bluuebunny/crossref_metadata_2025 huggingface dataset:
Myocardial Kinetics of a Putative Hypoxic Tissue Marker,
99m
Tc-Labeled Nitroimidazole (BMS-181321), After Regional Ischemia and Reperfusion
Authors: Stone Charles K. , Mulnix Timothy , Nickles Robert J. , Renstrom Britta , Nellis Stephen H. , Liedtke A. James , Nunn Adrian D. , Kuczynski Bruce L. , Rumsey William L.
Published: June 2012

Background
A new nitroimidazole complex,
99m
Tc-propylene amine oxime-1,2-nitroimidazole (BMS-181321), has been developed to allow the positive imaging of hypoxic myocardium by standard gamma camera techniques.

Methods and Results
To determine the myocardial kinetics of BMS-181321 during myocardial ischemia and reperfusion, seven open-chest swine were prepared according to a model of extracorporeal coronary perfusion in which left ventricular wall thickening (percent end-diastolic thickness) and substrate use in the left anterior descending (LAD) region ([
14
C]palmitate and [
3
H]glucose infusions) were determined. Measurements were obtained at baseline, during 40 minutes of ischemia produced by reducing flow in the LAD distribution by 60%, and during 70 minutes of reperfusion. Three aerobic control hearts were also studied in which LAD blood flow was not reduced. Regional coronary circulation was further assessed in all hearts by use of radiolabeled microspheres injected during ischemia. BMS-181321 (20 to 30 mCi) was injected after 30 minutes of ischemia, and its myocardial uptake was assessed by dynamic planar gamma imaging. Ischemia was associated with declines in fatty acid metabolism (15±11 μmol · h
−1
· g dry wt
−1
, mean±SEM), systolic wall thickening (20±6%), and myocardial oxygen consumption (3±1 mL · min
−1
· 100 g
−1
) and an increase in exogenous glucose utilization (75±13 μmol · h
−1
· g dry wt
−1
). Systolic wall thickening recovered by only 8±3% with reperfusion. Initial distribution of BMS-181321 in the aerobic hearts appeared homogeneous. Washout from the ischemic and reperfused LAD bed was slower than the aerobically perfused LAD bed in the control group (t
1/2
=136±1 versus 80±1 minutes,
P
<.05), allowing visualization of the LAD region during reperfusion. Tissue activity of BMS-181321 was inversely related to LAD blood flow during ischemia (
r
=−.68±.05), and the ratio of BMS-181321 in the LAD region versus normal myocardium was 1.7±0.2. Control swine lacked regional deposition of the tracer in the normally perfused LAD distribution.

Conclusions
Thus, acute regional ischemia in these studies was visualized as an increase in retention of BMS-181321, suggesting its applicability in the imaging of clinical conditions of myocardial hypoperfusion.
Bidirectional Effects of Aminophylline on Myocardial Ischemia
Authors: Minamino Tetsuo , Kitakaze Masafumi , Morioka Toshikazu , Node Koichi , Shinozaki BE Yoshiro , Chujo Mitsuaki , Mori Hidezo , Takeda Hiroshi , Inoue Michitoshi , Hori Masatsugu , Kamada Takenobu
Published: June 2012

Background
Aminophylline blocks adenosine receptors and increases levels of plasma catecholamines. We investigated the effect of aminophylline on myocardial ischemia by varying its severity and attempted to identify the mechanism by which aminophylline modulates myocardial ischemia in the canine model.

