bluuebunny/crossref_metadata_2025 huggingface dataset:
Cardiovascular Effects of Insulin-Like Growth Factor-1 and Growth Hormone in Chronic Left Ventricular Failure in the Rat
Authors: Duerr Robert L. , McKirnan M. Dan , Gim Ronald D. , Clark Ross G. , Chien Kenneth R. , Ross John
Published: June 2012

Background
Insulin-like growth factor-1 (IGF-1) appears to have favorable cardiac effects associated with left ventricular remodeling early after myocardial infarction in the rat. The present study was designed to determine whether IGF-1 combined with growth hormone would be beneficial later as well, when infarct healing and cardiac remodeling have occurred.

Methods and Results
Four weeks after coronary occlusion, 36 rats were randomized to IGF-1 (3 mg·kg
−1
·d
−1
) plus growth hormone (0.1 mg BID) or to placebo for 4 weeks. Treated rats had significant increases in body weight (22%), while the ratio of heart weight to body weight was unchanged. Under anesthesia, cardiac output (fluorescent microspheres) increased 46%, and systemic vascular resistance decreased by 21% (
P
<.001) in the treated group; a significant (22%) increase of the cardiac index was limited to treated rats with large myocardial infarctions. Small increases in the reduced left ventricular ejection fractions and left ventricular dP/dt
max
values with treatment were not significant. Treated rats showed a borderline (16%) increase in left ventricular end-diastolic volume (angiography), whereas the ratio of left ventricular end-diastolic volume to body weight was reduced in the treated group.

Conclusions
IGF-1 plus growth hormone administered to rats with left ventricular failure starting 1 month after MI was associated with substantial body growth, decreased systemic vascular resistance, and increased cardiac output. The failing heart also underwent treatment-induced increases in left and right ventricular weights in proportion to body growth, but left ventricular remodeling was minor, and a decrease in the ratio of left ventricular end-diastolic volume to body weight reflected relatively less chamber dilation compared with controls. A significant interaction between size of the myocardial infarction and treatment was observed for several variables, and IGF-1 and growth hormone increased the cardiac index (
P
<.035) in rats with a large myocardial infarction.
Enhancement of Platelet Deposition by Cross-Linked Hemoglobin in a Rat Carotid Endarterectomy Model
Authors: Olsen Stephen B. , Tang Douglas B. , Jackson Mark R. , Gomez Edward R. , Ayala Benjamin , Alving Barbara M.
Published: June 2012

Background
Purified human cross-linked hemoglobin, which is now being used in clinical trials, increases mean arterial pressure through binding of nitric oxide (NO). We postulated that binding of NO by cross-linked hemoglobin (ααHb) could also increase platelet deposition at sites of subintimal injury.

Methods and Results
Male Sprague-Dawley rats were infused with ααHb (0.88 g/kg, n=8) or with the NO synthase inhibitor
N
G
-monomethyl-
l
-arginine (L-NMMA, 30 mg/kg, n=7) before undergoing microsurgical carotid endarterectomy.
111
In-labeled platelets were infused after endarterectomy, and platelet deposition was measured 20 minutes later. In control endarterectomized rats (n=8), mean platelet deposition was 7.7±0.7×10
6
/mm
2
. Platelet deposition was significantly increased above controls in rats that received ααHb (13.2±0.9×10
6
/mm
2
,
P
=.0004) and in rats infused with L-NMMA (13.9±1.0×10
6
/mm
2
,
P
=.0002). The increase was prevented by infusion of
l
-arginine (150 mg/kg) immediately after ααHb or L-NMMA. To determine whether aspirin (ASA) blocked the increased deposition induced by ααHb, rats received oral ASA (10 mg/kg) 18 hours before endarterectomy. Platelet deposition in animals receiving ASA alone was 6.4±0.9×10
6
/mm
2
(n=8). This was significantly increased to 10.8±0.8×10
6
/mm
2
(
P
=.002) for the ASA-treated group that received ααHb at the time of endarterectomy (n=8). The prolonged bleeding times induced by ASA were unaffected by the infusion of ααHb.

Conclusions
These data suggest that in a rat endarterectomy model, ααHb increases platelet deposition at sites of subintimal injury by binding NO. Increased deposition induced by ααHb can be prevented by administration of
l
-arginine but not by pretreatment with aspirin.
Enhanced Regional Deformation at the Anterior Papillary Muscle Insertion Site After Chordal Transsection
Authors: Takayama Yasuo , Holmes Jeffrey W. , LeGrice Ian , Covell James W.
Published: June 2012

Background
Clinical and experimental studies of mitral valve replacement have shown a depression of ventricular function after chordal transsection; most recent studies have proposed that this is secondary to a depression of local function near the papillary muscle insertion site. However, there is no direct experimental evidence for changes in local fiber shortening in the wall of the left ventricle overlying the papillary muscle. Accordingly, we investigated the effect of chordal transsection on left ventricular shape and on three-dimensional regional deformation of the myocardium near the insertion of the anterior papillary muscle.

Methods and Results
In six open-chest dogs, two sets of three transmural columns of radiopaque markers were implanted in the anterior wall, one set at the tip of the papillary muscle (basal) and one at the site of papillary muscle fiber insertion (apical). A Björk-Shiley mitral valve was placed in the left atrium adjacent to the native valve. Markers were then tracked with biplane cineradiography, and deformation was quantified with the use of finite strain analysis. Chordal transsection resulted in reduced left ventricular end-systolic pressure and slowed relaxation. After chordal transsection, outward displacement of the ventricular wall and transverse shearing deformation were observed in the area of the papillary muscle during isovolumic contraction. Circumferential and radial strains during ejection were maintained at our basal site and enhanced on our apical site.

