypothesis of “last glucose on, first glucose off.”
Latent Hypoparathyroidism in Children With Conotruncal Cardiac Defects
Authors: Cuneo Bettina F. , Langman Craig B. , Ilbawi Michel N. , Ramakrishnan V. , Cutilletta Anthony , Driscoll Deborah A.
Published: June 2012

Background
DiGeorge anomaly is characterized by hypoplasia or atresia of the thymus and parathyroid glands resulting in T cell–mediated immune deficiency, hypocalcemic hypoparathyroidism, and conotruncal cardiac defects. It usually is associated with deletions of chromosomal region 22q11. We hypothesized that the stimulated (secretory reserve) but not the constitutive secretion of parathyroid hormone would be reduced in normocalcemic children with conotruncal cardiac defects but no overt immune deficiency and would be related to the presence of a deletion in the DiGeorge chromosomal region of 22q11.

Methods and Results
Blood-ionized calcium and serum-intact parathyroid hormone were measured at baseline and seven more times during hypocalcemia induced during cardiopulmonary bypass in 22 patients and 10 control subjects with an atrial septal defect. Chromosomal deletions were detected by fluorescent in situ hybridization and DNA dosage analysis. There were no differences in basal calcium and parathyroid hormone levels between patients and control subjects. All had increased parathyroid hormone in response to hypocalcemia; despite lower calcium levels, parathyroid hormone levels were lower in patients. The parathyroid hormone secretory reserve in 14 of 22 patients was reduced compared with control subjects; 4 of the 14 had deletions.

Conclusions
A significant number of children with conotruncal cardiac defects have normocalcemia and a normal constitutive level of parathyroid hormone but deficient parathyroid hormone secretory reserve; about 30% also have 22q11 deletions. Such children may be at risk for the later development of hypocalcemic hypoparathyroidism.
Remodeling Rather Than Neointimal Formation Explains Luminal Narrowing After Deep Vessel Wall Injury
Authors: Rud Andersen Henning , Mæng Michael , Thorwest Martin , Falk Erling
Published: June 2012

Background
Oversized balloon dilatation of normal porcine coronary arteries usually heals without stenosis formation.

Methods and Results
With the purpose of developing a stenotic model and examining the mechanisms of luminal narrowing after angioplasty, we produced a circumferential deep vessel wall injury by inflating and withdrawing an oversized chain-encircled angioplasty balloon in the left anterior descending coronary artery (LAD) of 20 pigs. Three pigs died and did not complete the study. In 8 pigs (group 1), serial coronary arteriography was performed. The lumen diameter (mean±SD) before dilatation was 3.4±0.4 mm; after dilatation, 4.2±0.6 mm; and at follow-ups 2 and 4 weeks later, 1.6±0.4 mm (
P
<.0001). In 9 pigs (group 2) examined postmortem 3 weeks after dilatation, histology revealed that the injury was deep (out to adventitia) in all arteries and completely circumferential (360°) in all but two arteries. Adventitia was markedly thickened as a result of neoadventitial formation. Injury correlated strongly with neointimal formation (middle LAD,
r
=.71,
P
=.00001), but neither injury nor neointima correlated with lumen size (
r
=.14,
P
=.46 and
r
=.34,
P
=.07, respectively); ie, neointimal formation did not explain late luminal narrowing. Lumen size, however, did correlate strongly with vessel size (
r
=.74,
P
=.000005). The late loss in lumen diameter observed angiographically in group 1 substantially exceeded that caused by neointimal formation seen by histology in group 2.

Conclusions
The chain-encircled angioplasty balloon produced a circumferential deep vessel wall injury that healed by luminal narrowing. In this porcine model, arterial remodeling was more important than neointimal formation in late luminal narrowing.
Dichotomy of Ischemic Preconditioning
Authors: Kolocassides Kyriacos G. , Galiñanes Manuel , Hearse David J.
Published: June 2012

Background
Acceleration of ischemic contracture is conventionally accepted as a predictor of poor postischemic function. Hence, protective interventions such as cardioplegia delay ischemic contracture and improve postischemic contractile recovery. We compared the effect of ischemic preconditioning and cardioplegia (alone and in combination) on ischemic contracture and postischemic contractile recovery.

