bluuebunny/crossref_metadata_2025 huggingface dataset:
Hyperhomocysteinemia Confers an Independent Increased Risk of Atherosclerosis in End-Stage Renal Disease and Is Closely Linked to Plasma Folate and Pyridoxine Concentrations
Authors: Robinson Killian , Gupta Anjan , Dennis Vincent , Arheart Kristopher , Chaudhary Debashish , Green Ralph , Vigo Paul , Mayer Ellen L. , Selhub Jacob , Kutner Michael , Jacobsen Donald W.
Published: June 2012

Background
A high level of total plasma homocysteine is a risk factor for atherosclerosis, which is an important cause of death in renal failure. We evaluated the role of this as a risk factor for vascular complications of end-stage renal disease.

Methods and Results
Total fasting plasma homocysteine and other risk factors were documented in 176 dialysis patients (97 men, 79 women; mean age, 56.3±14.8 years). Folate, vitamin B
12
, and pyridoxal phosphate concentrations were also determined. The prevalence of high total homocysteine values was determined by comparison with a normal reference population, and the risk of associated vascular complications was estimated by multiple logistic regression. Total homocysteine concentration was higher in patients than in the normal population (26.6±1.5 versus 10.1±1.7 μmol/L;
P
<.01). Abnormally high concentrations (>95th percentile for control subjects, 16.3 μmol/L) were seen in 149 patients (85%) with end-stage renal disease (
P
<.001). Patients with a homocysteine concentration in the upper two quintiles (>27.8 μmol/L) had an independent odds ratio of 2.9 (CI, 1.4 to 5.8;
P
=.007) of vascular complications. B vitamin levels were lower in patients with vascular complications than in those without. Vitamin B
6
deficiency was more frequent in patients than in the normal reference population (18% versus 2%;
P
<.01).

Conclusions
A high total plasma homocysteine concentration is an independent risk factor for atherosclerotic complications of end-stage renal disease. Such patients may benefit from higher doses of B vitamins than those currently recommended.
Left Ventricular, Peripheral Vascular, and Neurohumoral Responses to Mental Stress in Normal Middle-Aged Men and Women
Authors: Becker Lewis C. , Pepine Carl J. , Bonsall Robert , Cohen Jerome D. , Goldberg A. David , Coghlan Cecil , Stone Peter H. , Forman Sandra , Knatterud Genell , Sheps David S. , Kaufmann Peter G.
Published: June 2012

Background
The normal cardiovascular response to mental stress in middle-aged and older people has not been well characterized.

Methods and Results
We studied 29 individuals 45 to 73 years old (15 women, 14 men) who had no coronary risk factors, no history of coronary artery disease, and a negative exercise test. Left ventricular (LV) volumes and global and regional function were assessed by radionuclide ventriculography at rest and during two 5-minute standardized mental stress tasks (simulated public speaking and the Stroop Color-Word Test), administered in random order. A substantial sympathetic response occurred with both mental stress tests, characterized by increases in blood pressure, heart rate, rate-pressure product, cardiac index, and stroke work index and rises in plasma levels of epinephrine and norepinephrine but not β-endorphin or cortisol. Despite this sympathetic response, LV volume increased and ejection fraction (EF) decreased secondary to an increase in afterload. The change in EF during mental stress varied among individuals but was associated positively with changes in LV contractility and negatively with baseline EF and changes in afterload. EF decreased >5% during mental stress in 12 individuals and >8% in 5; 3 developed regional wall motion abnormalities.

Conclusions
Mental stress in the laboratory results in a substantial sympathetic response in normal middle-aged and older men and women, but EF commonly falls because of a concomitant rise in afterload. These results provide essential age- and sex-matched reference data for studies of mental stress–induced ischemia in patients with coronary artery disease.
Localization of Heparin-Binding Epidermal Growth Factor–Like Growth Factor in Human Coronary Arteries
Authors: Nakata Atsuyuki , Miyagawa Jun-ichiro , Yamashita Shizuya , Nishida Makoto , Tamura Ritsu , Yamamori Katsumi , Nakamura Tadashi , Nozaki Shuichi , Kameda-Takemura Kaoru , Kawata Sumio , Taniguchi Naoyuki , Higashiyama Shigeki , Matsuzawa Yuji
Published: June 2012

Background
Heparin-binding epidermal growth factor (EGF)–like growth factor (HB-EGF) is a newly identified member of the EGF family. Our previous in vitro studies showed that HB-EGF is a potent mitogen and chemoattractant for vascular smooth muscle cells (SMCs), suggesting the role of HB-EGF in the pathogenesis of atherosclerosis. The purposes of the present study were to investigate the localization of HB-EGF in both normal and atherosclerotic human coronary arteries and to elucidate the possible roles of this growth factor in the formation of atherosclerotic lesions.

Methods and Results
The immunohistochemical localization of HB-EGF, SMCs, macrophages, and EGF receptors (EGFRs) was examined in human coronary arteries obtained at autopsy. The medial SMCs of coronary arteries in neonates, infants, and children consistently synthesized HB-EGF protein. In normal adults, however, the relative number of HB-EGF–positive medial SMCs decreased gradually with age after about 30 years of age. In nonatherosclerotic coronary arteries with diffuse intimal thickening, SMCs of the intima, especially those located in the area of the medial side of the intima, were strongly positive for HB-EGF protein. In atherosclerotic plaques of coronary arteries with eccentric intimal thickening, both SMCs and macrophages in and around the core lesions, in addition to the intimal and medial SMCs located adjacent to the plaque, produced HB-EGF protein. A strong immunostaining of EGFRs was observed in these SMCs, suggesting a close association of HB-EGF and EGFR expression.