Conclusions
Chordal transsection led to enhanced local shortening and wall thickening and regional strain nonuniformity. These results indicate that chordal transsection induces an unloading of myocardium at the papillary muscle insertion site and that the resulting heterogeneity of regional function is the mechanism for the reduced global function and slowed ventricular relaxation.
Abnormal Systolic Intraventricular Flow Velocities After Valve Replacement for Aortic Stenosis
Authors: Bartunek Jozef , Sys Stanislas U. , Rodrigues Ana Clara , Van Schuerbeeck Eddy , Mortier Linda , de Bruyne Bernard
Published: June 2012

Background
Dynamic intraventricular flow velocities after valve replacement for aortic stenosis have been associated with high in-hospital morbidity and mortality. The aims of the present study were to determine the mechanisms and preoperative predictors of abnormal flow velocity (AFV) after valve replacement for aortic stenosis and to assess the clinical course of patients with AFV after surgery.

Methods and Results
One hundred consecutive patients with pure aortic stenosis were studied prospectively before operation by cardiac catheterization and Doppler echocardiography. After surgery, intraventricular flow was studied by Doppler echocardiography at rest, during nipride infusion, and during dobutamine infusion. AFV (defined as a systolic dagger-shaped Doppler spectrum >2 m/s) occurred in 14 patients at rest and in 27 patients during nipride and/or dobutamine infusion. In most patients, AFV was associated with left ventricular cavity squeezing. Left ventricular end-diastolic diameter, preoperative intraventricular flow velocity and septal-to-posterior wall thickness ratio by Doppler echocardiography, and mean transvalvular pressure gradient and ejection fraction by catheterization emerged as predictors of resting postoperative AFV. Patients with resting AFV had a higher incidence of dyspnea or hypotension (64% versus 21%,
P
<.01) and a longer hospital stay (13.1±5.8 versus 11.1±2.5,
P
<.05) than patients without AFV. In contrast, at a 1-year follow-up, no patient with resting AFV died.

Conclusions
First, AFV occurs in 14% of patients at rest after valve replacement for aortic stenosis and can be provoked or worsened by ventricular unloading or inotropic stimulation. Second, AFV is related more frequently to cavity squeezing than to systolic anterior motion of the mitral valve apparatus. Third, a typical pattern (small, hyperdynamic, and asymmetrically hypertrophied ventricle) is predictive for postoperative AFV and should be taken into account for the postoperative management. Finally, the presence of AFV at rest is associated with high in-hospital morbidity but good long-term prognosis.
Expression of Opioid Receptors During Heart Ontogeny in Normotensive and Hypertensive Rats
Authors: Zimlichman Reuven , Gefel Dov , Eliahou Heskel , Matas Zipora , Rosen Boaz , Gass Svetlana , Ela Catherine , Eilam Yael , Vogel Zvi , Barg Jacob
Published: June 2012

Background
The opioidergic systems are involved in modulating nociceptive stimuli. In addition, recent results suggest that endogenous and exogenous opioids could play a role in the modulation of blood pressure and cardiac functions. However, little is known regarding the expression and role of opioid-binding sites in the heart. The decreased sensitivity to noxious stimuli in hypertensive rats raises the possibility of different developmental pattern expression of opioid-binding sites in normotensive versus hypertensive rats.

Methods and Results
Opioid receptor expression in hearts from hypertensive and normotensive rats was studied during heart development by binding assays. From P1 until P90, the development of the heart in the two rat strains was accompanied by a gradual increase in the density of κ-opioid receptors. Hearts from hypertensive rats expressed significantly higher levels of κ receptors compared with those of normotensive rats. At ages older than P7, μ-opioid receptors could not be detected in hearts of both strains, whereas δ-opioid–binding sites gradually increased until reaching adult levels. Seven-day-old cardiomyocyte cultures of both rat strains expressed similar densities of δ or κ receptors to those observed in hearts from 7-day-old neonates. The μ-binding sites were not detected in cardiomyocyte cultures. Similar to the in vivo state, cultured myocytes from hypertensive rats had significantly higher levels of κ-binding sites (1.5-fold) compared with those of normotensive rats. The κ sites are pertussis toxin sensitive, and the state of coupling of the receptor to G protein is similar for the two rat strains.

Conclusions
The role of opioid-binding sites in the heart is not completely clear. Hypertensive rats are known to be less sensitive to noxious stimuli compared with normotensive rats. It is controversial whether the site of application of noxious stimuli plays an important role in the sensitivity to pain in hypertensive rats. We suggest that the opioidergic system could play a role in the modulation of blood pressure in addition to its known effect on nociception.
Exercise Thallium Tomography Predicts Future Clinically Manifest Coronary Heart Disease in a High-Risk Asymptomatic Population
Authors: Blumenthal Roger S. , Becker Diane M. , Moy Taryn F. , Coresh Josef , Wilder Lora B. , Becker Lewis C.
Published: June 2012

Background
Exercise testing, even when combined with radionuclide perfusion imaging, does not accurately predict future clinical coronary heart disease (CHD) in low-risk asymptomatic populations. We hypothesized that these tests would perform better in a higher-risk population with a high prevalence of occult CHD. Siblings of persons with premature CHD represent such a group in whom it would be advantageous to identify affected individuals before the occurrence of clinically manifest CHD.