Methods and Results
In 41 open-chest dogs, the left anterior descending coronary artery was cannulated and perfused with blood through a bypass tube from the left carotid artery. When coronary blood flow (CBF) was reduced to 80% of the control, aminophylline increased fractional shortening (FS) from 11.0±0.4% to 18.5±1.7% (
P
<.05) and lactate extraction ratio (LER) from 7.5±0.1% to 13.6±1.0% (
P
<.01). The endocardial to epicardial flow ratio (Endo/Epi ratio) of regional myocardium was also increased. Release of adenosine was increased compared with the nonischemic condition (7±3 versus 28±5 pmol/mL). Prazosin, an α
1
-adrenoceptor antagonist, blunted the aminophylline-induced improvement in contractile and metabolic function. Administration of 8-phenyltheophylline, a selective antagonist of adenosine receptors, did not increase FS, LER, or the Endo/Epi ratio when CBF was reduced to 80% of control. When CBF was reduced to 60% of control, aminophylline did not change the metabolic and contractile function. In contrast, when CBF was reduced to 33% of control, release of adenosine was increased markedly (243±19 pmol/mL) and aminophylline induced decreases in FS, LER, and Endo/Epi ratio similar to those observed with 8-phenyltheophylline.

Conclusions
Aminophylline had opposite effects on the ischemic myocardium depending on the severity of ischemia. It improved mild ischemia but worsened severe ischemia. The beneficial effect of aminophylline was attributable to α
1
-adrenoceptor stimulation, which improves endomyocardial flow in the ischemic myocardium. The deleterious effect was attributable to the aminophylline-induced blockade of adenosine receptors.
Effect of Rapid Pacing and T-Wave Scanning on the Relation Between the Defibrillation and Upper-Limit-of-Vulnerability Dose-Response Curves
Authors: Malkin Robert A. , Idriss Salim F. , Walker Robert G. , Ideker Raymond E.
Published: June 2012

Background
The critical-point and upper-limit-of-vulnerability (ULV) hypotheses predict that the ULV dose-response curve should be steeper and to the right of the defibrillation (DF) curve. Yet, some recent experimental data contradict this prediction. Two studies are presented that test two explanations for the contradiction: (1) Testing at a single point in the T wave underestimates the ULV dose-response curve and (2) ULV testing at normal heart rates does not mimic the mechanical or electrical state of the heart in ventricular fibrillation (VF).

Methods and Results
A nonthoracotomy lead system with a biphasic waveform was used throughout. In eight dogs, the dose-response curve widths (a measure of steepness) were compared between DF data and ULV data gathered at the peak (ULV
PK
), middownslope (ULV
DWN
), midupslope (ULV
UP
), and all times (scanning or ULV
SCN
) in the T wave. In another eight dogs, ULV data (ULV
RAP
) were gathered by scanning the T wave after 15 rapidly paced beats (166- to 198-ms pacing interval). The rapid pacing interval was chosen to more closely mimic the hemodynamics and activation rate of early VF. ULV data (ULV
STD
) at normal heart rates were gathered for all animals. In the first study, scanning significantly reduced the ULV curve width (ULV
SCN
, 63.5±29.7 V; ULV
PK
, 81.9±45.2 V; ULV
DWN
, 116±36.5 V; DF, 105±22.0 V;
P
<.03) and significantly shifted the ULV curve to the right (ULV
80 SCN
, 410±62.6 V; ULV
80 PK
, 266±35.3 V; ULV
80 DWN
, 355±80.4 V; DF
80
, 427±60.9 V;
P
<.001). The subscript 80 signifies that the subject was left in normal sinus rhythm 80% of the time after that stimulus strength was delivered. In the second study, the ULV
RAP
curve was shifted dramatically to the right, the average ULV
50 RAP
being greater than the average DF
90
. Furthermore, 92% of the ULV
RAP
VF inductions occurred between 10 ms before and 50 ms after the peak of the T wave, suggesting that scanning of the entire T wave may not be necessary.