Methods and Results
Isolated rat hearts were aerobically perfused with blood for 20 minutes before being subjected to zero-flow normothermic global ischemia for 35 minutes and reperfusion for 40 minutes. Hearts were perfused at a constant pressure of 60 mm Hg and were paced at 360 beats per minute. Left ventricular developed pressure and ischemic contracture were assessed with an intraventricular balloon. Four groups (n=8 hearts per group) were studied: control hearts with 35 minutes of unprotected ischemia, hearts preconditioned with one cycle of 3 minutes of ischemia plus 3 minutes of reperfusion before 35 minutes of ischemia, hearts subjected to cardioplegia with St Thomas’ solution infused for 1 minute before 35 minutes of ischemia, and hearts subjected to preconditioning plus cardioplegia before 35 minutes of ischemia. After 40 minutes of reperfusion, each intervention produced a similar improvement in postischemic left ventricular developed pressure (expressed as a percentage of its preischemic value: preconditioning, 44±2%; cardioplegia, 53±3%; preconditioning plus cardioplegia, 54±4%; and control, 26±6%,
P
<.05). However, preconditioning accelerated whereas cardioplegia delayed ischemic contracture; preconditioning plus cardioplegia gave an intermediate result. Thus, times to 75% contracture were as follows: control, 14.3±0.4 minutes; preconditioning, 6.2±0.3 minutes; cardioplegia, 23.9±0.8 minutes; and preconditioning plus cardioplegia, 15.4±2.4 minutes (
P
<.05 preconditioning and cardioplegia versus control). In additional experiments, using blood- and crystalloid-perfused hearts, we describe the relationship between the number of preconditioning cycles and ischemic contracture.

Conclusions
Although preconditioning accelerates, cardioplegia delays, and preconditioning plus cardioplegia has little effect on ischemic contracture, each affords similar protection of postischemic contractile function. These results question the utility of ischemic contracture as a predictor of the protective efficacy of anti-ischemic interventions. They also suggest that preconditioning and cardioplegia may act through very different mechanisms.
Correlation of Ischemia-Induced Extracellular and Intracellular Ion Changes to Cell-to-Cell Electrical Uncoupling in Isolated Blood-Perfused Rabbit Hearts
Authors: Owens Lisa M. , Fralix Teresa A. , Murphy Elizabeth , Cascio Wayne E. , Gettes Leonard S.
Published: June 2012

Background
The relationships between the metabolic, ionic, and electrical changes of acute ischemia have not been determined precisely because they have been studied under different experimental conditions. We used ion-selective electrodes, nuclear magnetic resonance spectroscopy, and the four-electrode method to perform four series of experiments in the isolated blood-perfused rabbit heart loaded with 5F-BAPTA during 30 to 35 minutes of no-flow ischemia. We sought to determine the relationship between changes in phosphocreatine (PCr), adenosine triphosphate (ATP), intracellular calcium ([Ca
2+
]
i
), intracellular pH (pH
i
), extracellular potassium ([K
+
]
e
), extracellular pH (pH
e
), and whole-tissue resistance (r
t
).

Methods and Results
In the first 8 minutes of ischemia, [K
+
]
e
rose from 4.9 to 10.8 mmol/L, PCr fell by 90%, ATP decreased by 25%, and pH
i
and pH
e
decreased by 0.5 U, while [Ca
2+
]
i
and r
t
changed only slightly. Between 8 and 23 minutes, [K
+
]
e
changed only slightly; pH
i
, pH
e
, and ATP continued to fall, and [Ca
2+
]
i
rose. r
t
did not increase until >20 minutes of ischemia, when pH
i
was <6.0 and [Ca
2+
]
i
had increased more than threefold. The increase in r
t
, indicating electrical uncoupling, coincided with the third phase of the [K
+
]
e
change.