Methods and Results
Exercise thallium scintigraphy was performed in 264 asymptomatic individuals less than 60 years of age who had a sibling with documented CHD before age 60. Despite an average age of only 46 years at the time of screening, 19 of the 264 siblings developed clinical CHD (sudden death in 1, myocardial infarction in 10, coronary revascularization in 8) over a mean of 6.2 years (range, 1 to 9 years) of follow-up. Abnormal thallium scans were observed in 29% of men and 9% of women, while abnormal exercise ECGs occurred in 12% and 5%, respectively. Of men ≥45 years of age, 45% had an abnormal exercise ECG, thallium scan, or both. In contrast, only 3% of women <45 years of age had an abnormal test result. Although abnormal exercise ECGs and thallium scans were both predictive of future clinical CHD, the thallium scan was associated with a higher relative risk. After adjustment for age, sex, and exercise ECG results, the relative risk of developing clinical CHD was 4.7 for an abnormal scan. Siblings with a concordant abnormal exercise ECG and thallium scan had a relative risk of 14.5. These siblings were all men >45 years of age at the time of screening and had a strikingly high incidence of clinical CHD (6 of 12, 50%).

Conclusions
Exercise thallium scintigraphy appears to be useful in the risk assessment of asymptomatic siblings of patients with premature CHD, particularly in male siblings who are 45 years of age or older.
Plasma Angiotensin II, Predisposition to Hypertension, and Left Ventricular Size in Healthy Young Adults
Authors: Harrap Stephen B. , Dominiczak Anna F. , Fraser Robert , Lever Anthony F. , Morton James J. , Foy Christopher J. , Watt Graham C.M.
Published: June 2012

Background
We studied the correlates of left ventricular mass (LVM) in 84 healthy young adults aged 16 to 24 years from the general population. Subjects were selected according to predisposition to hypertension into four groups with either high or low personal blood pressures and either high or low parental blood pressures.

Methods and Results
LVM was measured by echocardiography, and measurements of blood pressure, heart rate, body dimensions, and plasma concentrations of components of the renin-angiotensin system were made under resting conditions. LVM was similar in individuals predisposed to hypertension (high personal and parental blood pressures) and those with contrasting predisposition (low personal and parental pressures). Regression analysis of the combined groups showed that LVM correlated closely with body size, particularly lean body mass (
r
=.69,
P
<.0001) and systolic (
r
=.35,
P
<.0001) but not diastolic blood pressure. Plasma angiotensin II (
r
=.39,
P
<.0001), renin (
r
=.302,
P
<.01), and angiotensin-converting enzyme (
r
=.22,
P
<.05) showed significant correlation with LVM. Multiple regression analysis revealed that plasma angiotensin II was the most important component of the renin-angiotensin system and that its effect was independent of systolic blood pressure and body size.

Conclusions
These findings provide evidence in humans that angiotensin II exerts a direct effect on myocardial size. This association may have important implications for the complications and treatment of left ventricular hypertrophy.
Circadian Variation of Ambulatory Myocardial Ischemia
Authors: Krantz David S. , Kop Willem J. , Gabbay Frances H. , Rozanski Alan , Barnard Marie , Klein Jacob , Pardo Yosef , Gottdiener John S.
Published: June 2012

Background
The morning peak in myocardial ischemia has been related to diurnal variations in physical and mental activities and to postural changes upon awakening. This study assesses (1) the effects of exogenous activity triggers at different times of the day and (2) the contribution of an endogenous (ie, activity- and posture-independent) circadian vulnerability for ambulatory ischemia.

Methods and Results
Sixty-three stable coronary artery disease patients underwent ambulatory ECG monitoring and completed a structured diary assessing physical and mental activities. During 2519 hours of observation, a morning increase in ischemia coincided with increases in physical and mental activities, and an evening decrease in ischemia coincided with a decline in activities. During the morning, ischemic versus ischemia-free periods were more likely to occur with high levels of physical activity (
P
<.001). High physical activity triggered ischemia to a lesser but still significant extent (
P
<.05) in the afternoon but not in the evening (
P
=NS). High levels of mental activity triggered ischemia significantly during the morning (
P
<.04) and evening (
P
<.04) but not in the afternoon. When a residualized score procedure was used to correct ischemic time for each patient’s simultaneously measured activities, for hourly heart rates, or for activity-related heart rate fluctuations, the circadian variation in ischemia was still observed (
P
<.001), with a peak at 6
am.
A significant increase in ischemia occurred immediately after awakening (
P
<.05), but activity-adjusted increases in morning ischemia persisted (
P
<.05) for 2 hours after awakening.

Conclusions
Exogenous factors (physical and mental activities) are most potent as triggers of ischemia during the morning hours, and the postural change after awakening contributes to the morning increase in ischemia. There is also evidence for an endogenous, activity-independent circadian influence on ischemic susceptibility that is independent of exogenous factors and that sustains the increase in ischemia upon awakening.
Assignment of the Vascular Endothelial Growth Factor Gene to Human Chromosome 6p21.3
Authors: Vincenti Valeria , Cassano Caterina , Rocchi Mariano , Persico M. Graziella
Published: June 2012

Background
Vascular endothelial growth factor (VEGF) is an endothelial cell–specific growth factor and a regulator of physiological and pathological angiogenesis. Four different proteins are produced by alternative splicing of a unique transcript generated from a single-copy gene. Knowledge of the chromosomal location of the
VEGF
gene would help in determining a linkage to any known human congenital syndrome and/or to known chromosomal rearrangements in tumors.