Conclusions
With a single rapidly paced ULV sequence with limited T-wave scanning, it may be possible to estimate highly effective defibrillation doses with few VF episodes and high-voltage stimuli.
Determinants and Mechanisms of Flecainide-Induced Promotion of Ventricular Tachycardia in Anesthetized Dogs
Authors: Ranger Suzanne , Nattel Stanley
Published: June 2012

Background
Class IC antiarrhythmic agents such as flecainide are known to have potentially significant ventricular proarrhythmic actions, but the underlying mechanisms are incompletely understood. While some studies have reported proarrhythmia in both healthy dogs and dogs that previously have had a myocardial infarction (MI), there are no published, controlled studies comparing proarrhythmia in healthy dogs vs in dogs with MI. In addition, the concentration dependence of proarrhythmia is unknown and the electrophysiological changes associated with proarrhythmia are not well established.

Methods
We administered successive loading and maintenance infusions of flecainide until ventricular tachyarrhythmia or death occurred in 13 healthy dogs and 19 dogs with 72-hour-old MIs (MI dogs). Ventricular proarrhythmia, defined as reproducible ventricular tachycardia absent under control conditions and occurring in the presence of flecainide, was observed in 4 of 13 healthy dogs (31%) and 15 of 19 MI dogs (79%,
P
=.02), and drug-induced spontaneous ventricular tachycardia occurred in 8 of 19 MI dogs but in no healthy dogs (
P
=.007). Activation data at the time of proarrhythmia were available for 11 MI dogs and provided evidence for reentry in 9, with a complete epicardial reentry circuit identified in 4 dogs and a partial circuit in 5. While flecainide slowed ventricular conduction in both the longitudinal and transverse directions, there were no significant differences between overall drug-induced conduction changes in MI dogs compared with healthy dogs. However, in 7 MI dogs for whom activation data were available during ventricular pacing at concentrations comparable to those causing proarrhythmia, flecainide induced a new arc of block in 6 of 7, whereas an arc of block was never observed in the absence of proarrhythmia. Conduction block was induced transverse to fiber orientation in a rate-dependent fashion and was caused by a regionally-specific effect of the drug. No differences were noted between refractory periods proximal and distal to the site of block.

Conclusions
Prior MI strongly predisposes dogs to flecainide proarrhythmia, which occurs in the majority of such dogs in a concentration-related way. In most cases, activation data suggest that anisotropic reentry around a localized arc of rate-dependent transverse conduction block underlies proarrhythmia. These results provide insights into the conditions and mechanisms underlying the ability of flecainide to promote the occurrence of ventricular tachycardia.
Intracoronary Radiation Before Stent Implantation Inhibits Neointima Formation in Stented Porcine Coronary Arteries
Authors: Waksman Ron , Robinson Keith A. , Crocker Ian R. , Gravanis Michael B. , Palmer Spencer J. , Wang Chris , Cipolla Gustavo D. , King Spencer B.
Published: June 2012

Background
Stent implantation has been shown to reduce restenosis by establishing a larger lumen but not by reducing neointima formation. We have previously shown that ionizing radiation reduced neointima formation after balloon injury in a swine model of restenosis. The purpose of this study was to determine whether endovascular irradiation of the coronary artery before stent implantation would affect neointima formation.

Methods and Results
Nine normolipemic pigs underwent coronary angiography, and segments of the left anterior descending and left circumflex arteries were chosen as targets for stenting. A high-activity
192
Ir source was used to deliver 14 Gy by random assignment to one of the vessels. After this, 3.5-mm tantalum stents were implanted in both arteries. Three additional pigs were treated with a
90
Sr/Y source (a pure β-emitter) delivering 14 Gy to five segments of coronary vessels that were stented immediately after irradiation. Stent-to-artery ratio was similar in the radiated and the control arteries. Animals received aspirin 325 mg daily and were killed at 28 days. The intimal area was significantly reduced in the irradiated stented arteries compared with control arteries treated with stent only (1.98 mm
2
with
192
Ir and 2.53 mm
2
with
90
Sr/Y versus 3.82 mm
2
in the control stented arteries,
P
<.005).