Conclusions
Our study suggests that cellular uncoupling occurs only after a significant rise in [Ca
2+
]
i
and fall in pH
i
and that these ionic and electrical changes can be identified by the change in [K
+
]
e
. Our study underscores the importance of using a common model while attempting to formulate an integrated picture of the ionic, metabolic, and electrical events that occur during acute ischemia.
Antioxidant Vitamin C Improves Endothelial Dysfunction in Chronic Smokers
Authors: Heitzer Thomas , Just Hanjo¨rg , Mu¨nzel Thomas
Published: June 2012

Background
Chronic smoking is associated with endothelial dysfunction, an early stage of atherosclerosis. It has been suggested that endothelial dysfunction may be a consequence of enhanced degradation of nitric oxide secondary to formation of oxygen-derived free radicals. To test this hypothesis, we investigated the effects of the antioxidant vitamin C on endothelium-dependent responses in chronic smokers.

Methods and Results
Forearm blood flow responses to the endothelium-dependent vasodilator acetylcholine (7.5, 15, 30, and 60 μg/min) and the endothelium-independent vasodilator sodium nitroprusside (1, 3, and 10 μg/min) were measured by venous occlusion plethysmography in 10 control subjects and 10 chronic smokers. Drugs were infused into the brachial artery, and forearm blood flow was measured for each drug before and during concomitant intra-arterial infusion of the antioxidant vitamin C (18 mg/min). In control subjects, vitamin C had no effect on forearm blood flow in response to acetylcholine and sodium nitroprusside. In contrast, in chronic smokers the attenuated forearm blood flow responses to acetylcholine were markedly improved by concomitant administration of vitamin C, whereas the vasodilator responses to sodium nitroprusside were not affected.

Conclusions
The present studies demonstrate that the antioxidant vitamin C markedly improves endothelium-dependent responses in chronic smokers. This observation supports the concept that endothelial dysfunction in chronic smokers is at least in part mediated by enhanced formation of oxygen-derived free radicals.
Relationship to Blood Pressure of Combinations of Dietary Macronutrients
Authors: Stamler Jeremiah , Caggiula Arlene , Grandits Greg A. , Kjelsberg Marcus , Cutler Jeffrey A.
Published: June 2012

Background
Elevated blood pressure remains a widespread major impediment to health. Obesity and specific dietary factors such as high salt and alcohol intake and low potassium intake adversely affect blood pressure. It is a reasonable hypothesis that additional dietary constituents, particularly macronutrients, may also influence blood pressure.

Methods and Results
Participants were 11 342 middle-aged men from the Multiple Risk Factor Intervention Trial (MRFIT). Data from repeat 24-hour dietary recalls (four to five per person) and blood pressure measurements at six annual visits were used to assess relationships, singly and in combination, of dietary macronutrients to blood pressure, adjusted for multiple possible confounders (demographic, dietary, and biomedical). Multiple linear regression was used to assess diet–blood pressure relations in two MRFIT treatment groups (special intervention and usual care), with adjustment for confounders, pooling of coefficients from the two groups (weighted by inverse of variance), and correction of coefficients for regression-dilution bias. In multivariate regression models, dietary cholesterol (milligrams per 1000 kilocalories), saturated fatty acids (percent of kilocalories), and starch (percent of kilocalories) were positively related to blood pressure; protein and the ratio of dietary polyunsaturated to saturated fatty acids were inversely related to blood pressure. These macronutrient–blood pressure findings were obtained in analyses that controlled for body mass, dietary sodium and ratio of sodium to potassium, and alcohol intake, each positively related to blood pressure, and intake of potassium and caffeine, both inversely related to blood pressure.

Conclusions
These data support the concept that multiple dietary factors influence blood pressure; hence, broad improvements in nutrition can be important in preventing and controlling high-normal and high blood pressure.
Incidence and Clinical Relevance of the Occurrence of Bundle-Branch Block in Patients Treated With Thrombolytic Therapy
Authors: Newby Keith H. , Pisano´ Ennio , Krucoff Mitchell W. , Green Cindy , Natale Andrea
Published: June 2012

Background
Whether thrombolytic therapy alters the incidence and clinical outcome of bundle-branch block is unclear.