Methods and Results
A human chromosome mapping panel was used to assign the
VEGF
gene to human chromosomes by polymerase chain reaction using
VEGF
-specific oligonucleotide primers. Amplified DNA fragments were fractionated on a 1% agarose gel. A single band of the expected size was obtained only from the DNA of those hybrid cell lines that contained the human chromosome 6. Three YAC clones containing the
VEGF
gene were obtained by screening the ICI Diagnostics library. In situ hybridization was then used to locate the
VEGF
gene in the 6p21.3 region.

Conclusions
The location of the
VEGF
gene in the 6p21.3 region is a potential starting point for a linkage study. In addition, the isolation of YAC clones containing the
VEGF
gene will contribute to the construction of the physical map of this chromosomal region.
A Patent Infarct-Related Artery Is Associated With Reduced Long-term Mortality After Percutaneous Transluminal Coronary Angioplasty for Postinfarction Ischemia and an Ejection Fraction <50%
Authors: Welty Francine K. , Mittleman Murray A. , Lewis Stanley M. , Kowalker Wendy L. , Healy Robert W. , Shubrooks Samuel J. , Muller James E.
Published: June 2012

Background
Prognosis after myocardial infarction (MI) is influenced by the presence of post-MI ischemia and possibly the patency of the infarct-related artery. The purpose of this study was to compare long-term outcome (reinfarction and death) in patients with open versus closed coronary arteries after percutaneous transluminal coronary angioplasty performed for MI complicated by persistent ischemia.

Methods and Results
Between 1981 and 1989, 505 patients underwent percutaneous transluminal coronary angioplasty for post-MI ischemia at the Deaconess Hospital. Long-term incidence (mean follow-up, 34 months) of death, nonfatal reinfarction, repeated coronary angioplasty, and coronary bypass surgery was determined for 479 patients and then compared on the basis of the status of the artery, open versus closed, at the end of angioplasty. The 5-year Kaplan-Meier actuarial mortality rate was 4.9% for 456 patients with open infarct-related arteries and 19.4% for 23 patients with closed infarct-related arteries (
P
=.0008). Multivariate Cox proportional hazards analyses controlling for age, sex, number of diseased vessels, type and location of MI, and year of coronary angioplasty revealed a hazard ratio for death for closed compared with open arteries of 6.1 (95% CI, 1.8 to 20.0). Among patients with ejection fractions <50%, a closed artery was associated with a higher mortality (
P
=.0014) compared with patients with open arteries. The status of the artery was not associated with a difference in mortality in patients with ejection fractions ≥50%.

Conclusions
An open artery after coronary angioplasty for post-MI ischemia is associated with significantly lower long-term mortality, particularly in patients with ejection fractions <50%.
Assessment of Coronary Arterial Flow and Flow Reserve in Humans With Magnetic Resonance Imaging
Authors: Hundley W. Gregory , Lange Richard A. , Clarke Geoffrey D. , Meshack Benjamin M. , Payne Jerry , Landau Charles , McColl Roderick , Sayad Dany E. , Willett DuWayne L. , Willard John E. , Hillis L. David , Peshock Ronald M.
Published: June 2012

Background
The noninvasive measurement of absolute epicardial coronary arterial flow and flow reserve would be useful in the evaluation of patients with coronary circulatory disorders. Phase-contrast magnetic resonance imaging (PC-MRI) has been used to measure coronary arterial flow in animals, but its accuracy in humans is unknown.

Methods and Results
Twelve subjects (7 men, 5 women; age, 44 to 67 years) underwent PC-MRI measurements of flow in the left anterior descending coronary artery or one of its diagonal branches at rest and after administration of adenosine (140 μg·kg
−1
·min
−1
IV). Immediately thereafter, intracoronary Doppler velocity (IDV) and flow measurements were made during cardiac catheterization at rest and after intravenous administration of adenosine. For the 12 patients, the correlation between MRI and invasive measurements of coronary arterial flow and coronary arterial flow reserve was excellent: coronary flow
MRI
(mL/min)= 0.85×coronary flow
IDV
(mL/min)+17 (mL/min),
r
=.89, and coronary flow reserve
MRI
=0.79×coronary velocity reserve
IDV
+0.34,
r
=.89. For the range of coronary arterial flows (18 to 161 mL/min) measured by MRI, the limit of agreement between MRI and catheterization measurements of flow was −13±30 mL/min; for the range of coronary reserves (0.7 to 3.7) measured by MRI, the limit of agreement between the two techniques was 0.1±0.4.

Conclusions
Cine velocity-encoded PC-MRI can noninvasively measure absolute coronary arterial flow in the left anterior descending artery in humans. PC-MRI can detect pharmacologically induced changes in coronary arterial flow and can reliably distinguish between those subjects with normal and abnormal coronary artery flow reserve.
Electrophysiological Mechanisms of Spontaneous Termination of Sustained Monomorphic Reentrant Ventricular Tachycardia in the Canine Postinfarction Heart
Authors: El-Sherif Nabil , Yin Hong , Caref Edward B. , Restivo Mark
Published: June 2012

Background
The electrophysiological mechanisms of spontaneous termination of sustained monomorphic ventricular tachycardia (SMVT), in the postinfarction heart, generally considered secondary to a reentrant mechanism, have not been fully investigated.