Conclusions
These data suggest that HB-EGF might play important roles in the migration of SMCs from the media to the intima, the proliferation of intimal SMCs, and the interaction between SMCs and macrophages in the process of coronary atherogenesis.
Carvedilol Inhibits Clinical Progression in Patients With Mild Symptoms of Heart Failure
Authors: Colucci Wilson S. , Packer Milton , Bristow Michael R. , Gilbert E. Michael , Cohn Jay N. , Fowler Michael B. , Krueger Steven K. , Hershberger Ray , Uretsky Barry F. , Bowers John A. , Sackner-Bernstein Jonathan D. , Young Sarah T. , Holcslaw Terry L. , Lukas Mary Ann
Published: June 2012

Background
We tested the hypothesis that carvedilol inhibits clinical progression in patients with mildly symptomatic heart failure due to left ventricular (LV) systolic dysfunction.

Methods and Results
Patients (n=366) who had mildly symptomatic heart failure with an LV ejection fraction (LVEF) ≤0.35, had minimal functional impairment (defined as the ability to walk 450 to 550 m on a 6-minute walk test), and were receiving optimal standard therapy, including ACE inhibitors, were randomized double-blind to carvedilol (n=232) or placebo (n=134) and followed up for 12 months. The primary end point was clinical progression, defined as death due to heart failure, hospitalization for heart failure, or a sustained increase in heart failure medications. Clinical progression of heart failure occurred in 21% of placebo patients and 11% of carvedilol patients, reflecting a 48% (
P
=.008) reduction in the primary end point of heart failure progression (relative risk, 0.52; CI, 0.32 to 0.85). This effect of carvedilol was not influenced by sex, age, race, cause of heart failure, or baseline LVEF. Carvedilol also significantly improved several secondary end points, including LVEF, heart failure score, NYHA functional class, and the physician and patient global assessments. Carvedilol reduced all-cause mortality but had no effects on the Minnesota Living With Heart Failure scale, the distance walked in 9 minutes on a self-powered treadmill, or cardiothoracic index. The drug was well tolerated.

Conclusions
Carvedilol, when added to standard therapy, including an ACE inhibitor, reduces clinical progression in patients who are only mildly symptomatic with well-compensated heart failure.
Carvedilol Produces Dose-Related Improvements in Left Ventricular Function and Survival in Subjects With Chronic Heart Failure
Authors: Bristow Michael R. , Gilbert Edward M. , Abraham William T. , Adams Kirkwood F. , Fowler Michael B. , Hershberger Ray E. , Kubo Spencer H. , Narahara Kenneth A. , Ingersoll Henry , Krueger Steven , Young Sarah , Shusterman Neil
Published: June 2012

Background
We conducted a multicenter, placebo-controlled trial designed to establish the efficacy and safety of carvedilol, a “third-generation” β-blocking agent with vasodilator properties, in chronic heart failure.

Methods and Results
Three hundred forty-five subjects with mild to moderate, stable chronic heart failure were randomized to receive treatment with placebo, 6.25 mg BID carvedilol (low-dose group), 12.5 mg BID carvedilol (medium-dose group), or 25 mg BID carvedilol (high-dose group). After a 2- to 4-week up-titration period, subjects remained on study medication for a period of 6 months. The primary efficacy parameter was submaximal exercise measured by two different techniques, the 6-minute corridor walk test and the 9-minute self-powered treadmill test. Carvedilol had no detectable effect on submaximal exercise as measured by either technique. However, carvedilol was associated with dose-related improvements in LV function (by 5, 6, and 8 ejection fraction [EF] units in the low-, medium-, and high-dose carvedilol groups, respectively, compared with 2 EF units with placebo,
P<
.001 for linear dose response) and survival (respective crude mortality rates of 6.0%, 6.7%, and 1.1% with increasing doses of carvedilol compared with 15.5% in the placebo group,
P<
.001). When the three carvedilol groups were combined, the all-cause actuarial mortality risk was lowered by 73% in carvedilol-treated subjects (
P
<.001). Carvedilol also lowered the hospitalization rate (by 58% to 64%,
P=
.01) and was generally well tolerated.

Conclusions
In subjects with mild to moderate heart failure from systolic dysfunction, carvedilol produced dose-related improvements in LV function and dose-related reductions in mortality and hospitalization rate.
Comparative Hemodynamic, Left Ventricular Functional, and Antiadrenergic Effects of Chronic Treatment With Metoprolol Versus Carvedilol in the Failing Heart
Authors: Gilbert Edward M. , Abraham William T. , Olsen Stephanie , Hattler Brack , White Michel , Mealy Patrice , Larrabee Patti , Bristow Michael R.
Published: June 2012

Background
The basic pharmacology of the third-generation β-blocking agent carvedilol differs considerably from second-generation compounds such as metoprolol. Moreover, carvedilol may produce different, ie, more favorable, clinical effects in chronic heart failure. For these reasons, we compared the effects of carvedilol and metoprolol on adrenergic activity, receptor expression, degree of clinical β-blockade, hemodynamics, and left ventricular function in patients with mild or moderate chronic heart failure.

Methods and Results
The effects of carvedilol versus metoprolol were compared in two concurrent placebo-controlled trials with carvedilol or metoprolol that had common substudies focused on adrenergic, hemodynamic, and left ventricular functional measurements. All subjects in the substudies had chronic heart failure resulting from idiopathic dilated cardiomyopathy. Carvedilol at 50 to 100 mg/d produced reductions in exercise heart rate that were similar to metoprolol at 125 to 150 mg/d, indicating comparable degrees of β-blockade. Compared with metoprolol, carvedilol was associated with greater improvement in New York Heart Association functional class. Although there were no significant differences in hemodynamic effects between the carvedilol and metoprolol active-treatment groups, carvedilol tended to produce relatively greater improvements in left ventricular ejection fraction, stroke volume, and stroke work compared with changes in the respective placebo groups. Carvedilol selectively lowered coronary sinus norepinephrine levels, an index of cardiac adrenergic activity, whereas metoprolol did not lower coronary sinus norepinephrine and actually increased central venous norepinephrine levels. Finally, metoprolol was associated with an increase in cardiac β-receptor density, whereas carvedilol did not change cardiac β-receptor expression.