Conclusions
Endovascular radiation before coronary stenting reduces neointima formation and may further reduce the restenosis rate after stent implantation.
Insulin, Intact and Split Proinsulin, and Coronary Artery Disease in Young Men
Authors: Båvenholm Peter , Proudler Anthony , Tornvall Per , Godsland Ian , Landou Christian , de Faire Ulf , Hamsten Anders
Published: June 2012

Background
Glucose intolerance and hyperinsulinemia are common disturbances in nondiabetic men with premature coronary artery disease (CAD). To investigate the relation between insulin-like molecules and severity of coronary atherosclerosis, 62 consecutive nondiabetic men presenting with a first myocardial infarction before the age of 45 were studied along with 41 healthy, age-matched, male, population-based control subjects.

Methods and Results
Specific two-site immunoradiometric assays were used to distinguish intact proinsulin, (des 31,32)proinsulin, and “true” insulin in fasting plasma and during an oral glucose tolerance test (OGTT). Global coronary atherosclerosis and number and severity of distinct stenoses were determined in the patients in 15 proximal coronary arterial segments by use of separate semiquantitative classification systems. The patients had a two- to threefold increase in insulin and insulin propeptide concentrations in the fasting state as well as during the OGTT. Severity of coronary atherosclerosis correlated significantly (
P
<.05 to
P
<.01) with basal proinsulin (
r
=.40) and the proinsulin area under the curve (AUC) (
r
=.34), basal insulin (
r
=.31), basal C peptide (
r
=.30), and the glucose AUC (
r
=.30). In multiple stepwise regression analysis including insulin-like molecules, major plasma lipoproteins, and lipoprotein subfractions, basal proinsulin (increase in
R
2
=.09) and dense LDL triglycerides (increase in
R
2
=.10) predicted 19% of the variation of the global coronary atherosclerosis score after adjustment for age, body mass index, fasting insulin concentration, and VLDL triglycerides.

Conclusions
This study shows that young, nondiabetic, male survivors of myocardial infarction are truly hyperinsulinemic during an OGTT and suggests a close association between proinsulin and coronary atherosclerosis.
Alterations in Ultrasonic Backscatter During Exercise-Induced Myocardial Ischemia in Humans
Authors: Vitale Dino F. , Bonow Robert O. , Gerundo Giusto , Pelaggi Nicola , Lauria Gianfranco , Leosco Dario , Coltorti Fernando , Bordini Carlo , Rengo Carlo , Rengo Franco
Published: June 2012

Background
Experimentally induced myocardial ischemia in animals causes tissue modifications that alter characteristics of the ultrasonic beam backscattered from the myocardial muscle. Alterations of backscatter parameters have been evidenced in human subjects with acute or remote myocardial infarction and during ischemia induced by angioplasty balloon occlusion or pharmacological stimuli. The effects of transient effort ischemia in humans have not been reported. The purpose of this study is to assess ultrasonic backscatter parameter changes induced by transient effort myocardial ischemia in human subjects.

Methods and Results
Nineteen patients with single left anterior descending coronary stenosis and 15 healthy subjects underwent ultrasonic backscatter analysis (parasternal long-axis view) at rest, immediately after a supine stress test, and 30 minutes later. Two windows were selected in each ultrasonic study: one encompassing the septum; the other, the posterior wall. Integrated backscatter was computed throughout the cardiac cycle, yielding a power curve relative to the midmyocardial region of the myocardial wall (excluding pericardial and endocardial borders). Five parameters were computed from the backscatter power curve: the maximum−minimum difference, amplitude and phase of the first harmonic Fourier fitting, phase-weighted amplitude, and time-averaged integrated backscatter difference from rest (an index of overall myocardial reflectivity). This protocol allowed comparison of the backscatter data from a region at risk of ischemia (the septum) with that from a region normally perfused (posterior wall) and a comparison with the same regions of the control group during the three ultrasonic studies. All backscatter indexes in the septum were altered significantly by exercise compared with rest values, whereas no changes were found in the normally perfused posterior wall or in the septum of the control group. All modified parameters returned to baseline values at the time of the recovery study.