Method and Results
Epicardial activation maps of spontaneous termination of 20 different episodes of SMVT (lasting 30 seconds to 10 minutes) from 8 dogs, 4 to 5 days after one-stage ligation of the left anterior descending coronary artery, were analyzed with the use of 254 bipolar electrode recordings with high density (2.5 to 2.8 mm between bipolar electrodes) in the ischemic zone. All ventricular tachycardias (VTs) were due to circus movement reentry with a characteristic figure-8 configuration. Termination always occurred when the two circulating wave fronts blocked in the central common pathway (CCP). Two basic mechanisms of spontaneous termination were observed: (1) In 15 episodes, acceleration of conduction occurred in parts of the reentrant circuit and was associated with slowing of conduction and finally conduction block in the CCP. Acceleration of conduction occurred in the last few cycles of VT both at the outer border of the arcs of functional conduction block in the “normal” myocardial zone and at the pivot points to the entrance to the CCP. When acceleration of conduction was compensated on a beat-to-beat basis by an equal degree of slowing in the CCP, there was no discernible change in the cycle length of the VT in the ECG. In some episodes, the termination of the original reentrant circuit was followed by the development of a different, slower reentrant pathway that lasted for one or a few cycles prior to termination. (2) In 5 VT episodes, the activation wave front in the CCP abruptly broke across a stable arc of functional conduction block, resulting in premature activation of the CCP and conduction block.

Conclusions
Distinct electrophysiological changes always preceded spontaneous termination of stable SMVT. The electrophysiological basis for acceleration of conduction in parts of the reentrant circuit during the last few beats prior to termination and of the abrupt reactivation across a stable arc of block remains to be determined.
Mean Red Cell Volume as a Correlate of Blood Pressure
Authors: Sharp Dan S. , Curb J. David , Schatz Irwin J. , Meiselman Herbert J. , Fisher Timothy C. , Burchfiel Cecil M. , Rodriguez Beatriz L. , Yano Katsuhiko
Published: June 2012

Background
Clinical studies suggest that hypertensives have lower mean corpuscular volume (MCVs) than do normotensives. Epidemiological studies show no relation or higher MCVs. In the present study of elderly men (71 to 93 years of age) of the Honolulu Heart Program, elements of both findings are confirmed.

Methods and Results
Three groups are identified: (1) those receiving no hypertension treatment, (2) those receiving treatment with any diuretic, and (3) those receiving treatment with nondiuretics only. MCV is lower in group 3 than in group 1 (−0.85 fL,
P
<.001) but the same in groups 1 and 2. Within groups 1 and 3, inverse relations of −0.22 and −0.09 mm Hg/fL (
P
<.05) are noted for systolic (SBP) and diastolic (DBP) blood pressures. No relations are observed in group 2. MCV and red blood cell count (RBC) are inversely correlated (
r
=−.45). In group 2, adjustment for RBC unmasks a direct relation between MCV and SBP (0.5 mm Hg/fL,
P
=.02) and DBP (0.3 mm Hg/fL,
P
=.02). In groups 1 and 3, relations between SBP and MCV are lost after adjustment for RBC (0.005 mm Hg/fL). For DBP, adding RBC plus an MCV×RBC interaction is significant (
P
<.001). DBP is 5 mm Hg greater in the highest RBC quartile than in the lowest. A +3 mm Hg difference between extreme MCV quartiles is noted only at high RBC levels.

Conclusions
The relation between blood pressure and red cell measures is probably mediated by whole blood viscosity. Hematocrit is a determinant of whole blood viscosity. Viscosity affects peripheral resistance to blood flow, and peripheral resistance affects DBP. At high RBC levels, MCV may be “downregulated.” This may lower whole blood viscosity and partially reduce DBP without compromising flow.
Regulation of Nitric Oxide Production in Human Coronary Microvessels and the Contribution of Local Kinin Formation
Authors: Kichuk Maryanne R. , Seyedi Nahid , Zhang Xiaoping , Marboe Charles C. , Michler Robert E. , Addonizio Linda J. , Kaley Gabor , Nasjletti Alberto , Hintze Thomas H.
Published: June 2012

Background
The goal of this study was to define the regulation of nitric oxide release by coronary microvessels from the failing and nonfailing human heart and to determine the role of local kinin production in the elaboration of nitric oxide by human coronary microvascular endothelium.

Methods and Results
Ten hearts from humans with end-stage heart failure and two hearts from patients without heart failure were harvested at the time of orthotopic cardiac transplantation. Microvessels were sieved and the production of nitrite was determined by the Griess reaction. Microvessels were incubated in the presence of agonists for nitric oxide production (acetylcholine and bradykinin), which caused dose-dependent increases in nitrite, a response that was blocked by
N
G
-nitro-
l
-arginine methyl ester and receptor-specific antagonists (atropine and HOE 140, respectively). In addition, the production of nitrite by microvessels from the failing heart appeared to be less than that produced by microvessels from the nonfailing heart. Incubation with norepinephrine or the α
2
-adrenergic agonist BHT 920 also caused dose-dependent increases in nitrite production, which were blocked by the B
2
-receptor antagonist HOE 140. This implicated local kinin synthesis as an intermediate step in the production of nitric oxide in response to α
2
-adrenoceptor stimulation. The production of nitric oxide was also prevented by the addition of serine protease inhibitors, which blocked the action of local kallikrein, again suggesting a role for local kinin synthesis.

Conclusions
Our results indicate that nitric oxide is produced by human coronary microvessels, that nitric oxide production may be reduced but certainly not increased in microvessels from the failing human heart, and that there is active local kinin generation in these blood vessels.
Assessment of Blood Flow Distal to Coronary Artery Stenoses
Authors: Miller D. Douglas , Donohue Thomas J. , Wolford Thomas L. , Kern Morton J. , Bergmann Steven R. , Mechem Carol M. , Hartman Judy J.
Published: June 2012

Background
Previous studies have correlated quantitative coronary angiographic stenosis severity with positron emission tomography (PET) myocardial perfusion and proximal measurements of intracoronary flow velocities in normal and diseased coronary arteries. The aim of this study was to correlate regional myocardial blood flow (RMBF) derived from [
15
O]H
2
O PET with directly measured poststenotic intracoronary Doppler flow velocity data acquired under basal conditions and dipyridamole-induced hyperemia.