Conclusions
The third-generation β-blocking agent carvedilol has substantially different effects on left ventricular function, hemodynamics, adrenergic activity, and β-receptor expression than does the second-generation compound metoprolol. Some or all of these differences may explain the apparent differences in clinical results between the two compounds.
Fatty Acid Oxidation Enzyme Gene Expression Is Downregulated in the Failing Heart
Authors: Sack Michael N. , Rader Toni A. , Park Sonhee , Bastin Jean , McCune Sylvia A. , Kelly Daniel P.
Published: June 2012

Background
During the development of heart failure (HF), the chief myocardial energy substrate switches from fatty acids to glucose. This metabolic switch, which recapitulates fetal cardiac energy substrate preferences, is thought to maintain aerobic energetic balance. The regulatory mechanisms involved in this metabolic response are unknown.

Methods and Results
To characterize the expression of genes involved in mitochondrial fatty acid β-oxidation (FAO) in the failing heart, levels of mRNA encoding enzymes that catalyze the first and third steps of the FAO cycle were delineated in the left ventricles (LVs) of human cardiac transplant recipients. FAO enzyme and mRNA levels were coordinately downregulated (>40%) in failing human LVs compared with controls. The temporal pattern of this alteration in FAO enzyme gene expression was characterized in a rat model of progressive LV hypertrophy (LVH) and HF [SHHF/Mcc-

fa
cp

(SHHF) rat]. FAO enzyme mRNA levels were coordinately downregulated (>70%) during both the LVH and HF stages in the SHHF rats compared with controls. In contrast, the activity and steady-state levels of medium-chain acyl-CoA dehydrogenase, which catalyzes a rate-limiting step in FAO, were not significantly reduced until the HF stage, indicating additional control at the translational or posttranslational levels in the hypertrophied but nonfailing ventricle.

Conclusions
These findings identify a gene regulatory pathway involved in the control of cardiac energy production during the development of HF.
Impact of Reduced Heart Rate Variability on Risk for Cardiac Events
Authors: Tsuji Hisako , Larson Martin G. , Venditti Ferdinand J. , Manders Emily S. , Evans Jane C. , Feldman Charles L. , Levy Daniel
Published: June 2012

Background
Although heart rate variability (HRV) is altered in a variety of pathological conditions, the association of reduced HRV with risk for new cardiac events has not been studied in a large community-based population.

Methods and Results
The first 2 hours of ambulatory ECG recordings obtained on subjects of the Framingham Heart Study who were free of clinically apparent coronary heart disease or congestive heart failure were reprocessed to assess HRV. Five frequency-domain measures and three time-domain measures were obtained. The associations between HRV measures and the incidence of new cardiac events (angina pectoris, myocardial infarction, coronary heart disease death, or congestive heart failure) were assessed with proportional hazards regression analyses. There were 2501 eligible subjects with a mean age of 53 years. During a mean follow-up of 3.5 years, cardiac events occurred in 58 subjects. After adjustment for age, sex, cigarette smoking, diabetes, left ventricular hypertrophy, and other relevant risk factors, all HRV measures except the ratio of low-frequency to high-frequency power were significantly associated with risk for a cardiac event (
P
=.0016 to .0496). A one–standard deviation decrement in the standard deviation of total normal RR intervals (natural log transformed) was associated with a hazard ratio of 1.47 for new cardiac events (95% confidence interval of 1.16 to 1.86).

Conclusions
The estimation of HRV by ambulatory monitoring offers prognostic information beyond that provided by the evaluation of traditional cardiovascular disease risk factors.
Equipotent Antihypertensive Agents Variously Affect Pulsatile Hemodynamics and Regression of Cardiac Hypertrophy in Spontaneously Hypertensive Rats
Authors: Mitchell Gary F. , Pfeffer Marc A. , Finn Peter V. , Pfeffer Janice M.
Published: June 2012

Background
Converting enzyme inhibitors are more effective than arteriolar vasodilators at regressing left ventricular hypertrophy in spontaneously hypertensive rats (SHR), possibly because of nonhemodynamic factors. However, the pulsatile component of hemodynamic load has not been evaluated in this model.

Methods and Results
We measured pulsatile hemodynamics in 18-month-old male SHR after 6 months of therapy with either zofenopril (Z), hydralazine (H), or water (W). Hydralazine and zofenopril reduced mean arterial pressure comparably (W, 106±23 versus H, 81±12 versus Z, 84±18 mm Hg,
P
=.002) yet had a differential effect on the ratio of left ventricular weight to body weight (W, 3.9±0.5 versus H, 3.3±0.4 versus Z, 2.4±0.2 g/kg,
P
<.005). Hydralazine-treated SHR had increased characteristic impedance (
P
=.0011) and a persistently low ratio of the reflected-wave transit time to left ventricular ejection time (
P
<.001), which contributed to early and late systolic loading, respectively, of the left ventricle. Consequently, only zofenopril-treated SHR had a significant reduction in left ventricular systolic force-time integral (
P
=.02), a measure of total ventricular load. There were no differences in systolic stress-time integral, suggesting that mass was appropriate to load when all elements of steady-flow and pulsatile load were considered.