Conclusions
These data indicate that transient, exercise-induced ischemia is associated with reduction of the cardiac cycle–dependent variation of the integrated backscatter power curve, a temporal shift in the nadir of the power curve with respect to the R wave (phase increase), and a small but detectable increase of myocardial reflectivity. These changes may be detected noninvasively in humans with ultrasonic backscatter analysis.
Coronary α
1
-Constrictor Tone During Renovascular Hypertension
Authors: Gwirtz Patricia A.
Published: June 2012

Background
A coronary α
1
-adrenergic constrictor tone exists under conditions associated with increased sympathetic stimulation but not during resting conditions in the normal heart. During renovascular hypertension, elevated circulating angiotensin II may enhance sympathetic stimulation of the heart, even at rest. This study tested the hypothesis that an α
1
-adrenergic constrictor tone imposes limitations on coronary blood flow in resting dogs after development of renovascular hypertension, exacerbates coronary α-constrictor tone during exercise, and increases coronary vascular adrenergic responsiveness.

Methods and Results
Left circumflex blood flow velocity (CFV), aortic pressure (AoP), and heart rate (HR) were examined in five quietly resting dogs during control conditions and after selective α
1
-adrenergic blockade using an intracoronary injection of 0.5 mg prazosin. In the normotensive state, AoP was 87±7 mm Hg (mean±SD), HR was 105±25 beats per minute, and CFV was 28±6 cm/s. These parameters were not affected by α
1
-adrenergic blockade. During submaximal exercise, removal of an α
1
-adrenergic constrictor resulted in a 14±4% increase in CFV (
P
<.05). Two weeks after development of renovascular hypertension induced by stenosis of the left renal artery, mean AoP was 114±7 mm Hg (
P
<.05 versus normotensive state), HR was 111±28 beats per minute, and CFV was 21±8 cm/s. In contrast to the normotensive state, α
1
-adrenergic blockade caused a 28±6% increase in CFV at rest (
P
<.05) and a 27±13% increase in CFV during exercise in the hypertensive state (
P
<.05 versus exercise before blockade and versus normotensive state). This resting coronary constrictor tone was associated with enhanced vasoconstrictor responsiveness to norepinephrine and phenylephrine.

Conclusions
It appears that renovascular hypertension results in a significant coronary α
1
-adrenergic constrictor tone in the resting dog and an enhanced constrictor tone during exercise.
The Proarrhythmic Potential of Implantable Cardioverter-Defibrillators
Authors: Pinski Sergio L. , Fahy Gerard J.
Published: June 2012

Abstract
The implantable cardioverter-defibrillator (ICD) is remarkably effective in preventing sudden cardiac death in high-risk patients, but it also has the capacity to provoke or worsen cardiac arrhythmias. Tachyarrhythmias or bradyarrhythmias may result from the delivery of antitachycardia or antibradycardia therapies by tiered-therapy defibrillators. This proarrhythmia, although rarely fatal, increases the morbidity associated with defibrillator therapy. Proarrhythmia is related as much to suboptimal programming as to technical limitations of the device. The proarrhythmic potential of ICD therapy can be minimized by tailoring the “electrical prescription” according to characteristics of the clinical arrhythmia and individual ICD idiosyncrasies.
Early Morning Reduction in Ischemic Threshold in Patients With Unstable Angina and Significant Coronary Disease
Authors: Figueras Jaume , Lidón Rosa Maria
Published: June 2012

Background
The objective of this study was to investigate in patients with unstable angina and significant coronary stenosis (>70%) whether or not the morning peak of myocardial ishemia is associated with a reduction in the ischemic threshold. The morning increased incidence of ischemic episodes in stable angina appears to be attributable to a coincidence of several factors. Patients with unstable angina who remain at bed rest, however, also present a similar morning increased incidence of ischemia, but its mechanisms are not completely understood.