Methods and Results
Eleven consecutive patients 53±13 years old with ischemic chest pain and isolated proximal left coronary artery stenoses (left anterior descending, 9; left circumflex, 2; mean, 59±23% diameter stenosis) underwent [
15
O]H
2
O myocardial PET and intracoronary Doppler flow velocity studies within 1 week. PET RMBF (mL·g
−1
·min
−1
) and myocardial perfusion reserve (MPR) were calculated in poststenotic and normal reference vascular beds. Poststenotic Doppler average peak flow velocities (APV; cm/s) and coronary flow velocity reserve (CFR) were compared with corresponding PET data and quantitative angiographic lesional parameters. PET RMBF and Doppler APV were linearly correlated (
r
=.60;
P
<.001), as were poststenotic PET MPR and Doppler CFR (
r
=.76;
P
<.0002). Relative coronary flow velocity and MPR ratios between poststenotic and angiographically normal vascular beds were comparably reduced (0.83±0.25 versus 0.86±0.21, respectively;
P
=NS).

Conclusions
Intracoronary Doppler flow velocities acquired distal to isolated left coronary artery stenoses correlated with [
15
O]H
2
O PET regional myocardial perfusion and are useful for assessment of the physiological significance of coronary stenoses in humans.
Metabolic Adaptation During a Sequence of No-Flow and Low-Flow Ischemia
Authors: Ferrari R. , Cargnoni A. , Bernocchi P. , Pasini E. , Curello S. , Ceconi C. , Ruigrok T.J.C.
Published: June 2012

Background
Myocardial hibernation is an adaptive phenomenon occurring in patients with a history of acute ischemia followed by prolonged hypoperfusion.

Methods and Results
We investigated, in isolated rabbit heart, whether a brief episode of global ischemia followed by hypoperfusion maintains viability. Four groups were studied: group 1, 300 minutes of aerobia; group 2, 240 minutes of total ischemia and 60 minutes of reperfusion; group 3, 10 minutes of total ischemia, 230 minutes of hypoperfusion (90% coronary flow reduction), and 60 minutes of reperfusion; and group 4, 240 minutes of hypoperfusion followed by reperfusion. In group 3, viability was maintained. Ten minutes of ischemia caused quiescence, a fall in interstitial pH (from 7.2±0.01 to 6.1±0.8), creatine phosphate (CP), and ATP (from 54.5±5.0 and 25.0±1.9 to 5.0±1.1 and 15.3±2.5 μmol/g dry wt,
P
<.01). Subsequent hypoperfusion failed to restore contraction and pH but improved CP (from 5.0±1.1 to 20.1±3.4,
P
<.01). Reperfusion restored pH, developed pressure (to 92.3%), and NAD/NADH and caused a washout of lactate and creatine phosphokinase with no alterations of mitochondrial function or oxidative stress. In group 4, hypoperfusion resulted in progressive damage. pH fell to 6.2±0.7, diastolic pressure increased to 34±5.6 mm Hg, CP and ATP became depressed, and oxidative stress occurred. Reperfusion partially restored cardiac metabolism and function (47%).

Conclusions
A brief episode of total ischemia without intermittent reperfusion maintains viability despite prolonged hypoperfusion. This could be mediated by metabolic adaptation, preconditioning, or both.
Myocardial Uptake of
99m
Tc-Tetrofosmin, Sestamibi, and
201
Tl in a Model of Acute Coronary Reperfusion
Authors: Takahashi Norio , Reinhardt Christopher P. , Marcel Robin , Leppo Jeffrey A.
Published: June 2012

Background
To investigate whether tetrofosmin uptake is affected by myocardial viability as has been noted for
201
Tl and sestamibi, we analyzed the initial and delayed distribution patterns of tetrofosmin in a rat coronary artery occlusion-reperfusion model.

Methods and Results
Animals were intubated and ventilated, and their arterial pressures were monitored. A left thoracotomy was performed. After 1-hour occlusion and 1-hour reperfusion of a major branch of the circumflex artery,
201
Tl and either tetrofosmin or sestamibi were injected intravenously. Radiolabeled microspheres were used to document the area at risk and reperfusion. Five minutes or 1 hour after administration of the diffusible tracers, the animals were killed. Tracer distribution was determined by use of segmental tissue analysis, and tissue viability was determined by use of histochemical staining. Both the initial and delayed retention of tetrofosmin were sensitive to myocardial viability, as shown by significantly lower uptake (30±14%) and retention (24±12%) of tetrofosmin in the nonviable segments compared with the viable segments. In addition, the initial myocardial distribution of tetrofosmin was similar to that noted for
201
Tl, but after 1 hour of tracer circulation, the tetrofosmin tissue distribution appeared unchanged compared with the initial regional blood flow distribution. This is in direct contrast to our present observations of significant
201
Tl redistribution and some changes in sestamibi distribution as well.