Methods and Results
We examined the occurrence of new-onset bundle-branch block, both transient and persistent, in 681 patients with acute myocardial infarction enrolled in the Thrombolysis and Angioplasty in Myocardial Infarction 9 and Global Utilization of Streptokinase and t-PA for Occluded Arteries 1 protocols. Each patient underwent continuous 12-lead ECG monitoring for 36 to 72 hours with the Mortara ST monitoring system. Bundle-branch block was characterized as right, left, alternating, transient, or persistent. The overall incidence of bundle-branch block was 23.6% (n=161), with transient block in 18.4% (n=125) and persistent block in 5.3% (n=36). Right bundle-branch block was found in 13% (n=89) of the population; left bundle-branch block was found in 7% (n=48). Alternating bundle-branch block was seen in 3.5% (n=24) of patients. Left anterior descending artery infarcts accounted for most bundles (54%, n=79). Patients with bundle-branch block had lower ejection fractions, higher peak creatine phosphokinase levels (
P
<.0001), and more diseased vessels (
P
<.019). Mortality rates in patients with and without bundle-branch block were 8.7% and 3.5%, respectively (
P
<.007). A higher mortality rate was observed in the presence of persistent (19.4%) versus transient (5.6%) or no (3.5%) bundle-branch block (
P
<.001).

Conclusions
Thrombolytic therapy reduces the overall mortality rate associated with persistent bundle-branch block. However, persistent bundle-branch block remains predictive of a higher mortality rate than either transient or no bundle-branch block. Continuous 12-lead ECG monitoring provides an accurate characterization of the incidence and type of conduction disturbances after acute myocardial infarction.
α-Tocopherol Inhibits Aggregation of Human Platelets by a Protein Kinase C–Dependent Mechanism
Authors: Freedman Jane E. , Farhat John H. , Loscalzo Joseph , Keaney John F.
Published: June 2012

Background
Epidemiological studies indicate that vitamin E (α-tocopherol) exerts a beneficial effect on cardiovascular disease. The effect of vitamin E has generally been attributed to its antioxidant activity and the antioxidant protection of LDL. Distinct from its effect on LDL, vitamin E is also known to inhibit platelet aggregation and adhesion in vitro, but the mechanism(s) responsible for these observations are not known.

Methods and Results
Using gel-filtered platelets derived from platelet-rich plasma treated with α-tocopherol (500 μmol/L) or vehicle (0.5% ethanol), we found that inhibition of platelet aggregation by α-tocopherol was closely linked to its incorporation into platelets (
r
=−.78;
P
<.02). Platelet incorporation of α-tocopherol was associated with a significant reduction in platelet sensitivity to aggregation by adenosine 5′-diphosphate, arachidonic acid, and phorbol ester (PMA) by approximately 0.15-, 2-, and 100-fold, respectively. In contrast, platelets treated similarly with butylated hydroxytoluene, another potent lipid-soluble antioxidant, did not demonstrate any change in sensitivity to these agents. Platelet incorporation of α-tocopherol inhibited PMA-induced stimulation of platelet protein kinase C (PKC) as determined by phosphorylation of the 47-kD PKC substrate. In 15 normal subjects, oral supplementation with α-tocopherol (400 to 1200 IU/d) resulted in an increase in platelet α-tocopherol content that correlated with marked inhibition of PMA-mediated platelet aggregation (
r
=.67;
P
<.01). Platelets derived from these subjects after supplementation also demonstrated apparent complete inhibition of PKC stimulation by PMA.

Conclusions
These data indicate that platelet incorporation of α-tocopherol at levels attained with oral supplementation is associated with inhibition of platelet aggregation through a PKC-dependent mechanism. These observations may represent one potential mechanism for the observed beneficial effect of α-tocopherol in preventing the development of coronary artery disease.
Lanreotide Reduces Serum Free and Total Insulin-Like Growth Factor-I After Angioplasty
Authors: Frystyk Jan , Skjærbæk Christian , Alexander Niels , Emanuelsson Håkan , Suryapranata Harry , Beyer Horst , Foegh Marie , Ørskov Hans
Published: June 2012

Background
Several experiments point to a participating role of insulin-like growth factor-I (IGF-I) in the vascular events leading to restenosis after percutaneous transluminal coronary angioplasty (PTCA).