Conclusions
A blunted reduction in total left ventricular load, due to increased pulsatile load in SHR treated with hydralazine, provided a hemodynamic basis for the differential regression of hypertrophy in this model of genetic hypertension.
Relationship Between Local Atrial Fibrillation Interval and Refractory Period in the Isolated Canine Atrium
Authors: Kim Ki-Bong , Rodefeld Mark D. , Schuessler Richard B. , Cox James L. , Boineau John P.
Published: June 2012

Background
Atrial refractory periods and their spatial distribution are important determinants of atrial reentrant arrhythmias. The objective of this study was to demonstrate a correlation between the local atrial fibrillation interval (AFI) and local effective refractory period (ERP).

Methods and Results
To measure the local ERP and local AFI under stable conditions without hemodynamic, autonomic, or reflex influences, isolated perfused canine whole atria were used (n=8). The isolated atria were mounted on two endocardial electrodes. Bipolar electrograms were simultaneously recorded from 253 endocardial sites, and 16 to 20 randomly distributed electrodes were used to measure the local ERP by the extrastimulus technique. In all studies, several episodes of AF were induced by a single extrastimulus. The ERP and minimum AFI converged with increasing duration of AF. The convergence was more rapid if the total duration of AF analyzed came from multiple episodes of AF. The correlation coefficient between the local ERP and minimum local AFI was .92 (n=119,
P
<.001). The minimum AFI was used to construct AFI distribution maps at all 253 sites. Activation block during premature stimulation correlated with regions of long AFI.

Conclusions
The minimum local AFI measured from at least 10 seconds of AF approximates the local ERP. Construction of a minimum local AFI map during AF can be used to predict the distribution of refractoriness and can be used to predict sites of functional block. Contrary to studies done in intact animals and patients, the AFI were longer than the ERPs, suggesting that reflex changes may shorten ERP in the intact heart.
Macrophage Infiltration Predicts Restenosis After Coronary Intervention in Patients With Unstable Angina
Authors: Moreno Pedro R. , Bernardi Vi´ctor H. , Lo´pez-Cue´llar Julio , Newell John B. , McMellon Charles , Gold Herman K. , Palacios Igor F. , Fuster Valenti´n , Fallon John T.
Published: June 2012

Background
Restenosis remains the major limitation of percutaneous coronary revascularization. Macrophages release cytokines, metalloproteinases, and growth factors that may induce smooth muscle cell migration and proliferation. We tested the hypothesis that primary lesions that develop restenosis after coronary atherectomy have more macrophages and smooth muscle cells than primary lesions that do not develop restenosis.

Methods and Results
Fifty patients with unstable angina were identified. Total and segmental areas were quantified on trichrome-stained sections of coronary atherectomy tissue. Macrophages and smooth muscle cells were identified by immunohistochemical staining. Restenosis, defined as >50% stenosis diameter by quantitative cineangiography, was present in 30 patients. The other 20 patients (<50% stenosis) constitute the “no restenosis” group. The percentages of smooth muscle cell areas were similar in specimens from patients with and without restenosis (57±5% and 52±6%) (
P
=NS). However, macrophage-rich areas were larger in plaque tissue from patients with restenosis (20.4±2%) than in tissue from patients without restenosis (9.3±2%) (
P
=.0007). Multiple stepwise logistic regression analysis identified macrophages as the only independent predictor for restenosis (
P
=.006).

Conclusions
Macrophages are increased in coronary atherectomy tissue from primary lesions that develop restenosis, suggesting a possible role for macrophages in the restenotic process after percutaneous coronary intervention.
Long-term Smoking Impairs Platelet-Derived Nitric Oxide Release
Authors: Ichiki Kazuya , Ikeda Hisao , Haramaki Nobuya , Ueno Takafumi , Imaizumi Tsutomu
Published: June 2012

Background
Long-term smoking impairs endothelium-dependent vasodilation, which is mediated by nitric oxide (NO). However, it is unknown whether long-term smoking impairs the platelet-derived NO release, which regulates platelet aggregation.

Methods and Results
Platelet-derived electrical current induced by collagen was measured with an NO-selective electrode in 12 smokers and 11 nonsmokers. Collagen-induced intraplatelet cGMP and platelet aggregation was measured in smokers and nonsmokers.
S
-nitroso-
N
-acetyl-
dl
-penicillamine, a direct NO donor, dose dependently increased in electrical current (
r
=.99). Collagen induced platelet aggregation and dose dependently increased electrical current (
r
=.94). Collagen-induced electrical current and cGMP were significantly augmented by
l
-arginine, a precursor of NO, and attenuated by
N
G
-monomethyl-
l
-arginine, an inhibitor of NO synthesis. Significant correlation was found between collagen-induced electrical current and cGMP (
r
=.73). These findings indicate that the change in electrical current reflects the NO release through the
l
-arginine–NO pathway in platelets. Collagen-induced electrical current (6.7 versus 13.8 pA;
P
<.001) and cGMP (1.2 versus 3.0 pmol/10
9
platelets;
P
<.005) were significantly lower in smokers than in nonsmokers. Although
l
-arginine increased cGMP levels in both smokers and nonsmokers, the level was still lower in smokers than in nonsmokers. The inhibitory effect of
l
-arginine on collagen-induced platelet aggregation was significantly lower in smokers than in nonsmokers (
P
<.05).

Conclusions
These findings provide evidence that platelet-derived NO release is significantly impaired in long-term smokers, resulting in the augmentation of platelet aggregability.
Effect of Hypertension and Cardiac Hypertrophy on Coronary Artery Morphology in Sudden Cardiac Death
Authors: Burke Allen P. , Farb Andrew , Liang You-hui , Smialek John , Virmani Renu
Published: June 2012

Background
Epidemiological studies have shown that hypertension and left ventricular hypertrophy (LVH) increase the risk of sudden cardiac death (SCD) in patients with severe coronary artery disease (CAD). However, autopsy studies comparing the morphological substrates for SCD in normotensives and hypertensives are lacking.