Conclusions
The clinical implication of these observations suggests that initial and delayed imaging after tetrofosmin administration would reflect both the initial regional blood flow pattern and myocardial viability.
Testosterone Induces Dilation of Canine Coronary Conductance and Resistance Arteries In Vivo
Authors: Chou Tony M. , Sudhir Krishnankutty , Hutchison Stuart J. , Ko Eitetsu , Amidon Thomas M. , Collins Peter , Chatterjee Kanu
Published: June 2012

Background
Although estrogens have been shown to be vasoactive hormones, the vascular effects of testosterone are not well defined. Like estrogen, testosterone causes relaxation of isolated rabbit coronary arterial segments. We examined the vasodilator effects of testosterone in vivo in the coronary circulation and the potential mechanisms of its actions.

Methods and Results
Using simultaneous intravascular two-dimensional and Doppler ultrasound, we examined the effect of intracoronary testosterone in coronary conductance and resistance arteries in 10 anesthetized dogs (5 male, 5 female). We also assessed the contribution of NO, prostaglandins, ATP-sensitive K
+
channels, and classic estrogen receptors to testosterone-induced vasodilation. Testosterone induced a significant increase in cross-sectional area, average coronary peak flow velocity, and calculated volumetric coronary blood flow at the 0.1 and 1 μmol/L concentrations. This effect was independent of sex. Pretreatment with
N
ω
-nitro-
l
-arginine methyl ester to block NO synthesis decreased testosterone-induced increase in cross-sectional area, average coronary peak flow velocity, and coronary blood flow. Pretreatment with glybenclamide to assess the role of ATP-sensitive K
+
channels did not influence testosterone-induced dilation in epicardial arteries but did attenuate its effect in the microcirculation. Pretreatment with indomethacin or the classic estrogen-receptor antagonist ICI 182,780 did not alter testosterone-induced changes.

Conclusions
Short-term administration of testosterone induces a sex-independent vasodilation in coronary conductance and resistance arteries in vivo. Acute testosterone-induced coronary vasodilation of epicardial and resistance vessels is mediated in part by endothelium-derived NO. ATP-sensitive K
+
channels appear to play a role in the vasodilatory effect of testosterone in resistance arteries.
Functional Recovery After Human Heart Transplantation Is Related to the Metabolic Condition of the Hypothermic Donor Heart
Authors: Van Dobbenburgh J. Onno , Lahpor Jaap R. , Woolley Stephen R. , de Jonge Nicolaas , Klo¨pping Corinne , Van Echteld Cees J.A.
Published: June 2012

Background
Although strict selection criteria are being used for the acceptance of human donor hearts for transplantation, problems with respect to functional recovery on reperfusion sometimes still occur. Therefore, evaluation of the viability of a human donor heart before implantation during heart transplantation may be of great value.

Methods and Results
In the present study, the energy metabolism of 25 excised human donor hearts arrested with St Thomas' Hospital No. 2 cardioplegic solution was evaluated noninvasively by use of
31
P magnetic resonance spectroscopy (MRS) before implantation and was correlated with myocardial function measured with thermodilution in heart transplant patients. No significant correlation was observed between the cardiac index of heart transplant patients during the first hours after transplantation and the phosphocreatine/ATP (
r
=.13,
P
=.54), inorganic phosphate/ATP (
r
=.26,
P
=.21), phosphomonoesters/ATP (
r
=.02,
P
=.92), or phosphocreatine/inorganic phosphate (
r
=.16,
P
=.44) ratio or the intracellular pH (
r
=.06,
P
=.78) at the time of reperfusion. However, 1 week after transplantation, a significant correlation was observed between the cardiac index and the phosphocreatine/ATP (
r
=.49,
P
=.01), phosphomonoesters/ATP (
r
=.45,
P
=.02), and phosphocreatine/inorganic phosphate (
r
=.40,
P
=.05) ratios at the time of reperfusion. In contrast, the inorganic phosphate/ATP (
r
=.10,
P
=.63) ratio and pH (
r
=.31,
P
=.13) at the time of reperfusion showed a poor correlation with the cardiac index 1 week after transplantation.

Conclusions
Functional recovery after human heart transplantation is related to the metabolic condition of the hypothermic donor heart.
Refractory Interval After Transcardiac Shocks During Ventricular Fibrillation
Authors: Sweeney Robert J. , Gill Robert M. , Reid Philip R.
Published: June 2012

Background
Measurements of refractory period extension by shocks during ventricular pacing at fast rates predict that all tissue should be refractory for a brief interval after shocks during fibrillation. This study experimentally determined whether a refractory interval was present just after a shock during fibrillation.

Methods and Results
In pentobarbital-anesthetized dogs, rectangular monophasic (4-ms) or biphasic (2.5/1.5-ms) shocks were followed with a 2-ms postshock stimulus (PSS) delivered to the defibrillation electrodes. We measured the effect of PSS on the shock current (I
50
) required for 50% defibrillation success. In group 1 (n=6), a 1.0-A PSS had no effect on I
50
when delivered up to 35 ms after monophasic shocks but greatly increased I
50
when delivered at 50 to 90 ms. A 0.5-A PSS had no effect at any timing. In group 2 (n=6), we compared 1.0-A PSSs after monophasic and biphasic shocks. The effect of PSS after monophasic shocks was similar to group 1. After biphasic shocks, PSS at the same timings had similar effects but caused even greater increases in I
50
.