Methods and Results
We measured fasting serum total (extractable) IGF-I in 553 patients in a controlled clinical trial. Half of the patients received continuous subcutaneous infusion of the somatostatin analogue lanreotide from the day before (baseline) and for 4 days after PTCA. We also measured ultrafiltrated serum free IGF-I and IGF-II, total IGF-II, IGF-binding protein-1 (IGFBP-1), IGFBP-3, and insulin in a subgroup of 18 placebo-treated and 20 lanreotide-treated patients. Total IGF-I had decreased by 7% (
P
<.0001) 1 day after initiation of lanreotide infusion and stayed reduced, whereas no early changes occurred in placebo-treated patients. The same pattern was observed in the subgroup. Free IGF-I decreased significantly from baseline by 22% to 27% (
P
<.05) in lanreotide-treated patients and increased insignificantly by 10% to 30% (
P
=.054) in placebo-treated patients. IGFBP-1 increased (
P
<.05) in both groups postoperatively, but levels in lanreotide-treated patients exceeded (
P
<.05) those of placebo-treated patients. Lanreotide treatment resulted in minor reductions (
P
<.05) in free and total IGF-II and IGFBP-3, whereas insulin was unaltered.

Conclusions
Lanreotide administration acutely decreases circulating total and free IGF-I, the latter relatively more, and increases IGFBP-1. These alterations in the IGF system may participate in the improvement of the long-term outcome after PTCA noted with lanreotide treatment.
Hemodynamic Effects of Nonionic Contrast Bolus Injection and Oxygen Inhalation During Pulmonary Angiography in Patients With Chronic Major-Vessel Thromboembolic Pulmonary Hypertension
Authors: Pitton Michael Bernhard , Du¨ber Christoph , Mayer Eckhard , Thelen Manfred
Published: June 2012

Background
Pulmonary angiography is the gold standard for the diagnosis of chronic thromboembolic pulmonary hypertension; however, major complications have been reported. This study evaluates the hemodynamic effects of direct pulmonary nonionic contrast bolus injection and oxygen inhalation in patients with chronic thromboembolic pulmonary hypertension.

Methods and Results
In 33 patients, hemodynamic parameters were measured after oxygen inhalation and during bolus injection of nonionic contrast medium in a control group (group 1, n=11), in a group of patients with moderately severe pulmonary hypertension (group 2, n=9), and in a group with severe pulmonary hypertension (group 3, n=13). Oxygen inhalation significantly improved oxygen supply. Pulmonary artery pressure and heart rate were reduced, but pulmonary vascular resistance and total pulmonary resistance were not significantly affected. One hundred ninety-eight angiograms were performed selectively on both pulmonary arteries in the posterior-anterior, oblique, and lateral views. Before contrast bolus injection, RAP and PAP significantly increased because of initial inspiration. Contrast bolus injection caused only a minor pressure increase (ΔPA systolic, 2.3±1.4, 2.5±1.8, and 5.0±5.2 mm Hg, groups 1, 2, and 3, respectively) without significance between the groups. After the angiography, pulmonary artery pressure was moderately increased, predominantly in group 3, but pulmonary vascular resistance was not significantly changed. Systemic vascular resistance was decreased. Cardiac index increased in groups 1 and 2 but was unchanged in group 3. Systemic pressure therefore decreased in group 3.

Conclusions
We concluded that bolus injection of nonionic contrast medium causes no major hemodynamic effects even in patients with severe chronic thromboembolic pulmonary hypertension. Oxygen contributes to safety during the procedure.
Adrenomedullin Augments Inducible Nitric Oxide Synthase Expression in Cytokine-Stimulated Cardiac Myocytes
Authors: Ikeda Uichi , Kanbe Toshiko , Kawahara Yasuhiro , Yokoyama Mitsuhiro , Shimada Kazuyuki
Published: June 2012

Background
Plasma levels of adrenomedullin are increased in patients with congestive heart failure, but there has been no report concerning the effects of adrenomedullin on the heart. We investigated the effects of adrenomedullin on NO synthase activity in cardiac myocytes.