Methods and Results
Heart weight and coronary plaque morphology were prospectively compared in SCD in 36 hypertensive and 63 normotensive individuals. The frequency of CAD was similar in hypertensives (69%, n=25) and normotensives (73%, n=46). In 71 hearts with CAD, acute coronary thrombi were present in 76% of normotensives versus 36% of hypertensives (
P
=.002), LVH was present in 64% of hypertensives versus 33% of normotensives (
P
=.01) and in 72% of hypertensives with one-vessel disease versus 17% of normotensives with one-vessel disease (
P
=.0005), and a healed or acute infarct without acute thrombus was present in 36% of hypertensives versus 9% of normotensives (
P
=.007). Heart weight was higher in all cases of plaque rupture (519±109 g) than eroded plaque (381±92 g,
P
=.0002). In contrast to hypertensives, normotensive hearts with severe CAD showed a stepwise increase in heart weight with one-, two-, and three-vessel disease (
P
=.01).

Conclusions
Severe CAD is present in most SCD in hypertensive and normotensive individuals, but acute thrombi are more common in normotensives. LVH is an important contributing mechanism of SCD in hypertensives, especially in cases of one-vessel disease. LVH is associated with plaque rupture and extent of disease in SCD in normotensives with severe CAD.
Right Ventricular Performance and Contractile Reserve in Patients With Severe Heart Failure
Authors: Gorcsan John , Murali Srinivas , Counihan Peter J. , Mandarino William A. , Kormos Robert L.
Published: June 2012

Background
Right ventricular (RV) performance appears to be important in patients with severe heart failure. Although clinical assessments of RV function previously have been limited to load-dependent ejection phase indices, a new method has been developed using the relatively load-insensitive concepts of pressure-volume relations with automated echocardiographic measures of RV cross-sectional area as a surrogate for volume.

Methods and Results
Sixteen patients with New York Heart Association functional class IV heart failure and group mean left ventricular ejection fraction of 20±5% were studied. RV pressure-area loops were recorded on-line from echocardiographic measures of RV area and high-fidelity pressure during transient inferior vena caval balloon occlusions. RV contractile reserve was assessed as its functional response to an increase in dobutamine from 5.7±4.1 to 13.1±4.7 μg/kg per minute. Complete data sets were available in 13 patients. Group mean RV end-systolic elastance (E'es) and maximal elastance (E'max) increased with augmented dobutamine infusion (2.9±1.5 to 5.5±3.3 mm Hg/cm
2
and 3.3±1.6 to 6.4±3.9 mm Hg/cm
2
, respectively;
P
<.01 versus baseline), although individual responses were variable. During a 30-day follow-up, 9 patients remained unstable, requiring continuous intravenous inotropic therapy; 6 of these had profound deterioration requiring mechanical circulatory support. The remaining 4 patients had a comparatively good short-term outcome with clinical stability. A 100% increase in RV E'es or E'max was associated with a good short-term outcome (
P
<.05).

Conclusions
RV performance can be assessed by pressure-area relations in patients with heart failure. RV contractile reserve in response to increases in dobutamine was associated with a good short-term outcome and may be of prognostic value in patients with severe heart failure.
Noninvasive Evaluation of Intrarenal Oxygenation With BOLD MRI
Authors: Prasad Pottumarthi V. , Edelman Robert R. , Epstein Franklin H.
Published: June 2012

Background
The countercurrent arrangement of capillary blood flow in the medulla of mammalian kidneys generates a gradient of oxygen tension between the renal cortex and the papillary tip that results in a state of relative hypoxia within the renal medulla. Exploration of the pathophysiological implications of medullary hypoxia has been hampered by the absence of a noninvasive technique to estimate intrarenal oxygenation in different zones of the kidney. In the present study, we demonstrate the feasibility of such a method on the basis of blood oxygenation level–dependent (BOLD) MRI, which allows sequential measurements in humans in response to a variety of physiological/pharmacological stimuli in health and disease.

Methods and Results
BOLD MRI measurements were obtained in healthy young human subjects (n=7), and the effects of three different pharmacological/physiological maneuvers that induce diuresis were studied. Spin-spin relaxation rate, R
2
*, was measured, which is directly related to the amount of deoxyhemoglobin in blood and in turn to tissue P
o
2
. Furosemide but not acetazolamide (n=6 each) increased medullary oxygenation (ΔR
2
*=7.62 Hz;
P
<.01), consistent with the separate sites of action of these diuretics in the nephron and with previous direct measurements of their effects in anesthetized rats with oxygen microelectrodes. A new finding is that water diuresis improves medullary oxygenation (ΔR
2
*=6.43 Hz;
P
<.01) in young human subjects (n=5).

Conclusions
BOLD MRI can be used to monitor changes in intrarenal oxygenation in humans in a noninvasive fashion.
Relationship Between Type of Outflow Tract Repair and Postoperative Right Ventricular Diastolic Physiology in Tetralogy of Fallot
Authors: Norgård Gunnar , Gatzoulis Michael A. , Moraes Fernando , Lincoln Christopher , Shore Darryl F. , Shinebourne Elliot A. , Redington Andrew N.
Published: June 2012

Background
Restrictive right ventricular (RV) physiology can be present early and late after tetralogy of Fallot repair. It is associated with a complicated early postoperative course but is favorable late after repair because it is associated with less pulmonary regurgitation, better exercise tolerance, and less QRS prolongation and symptomatic ventricular arrhythmias. It is not known, however, whether in the current surgical era, this physiology is present in tetralogy of Fallot patients at mid-term follow-up and whether it is related to the type of RV outflow tract repair. Finally, the impact of this physiology on the early evolution of QRS prolongation has not been examined previously. In this study we attempted to address these issues in a cohort of recently operated patients.