Methods and Results
The ischemic threshold was assessed by atrial pacing at 7 to 8
am
and at 12 to 1
pm
in 46 patients. In the 34 with a positive pacing response (ST segment shift >1.0 mm), ischemic threshold was lower at 7 to 8
am
than at 12 to 1
pm
(131±16 versus 139±15 beats per minute,
P
<.001), whereas in the remaining 12 patients, the pacing response was negative. Moreover, 4 patients presented ST segment elevation during pacing in the morning but only 1 at noon and at a higher threshold. Baseline heart rate and diastolic blood pressure were higher at noon than in the morning (81±16 versus 76±13 beats per minute,
P
<.01, and 87±11 versus 82±10 mm Hg,
P
<.05).

Conclusions
The morning lowering of ischemic threshold in the absence of increases in baseline blood pressure or heart rate suggests that a reduced coronary vasodilator capacity or an increased coronary tone may favor the increased incidence of ischemic events during this interval.
Photodynamic Therapy Inhibits Experimental Allograft Rejection
Authors: LaMuraglia Glenn M. , Adili Farzin , Schmitz-Rixen Thomas , Michaud Norman A. , Flotte Thomas J.
Published: June 2012

Background
Biological vascular allografts have proved unsatisfactory because of thrombosis, occlusion, and aneurysmal degeneration during chronic rejection. Photodynamic therapy (PDT), a technique that leads to the production of cytotoxic free radicals, was investigated as a novel method to prepare arterial allografts.

Methods and Results
Shortly after impregnation with the photosensitizer drug chloroaluminum sulfonated phthalocyanine, infrarenal aortas of ACI rats were PDT-treated and orthotopically grafted in Lewis rats (PDT). The transplanted grafts were sequentially analyzed at 2, 4, and 8 weeks by morphometry, immunohistochemistry, and scanning electron microscopy. Of 25 untreated allografts, 4 (16%) developed aneurysms compared with 0 of 33 in PDT or untreated isografts (ISO,
P
<.001). PDT treatment of allografts significantly inhibited intimal hyperplasia (
P
<.001) and resulted in intimal areas comparable to those in ISO. However, medial thickness in both control allografts and PDT grafts was markedly decreased compared with ISO. External graft diameters of control allografts at 8 weeks were significantly enlarged (
P
<.02) compared with PDT or ISO. At all time points, T lymphocytes were found in a substantially larger number in untreated control grafts than in PDT or ISO. Scanning electron microscopy at 4 weeks confirmed complete repopulation with endothelial cells in PDT, which was not seen in the control allografts.

Conclusions
Our findings suggest that local PDT treatment of arterial allografts inhibits inflammatory infiltration, aneurysmal dilatation, and development of intimal hyperplasia and may be used to develop vascular bioprostheses for use in humans.
Serum Cardiac Troponin T and Creatine Kinase–MB Elevations in Murine Autoimmune Myocarditis
Authors: Bachmaier Kurt , Mair Johannes , Offner Felix , Pummerer Christian , Neu Nikolaus
Published: June 2012

Background
We used a murine model of autoimmune myocarditis to investigate systematically whether serum markers of myocardial cell injury, that is, cardiac troponin T (TnT) and the MB isoenzyme of creatine kinase (CK-MB) are useful for the diagnosis of inflammatory heart disease.

Methods and Results
Fifty-two A.SW mice were immunized with cardiac myosin to induce myocarditis. The disease was evident on day 12 after the initial immunization in 14 of 22 immunized mice, on day 16 in 7 of 10 mice, on day 19 in 6 of 10 mice, and on day 23 in 5 of 10. The severity of myocarditis increased between days 12 and 16 and remained constant thereafter. TnT was elevated in a considerable number of mice with myocarditis, resulting in a diagnostic sensitivity (number of marker elevations per number of mice with myocarditis) of 0.43 on day 12, 0.71 on day 16, and 0.50 on day 19. CK-MB elevations were not seen on day 12 but resulted in a diagnostic sensitivity of 0.71 on day 16 and of 0.33 on day 19. No elevations of CK-MB or TnT were observed on day 23. All elevations were specific for the disease, as none of the mice lacking myocarditis showed increased markers.