Methods and Results
We measured the production of nitrite, a stable metabolite of NO, in cultured neonatal rat cardiac myocytes with the Griess reagent. Inducible NO synthase mRNA and protein expression were assayed by Northern and Western blotting, respectively. Incubation of the cultures with interleukin-1β (10 ng/mL) for 24 hours caused a significant increase in nitrite accumulation. Adrenomedullin significantly augmented nitrite production by interleukin-1β–stimulated but not by unstimulated cardiac myocytes in a dose-dependent manner (10
−10
to 10
−6
mol/L). The adrenomedullin-induced nitrite production by interleukin-1β–stimulated cells was accompanied by increased inducible NO synthase mRNA and protein expression. In the presence of dibutyryl cAMP, the interleukin-1β–induced nitrite accumulation was increased further, but the stimulatory effect of adrenomedullin on nitrite production was abolished. Adrenomedullin dose-dependently increased intracellular cAMP levels in cardiac myocytes. Addition of the calcitonin gene–related peptide (CGRP) receptor antagonist CGRP[8-37] to the culture dose-dependently inhibited both cAMP and NO generation stimulated by adrenomedullin.

Conclusions
These results indicate that adrenomedullin acts on cardiac myocytes and augments NO synthesis in these cells under cytokine-stimulated conditions, at least partially through a cAMP-dependent pathway.
New Activity of Spironolactone
Authors: Klauber Nancy , Browne Fiona , Anand-Apte Bela , D'Amato Robert J.
Published: June 2012

Background
The formation of new blood vessels (angiogenesis) is a critical component in a variety of pathological settings, including solid tumor growth, macular degeneration, and atherosclerosis.

Methods and Results
We have found that orally administered spironolactone inhibited the area of angiogenesis induced by basic fibroblast growth factor (bFGF) in a rabbit corneal micropocket assay. Additionally, spironolactone inhibited bFGF- and vascular endothelial growth factor–stimulated capillary endothelial cell proliferation in vitro, inhibited bFGF-stimulated capillary endothelial cell chemotaxis in vitro, and caused avascular zones when placed on the chick chorioallantoic membrane. Experiments analyzing spironolactone metabolites revealed that the major human metabolites 6β-hydroxy-7α-thiomethyl spironolactone and canrenoic acid retained antiangiogenic activity. The antiangiogenic activity appears to be unrelated to the antiandrogenic and antimineralocorticoid effects of spironolactone.

Conclusions
These experiments hold promise for the potential use of spironolactone as an orally administered drug for the treatment of many diverse diseases dependent on angiogenesis.
Results of Percutaneous Transluminal Coronary Angioplasty in Unstable Angina and Non–Q-Wave Myocardial Infarction
Authors: Williams David O. , Braunwald Eugene , Thompson Bruce , Sharaf Barry L. , Buller Chris E. , Knatterud Genell L.
Published: June 2012

Background
This report describes the results of percutaneous transluminal coronary angioplasty (PTCA) in the Thrombolysis in Myocardial Ischemia (TIMI) IIIB Investigation.

Methods and Results
PTCA was performed before hospital discharge in 444 of 1473 patients with either unstable angina pectoris or non–Q-wave myocardial infarction (NQWMI) enrolled in TIMI IIIB. Angiographic success was observed in 96.1% of patients. For the entire cohort, the cumulative incidences of death and infarction at 1 year were 2.0% and 8.2%, respectively. The periprocedural incidence of myocardial infarction was 2.7%; emergency coronary bypass surgery, 1.4%; and death, 0.5%. By 1 year of follow-up, 122 patients (28.0%, Kaplan-Meier) had an additional revascularization procedure, 75 (61.5%) had PTCA only, 30 (24.6%) had coronary bypass surgery only, and 17 (13.9%) had both procedures. The results of PTCA were not improved by routine pretreatment with intravenous tissue plasminogen activator (TPA). Periprocedural myocardial infarction was more common among patients receiving TPA than placebo (odds ratio [OR], 2.19;
P
=.03) and among those with unstable angina than those with NQWMI (OR, 15.5;
P
=.007). No difference in outcome was observed when patients were analyzed according to age (OR, 1.06;
P
=.092) or sex (OR, 1.54;
P
=.51). Variables predictive of poor outcome were PTCA within the first 24 hours of enrollment, PTCA site being the left anterior descending coronary artery, and unsuccessful angiography.

Conclusions
In TIMI IIIB, PTCA was performed for patients with unstable angina and NQWMI with a very high rate of angiographic success and a low incidence of complications. By 1 year, repeat revascularization was performed in 28.0% of patients. Routine pretreatment with thrombolysis did not enhance outcome.