Methods and Results
Ninety-five patients were studied 4.3 years after repair by Doppler echocardiography, serial electrocardiograms, and chest radiographs. Restrictive RV physiology defined by the presence of antegrade pulmonary artery flow in late diastole was present in 38% of the patients. It was more common in patients with transannular patch (TAP) repair compared with non-TAP repair (50% versus 21%,
P
<.05). QRS duration at follow-up was 121.2±17.6 and 132.6±11.8 ms in restrictive and nonrestrictive patients with TAP repair, respectively (
P
<.02).

Conclusions
Restrictive RV physiology has been identified at mid-term follow-up in a contemporary surgical series. It is associated with less QRS prolongation, regardless of the technique used for outflow tract repair, and may be associated with fewer long-term complications. Nonrestrictive physiology is associated with the most marked QRS prolongation. This subgroup is most at risk from the late deleterious consequences of chronic pulmonary regurgitation.
Myocardial Gd-DTPA Kinetics Determine MRI Contrast Enhancement and Reflect the Extent and Severity of Myocardial Injury After Acute Reperfused Infarction
Authors: Kim Raymond J. , Chen Enn-Ling , Lima Joa˜o A.C. , Judd Robert M.
Published: June 2012

Background
Contrast medium–enhanced magnetic resonance images of acute, reperfused infarcts have shown hypoenhanced and hyperenhanced regions in areas of injured myocardium. The precise mechanisms that lead to these altered enhancement patterns are unknown. This study was designed to evaluate possible mechanisms and to relate altered enhancement patterns to myocardial perfusion and viability.

Methods and Results
Thirteen rabbits underwent in situ coronary artery occlusion and reperfusion followed by isolated perfusion with cardioplegic solution. T1-weighted spin-echo images were acquired continuously during step changes in perfusate Gd-DTPA concentration. Regional blood flow was also measured by use of radioactive microspheres in all rabbits. There were marked differences in Gd-DTPA wash-in and washout time constants (wash-in, 0.8±0.1, 2.1±0.2, and 16.3±2.4 minutes,
P
<.001; washout, 1.6±0.1, 4.8±0.5, and 31.1±3.3 minutes,
P
<.001) in normal, infarct rim, and infarct core regions, respectively, resulting in differential enhancement of these regions. Microsphere flows in the infarct rim and core were 42.9±4.0% and 12.0±1.6% of normal myocardium and correlated well with washout time constants (
r
=.86,
y
=0.77
x
−0.002,
P
<.001), suggesting that these time constants index the severity of microvascular damage. In addition, spatial maps of washout time constants were produced. The extent of regions with abnormal time constants correlated well with triphenyltetrazolium chloride–determined infarct size (
r
=.94,
y
=0.95
x
+4.17,
P
<.001).

Conclusions
In contrast-enhanced magnetic resonance images of acute, reperfused rabbit infarcts, differential image intensity is primarily due to regional differences in contrast agent wash-in and washout time constants. These regional differences in time constants also indicate the extent and severity of myocardial injury.
Antibody to Platelet/Endothelial Cell Adhesion Molecule-1 Reduces Myocardial Infarct Size in a Rat Model of Ischemia-Reperfusion Injury
Authors: Gumina Richard J. , Schultz Jo El , Yao Zhenhai , Kenny Dermot , Warltier David C. , Newman Peter J. , Gross Garrett J.
Published: June 2012

Background
Antibodies to selected neutrophil or endothelial cell adhesion molecules decrease myocardial infarct size in vivo. Platelet/endothelial cell adhesion molecule-1 (PECAM-1) is an immunoglobulin gene superfamily member expressed constitutively on neutrophils and endothelium. F(ab′)
2
fragments of antibody against PECAM-1 inhibit transendothelial migration of neutrophils in several in vivo models of acute inflammation. Therefore, we examined the effect of F(ab′)
2
fragments of anti–PECAM-1 antibody in a rat model of myocardial infarction.

Methods and Results
F(ab′)
2
fragments of the anti–PECAM-1 antibody SEW16 and control normal rabbit IgG (NRIgG) were administered at 5 mg/kg to male Wistar rats, and the rats were subjected to a 30-minute coronary artery occlusion followed by 2 hours of reperfusion. At the completion of each experiment, the area at risk, infarct size (IS), and myeloperoxidase (MPO) activity were determined. Compared with untreated (n=8; IS, 57±5%) or NRIgG-treated (n=10; IS, 62±3%) control rats, SEW16-treated rats (n=15; IS, 28.5±4%) displayed a 54% decrease in myocardial infarct size (
P
<.001). Hemodynamic parameters, leukocyte counts, total left ventricular weight, and area-at-risk weights did not differ significantly between the treatment groups. However, measurement of MPO activity revealed that neutrophil accumulation was reduced 83% (NRIgG, 975±55 mU/g; SEW16, 167±62 mU/g).

Conclusions
These results demonstrate that blocking PECAM-1 exerts a significant protective effect in a rat model of myocardial ischemia-reperfusion injury via blockade of neutrophil accumulation in the myocardium.
A Novel Site-Targeted Ultrasonic Contrast Agent With Broad Biomedical Application
Authors: Lanza Gregory M. , Wallace Kirk D. , Scott Michael J. , Cacheris William P. , Abendschein Dana R. , Christy Donald H. , Sharkey Angela M. , Miller James G. , Gaffney Patrick J. , Wickline Samuel A.
Published: June 2012

Background
In this work, we report a novel targetable ultrasonic contrast agent with the potential to noninvasively define and localize myriad pathological tissues for diagnosis or therapy. The agent is a biotinylated, lipid-coated, perfluorocarbon emulsion that has low inherent echogenicity unless bound to a surface or itself.