Conclusions
We conclude that after both monophasic and biphasic shocks during fibrillation, there is a postshock interval during which the heart is refractory to the refibrillating effect of PSS. The interval is shorter for biphasic than for monophasic shocks with the same duration and defibrillation efficacy. These findings support the refractory period extension hypothesis for defibrillation and suggest that propagating depolarization activity is absent immediately after defibrillation shocks but that it develops again at the end of the refractory interval or later.
Influence of Isoproterenol and Ouabain on Excitation-Contraction Coupling, Cross-Bridge Function, and Energetics in Failing Human Myocardium
Authors: Hasenfuss Gerd , Mulieri Louis A. , Allen Paul D. , Just H. , Alpert N.R.
Published: June 2012

Background
In patients with heart failure, long-term treatment with catecholamines and phosphodiesterase inhibitors, both of which increase cyclic AMP levels, may be associated with increased mortality, whereas mortality may not be increased with glycoside treatment. Differences in clinical benefit between cyclic AMP–dependent inotropic agents and cardiac glycosides may be related to differences of these drugs on calcium cycling and myocardial energetics.

Methods and Results
Isometric heat and force measurements were used to investigate the effects of isoproterenol and ouabain on myocardial performance, cross-bridge function, excitation-contraction coupling, and energetics in myocardium from end-stage failing human hearts. Isoproterenol (1 μmol/L) increased peak twitch tension by 55% and decreased time to peak tension and relaxation time by 30% and 26%, respectively (
P
<.005). Ouabain (0.38±0.11 μmol/L) increased peak twitch tension and relaxation time by 41% and 20%, respectively, and decreased time to peak tension by 12% (
P
<.05). With isoproterenol, the amount of excitation-contraction coupling–related heat evolution (tension-independent heat) increased by 246% (
P
<.05) and the economy of excitation-contraction coupling decreased by 61% (
P
<.05). Ouabain increased tension-independent heat by only 61% (
P
<.05) and did not significantly influence economy of excitation-contraction coupling. The effects of isoproterenol on excitation-contraction coupling resulted in a 21% (
P
<.005) decrease of overall contraction economy, which was not significantly changed with ouabain. Neither isoproterenol nor ouabain influenced energetics of cross-bridge cycling or recovery metabolism.

Conclusions
Major differences between the effects of isoproterenol and ouabain in failing human myocardium are related to calcium cycling with secondary effects on myocardial energetics.
Chronotropic Response to Exercise
Authors: Okin Peter M. , Lauer Michael S. , Kligfield Paul
Published: June 2012

Background
Heart rate (HR) response to exercise plays an important role in the diagnosis of coronary artery disease (CAD). Adjustment of ST-segment depression for the change in HR with exercise increases the accuracy of the exercise ECG in the detection of CAD. In addition, an attenuated HR response to exercise, a manifestation of chronotropic incompetence, may have independent diagnostic value for CAD.

Methods and Results
The diagnostic value of adjusting the magnitude of ST-segment depression, the ST-segment (ST)/HR index, and the ST/HR slope for chronotropic response to exercise was assessed in 283 control subjects and 337 patients with CAD by dividing each ST measurement by the fraction of HR reserve achieved. At a matched specificity of 96%, ST-segment depression of >160 μV identified CAD with a sensitivity of 52%, an ST/HR index of >1.69 μV/bpm identified CAD with a sensitivity of 90%, and an ST/HR slope of >2.96 μV/bpm identified CAD with a sensitivity of 88%. Adjustment for HR reserve improved the sensitivity of each method: adjusted ST-segment depression of >176 had a sensitivity of 87% (
P
<.0001), an adjusted ST/HR index of >2.14 had a sensitivity of 94% (
P
=.005), and an adjusted ST/HR slope of >3.47 had a sensitivity of 93% (
P
=.0001). In addition, the 94% and 93% sensitivities of the adjusted ST/HR index and ST/HR slope were significantly greater than the 87% sensitivity of adjusted ST-segment depression (
P
<.0001).

Conclusions
Correction for an attenuated HR response to exercise improves performance of the simple and HR-adjusted ST-segment depression criteria for the identification of CAD. These findings support assessment of the degree of chronotropic reserve in routine evaluation of the exercise ECG.
Association Between Intima-Media Thickness and Wall Shear Stress in Common Carotid Arteries in Healthy Male Subjects
Authors: Gnasso Agostino , Carallo Claudio , Irace Concetta , Spagnuolo Vitaliano , De Novara Giuseppina , Mattioli Pier Luigi , Pujia Arturo
Published: June 2012

Background
Atherosclerotic lesions lie in regions of low wall shear stress. No relationship between wall shear stress and intima-media thickness in vivo has been reported. Aims of the present study were to verify the reproducibility of wall shear stress measurement in vivo and to evaluate its association with intima-media thickness in the common carotid artery in healthy subjects.

Methods and Results
Wall shear stress was calculated according to the following formula: Shear Stress=Blood Viscosity×Blood Velocity/Internal Diameter. Blood viscosity was measured by use of a cone/plate viscometer. Blood velocity, internal diameter, and intima-media thickness were measured by high-resolution echo Doppler. Twenty-one healthy male subjects were investigated. Peak and mean shear stress values were 29.5±8.2 and 12.1±3.1 dynes/cm
−2
(mean±SD), respectively. Peak shear stress was inversely related to intima-media thickness (
r
=.62), age (
r
=.77), systolic blood pressure (
r
=.61), and body mass index (
r
=.59) (
P
<.0001 for all coefficients). Mean shear stress yielded similar results. The relationship between shear stress and intima-media thickness was independent of age, blood pressure, and body mass index. The reproducibility, calculated by Kendall's
W
test, was statistically significant.

Conclusions
Our results demonstrate that common carotid artery wall shear stress measurement in vivo is reproducible. It inversely relates to intima-media thickness, age, systolic blood pressure, and body mass index. These findings confirm in vivo the role of shear stress in intima-media thickening.