Methods and Results
In study 1, emulsions with and without biotin were suspended in buffered saline and imaged with a 7.5-MHz linear-array transducer. Neither emulsion manifested significant ultrasonic backscatter until avidin was added. Avidin-induced aggregation produced a marked enhancement in backscatter from the biotinylated but not from the control emulsion. In study 2, porcine fibrin clots in vitro were pretargeted with biotinylated antifibrin monoclonal antibodies and then exposed to avidin and then to biotinylated or control perfluorocarbon emulsions. The basal acoustic reflectivity of clots imaged with a 7.5-MHz linear-array transducer was uniformly low and was increased substantially by exposure to the targeted biotinylated emulsion. In study 3, partially occlusive arterial thrombi were created in dogs and then exposed to antifibrin antibodies and avidin in situ. Biotinylated or control emulsion was administered either in situ or systemically. At baseline, all thrombi were undetectable with a 7.5-MHz linear-array transducer. Thrombi exposed to antifibrin-targeted contrast exhibited increased echogenicity (
P
<.05); control thrombi remained acoustically undetectable.

Conclusions
These data provide the first in vivo demonstration of a site-specific ultrasonic contrast agent and have potential for improved sensitivity and specificity for noninvasive diagnosis of thrombi and other pathological diseases.
Inhibition of Transplant Coronary Arteriosclerosis in Rabbits by Chronic Estradiol Treatment Is Associated With Abolition of MHC Class II Antigen Expression
Authors: Lou Hong , Kodama Teruaki , Zhao Ye Jun , Maurice Peter , Wang Yi Ning , Katz Nevin , Foegh Marie L.
Published: June 2012

Background
Accelerated coronary arteriosclerosis is a major complication in long-term survivors of cardiac transplantation. Estrogen prevents transplant arteriosclerosis in experimental cardiac and aortic allografts and may act by an immune mechanism.

Methods and Results
New Zealand White rabbits immunosuppressed with cyclosporine were recipients of cardiac allografts from Dutch Belted rabbits. The recipients received either estradiol or placebo daily until they were killed 6 weeks later. Histological cross sections of the cardiac allograft were used for quantification of major histocompatibility complex (MHC) class II antigen expression, T lymphocytes, and macrophages by immunohistochemistry using monoclonal antibodies. MHC class II antigen expression was not detectable in allograft coronary arteries from any of the estradiol-treated recipients, whereas this antigen expression was present in the allograft coronary arteries from all the placebo-treated recipients. Macrophage and lymphocyte infiltration of the allograft coronary artery myointima was significantly less frequent in the estradiol-treated group. Rejection was moderate but slightly less in the estradiol-treated group. These findings were associated with a 60% decrease in allograft coronary artery myointimal thickening (determined by morphometry) in the estradiol-treated compared with the placebo-treated group.

Conclusions
Estradiol treatment of cardiac allograft recipients abolishes MHC class II antigen expression in the coronary arteries and decreases macrophage infiltration in all three layers of the vessel wall, whereas T-lymphocyte infiltration is decreased only in the myointima. These findings are associated with estradiol inhibition of myointimal proliferation. Thus, estradiol treatment may have a beneficial effect on graft arteriosclerosis through immune mechanisms.
Rapid Rates During Bradycardia Prolong Ventricular Refractoriness and Facilitate Ventricular Tachycardia Induction With Cesium in Dogs
Authors: Satoh Tadashi , Zipes Douglas P.
Published: June 2012

Background
Bradycardia can promote the development of some ventricular tachycardias (VTs). We investigated whether relative bradycardia per se or the transition from a rapid to a slower ventricular rate might be important in developing VT.

Methods and Results
We studied groups of anesthetized closed-chest dogs that had AV block produced by radiofrequency catheter ablation of the AV junction. One group had uninterrupted AV block; the other group underwent a period of rapid left ventricular pacing. Both groups then received incremental doses of CsCl until sustained VT resulted. We also measured ventricular effective refractory period (V-ERP) and QT interval in separate groups of dogs that had AV block for 1 week or 3 days with and without rapid pacing (pacing cycle length [PCL]=500 or 250 ms) for 1 hour or 30 minutes. Finally, we investigated the effects of rapid pacing on V-ERP by testing the effects of verapamil and autonomic denervation on these changes. We found that CsCl induced larger early afterdepolarizations and a greater prevalence of VT in dogs with rapid pacing than in dogs without. In dogs that had AV block for 1 week, 1 hour of rapid pacing prolonged V-ERP and QT interval compared with V-ERP and QT interval before pacing. Changes persisted for at least 3 hours. Rapid pacing for only 30 minutes and at a PCL of 250 ms, as well as superimposition on sinus rhythm, each prolonged V-ERP but to a lesser extent. Only 3 days of complete AV block and autonomic denervation did not affect the prolongation of V-ERP produced by rapid pacing, whereas verapamil significantly blunted but did not eliminate the prolongation.

Conclusions
At the same PCLs, the heart exposed to transient tachycardia superimposed on bradycardia exhibited a longer V-ERP, QT interval, and monophasic action potential duration and greater ease for developing VT than the heart exposed only to bradycardia. The prolongation of refractoriness lasted for at least 3 hours, and the Δ-ERP was influenced by the heart rate before pacing, the duration of pacing, and the PCL. The mechanism for this response to rapid rates appears to involve calcium, at least in part.
Acute Effects of β
1
-Selective and Nonselective β-Adrenergic Receptor Blockade on Cardiac Sympathetic Activity in Congestive Heart Failure
Authors: Newton Gary E. , Parker John D.
Published: June 2012

Background
β-Blockers may reduce cardiac sympathetic activity in patients with heart failure by antagonizing β-adrenergic receptors that facilitate sympathetic outflow to the heart. To explore this possible effect of β-blockade, we measured cardiac norepinephrine spillover responses in patients with heart failure after the acute administration of either propranolol, a nonselective β-blocker, or metoprolol, a β
1
-selective agent.

Methods and Results
Eighteen patients were studied. Repeated intravenous doses of propranolol (0.5 mg; nine patients; left ventricular ejection fraction, 14±2%) or metoprolol (1.0 mg; nine patients; left ventricular ejection fraction, 18±2%) were administered until one of the following end points was reached: a 15% decrease in heart rate, left ventricular +dP/dt, or mean arterial blood pressure or a 5 mm Hg increase in left ventricular end-diastolic pressure. Propranolol (mean dose, 2.0 mg) and metoprolol (mean dose, 3.6 mg) caused similar reductions in heart rate, +dP/dt, and coronary sinus plasma flow. Cardiac norepinephrine spillover was reduced after propranolol (277±55 to 262±53 pmol/min,
P
<.05) but was increased after metoprolol (233±57 to 296±82 pmol/min,
P
<.05). In a comparison of the two groups, the decrease in spillover after propranolol was significantly different than the increase seen after metoprolol (
P
<.01).

Conclusions
The administration of a β
1
-selective antagonist was associated with increased cardiac norepinephrine spillover. In contrast, the administration of a nonselective β-blocker until similar hemodynamic end points were reached caused a reduction in norepinephrine spillover. This suggests that in patients with heart failure, nonselective β-blockade may have favorable inhibitory effects on cardiac sympathetic activity.
Fibrin
d
-Dimer and β-Thromboglobulin as Markers of Thrombogenesis and Platelet Activation in Atrial Fibrillation
Authors: Lip Gregory Y.H. , Lip Peck Lin , Zarifis John , Watson Robert D.S. , Bareford David , Lowe Gordon D.O. , Beevers D. Gareth
Published: June 2012

Background
Previous studies have demonstrated increased markers of thrombogenesis in patients with atrial fibrillation (AF), suggesting the presence of a hypercoagulable or prothrombotic state. The objective of this study was to determine the effects of introducing ultra–low-dose warfarin (1 mg), conventional warfarin, and aspirin (300 mg) therapy on thrombogenesis and platelet activation in AF.

Methods and Results
We measured sequential changes in plasma fibrin
d
-dimer (an index of thrombogenesis) and β-thromboglobulin (β-TG, a measure of platelet activation) in 51 patients with chronic AF before and at 2 and 6 weeks after randomization to either 1 mg warfarin or 300 mg aspirin (phase 1). Then all patients were started on conventional warfarin therapy (phase 2) with samples taken 2 and 6 weeks later. Pretreatment results were compared with those from 26 healthy control subjects in sinus rhythm. Baseline (pretreatment) β-TG and
d
-dimer levels in patients with AF were elevated compared with those of control subjects (
P
<.001). In phase 1, there were no significant changes in median levels of fibrin
d
-dimer or β-TG, despite warfarin 1 mg or aspirin 300 mg. With standard warfarin therapy (phase 2), there was a reduction in median β-TG at 6 weeks (
P
=.025) and a sequential reduction in median
d
-dimer levels at 2 (
P
=.001) and 6 (
P
<.001) weeks compared with baseline levels.

Conclusions
Patients with AF have increased intravascular thrombogenesis and platelet activation compared with patients in sinus rhythm. Introduction of ultra–low-dose warfarin (1 mg) or aspirin 300 mg does not significantly alter these markers, although conventional warfarin therapy reduces β-TG and fibrin
d
-dimer levels. This is consistent with the beneficial effect of full-dose warfarin in preventing stroke and thromboembolism in AF and suggests that ultra–low-dose warfarin and aspirin may not exert similar beneficial effects.
Relation Between Air-Filled Albumin Microbubble and Red Blood Cell Rheology in the Human Myocardium
Authors: Ismail Suad , Jayaweera Ananda R. , Camarano Gustavo , Gimple Lawrence W. , Powers Eric R. , Kaul Sanjiv
Published: June 2012

Background
We have previously shown that the intravascular rheology of sonicated air-filled albumin microbubbles is similar to that of red blood cells (RBCs) and that their myocardial transit rate is also similar to that of RBCs in the beating canine heart. In the present study, we tested the hypothesis that the myocardial transit rates of these microbubbles reflect those of RBCs in humans at different coronary flow rates.

Methods and Results
RBC and microbubble transit rates were measured in 17 patients undergoing coronary angiography: in 8, measurements were made only at rest, whereas in 9, they were performed both at rest and during a pacing-induced increase in coronary blood flow. A γ-variate function was used to derive mean RBC and microbubble transit rates from the time-activity and time-intensity plots after the left main injection of RBCs and microbubbles, respectively. There was linear correlation between the myocardial transit rates with both tracers with the slope of the correlation determined by the specific echocardiographic system that was used. Microbubble transit rate consistently overestimated RBC transit rate due to artificial narrowing of the time-intensity curves caused by chest wall attenuation of the echocardiographic signal, which was confirmed through in vitro experiments.

Conclusions
There is close correlation between air-filled albumin microbubbles and RBC rheology in the human myocardium. The use of these microbubbles in the cardiac catheterization laboratory could, therefore, provide further insights into myocardial blood flow/myocardial blood volume relations in humans.