Conclusions
In murine autoimmune myocarditis, TnT is a more sensitive marker for the disease than CK-MB. Elevations clearly indicate myocarditis, but negative test results do not exclude the presence of the disease. These data suggest that the determination of CK-MB and, in particular, of TnT, can be useful for the diagnostic evaluation of patients with suspected myocarditis.
Paracrine Coronary Endothelial Control of Left Ventricular Function in Humans
Authors: Paulus Walter J. , Vantrimpont Pascal J. , Shah Ajay M.
Published: June 2012

Background
Similar to endothelial modulation of vascular tone, myocardial contraction may be modulated by cardioactive agents released from the coronary endothelium. To investigate such modulation in humans, we performed invasive assessment of left ventricular (LV) function before, during, and after bicoronary infusion of substance P, which releases nitric oxide from the endothelium.

Methods and Results
Eight healthy subjects were investigated during diagnostic coronary angiography and eight transplant recipients during annual catheterization. Tip-micromanometer LV pressure was recorded before, during, and after bicoronary (n=16) and right atrial (n=14) infusion of substance P (20 pmol/min). LV angiograms (n=11) were obtained before and at the end of the substance P infusion. At the end of the intracoronary substance P infusion, we observed (1) a fall in LV peak systolic pressure from 147±16 to 139±15 mm Hg (
P
<.01) in healthy subjects and from 147±25 to 141±22 mm Hg (
P
<.05) in transplant recipients; (2) a downward and rightward shift of the average LV end-systolic pressure-volume point consistent with depressed systolic performance; and (3) a rise in LV end-diastolic volume at comparable end-diastolic pressure, consistent with increased end-diastolic distensibility. Five minutes after the substance P infusion, LV peak systolic pressure was higher than at baseline in healthy subjects (154±18 mm Hg;
P
<.05). Right atrial infusion of substance P did not reproduce these changes.

Conclusions
Bicoronary infusion of substance P modulates LV function in humans, probably through paracrine myocardial action of cardioactive agents released from the coronary endothelium.
Noninvasive Measurement of Tissue Magnesium and Correlation With Cardiac Levels
Authors: Haigney Mark C.P. , Silver Burton , Tanglao Emmanuel , Silverman Howard S. , Hill J. Donald , Shapiro Edward , Gerstenblith Gary , Schulman Steven P.
Published: June 2012

Background
Intracellular magnesium ([Mg]
i
) plays an important role in the regulation of myocardial metabolism, contractility, and the maintenance of transsarcolemmal and intracellular ionic gradients. An understanding of the role of magnesium in the clinical setting, however, is hampered by the lack of an assay of intracellular tissue magnesium levels.

Methods and Results
We used energy-dispersive x-ray analysis to measure [Mg]
i
in sublingual epithelial cells and to correlate the level with those in atrial biopsy specimens from the same patients during cardiopulmonary bypass. Levels were also measured in acute myocardial infarction (AMI) patients before and after intravenous magnesium sulfate administration and compared with those from intensive care unit (ICU) patients and healthy individuals. A strong correlation between sublingual epithelial cell (mean, 32.1±0.3 mEq/L) and atrial tissue (mean, 32.1±0.3 mEq/L) [Mg]
i
was present in 18 cardiac surgery patients (
r
=.68,
P
<.002). Epithelial and atrial [Mg]
i
levels were lower than in healthy individuals (33.7±0.5 mEq/L,
P
<.01) studied at that time and correlated poorly with serum magnesium. Mean [Mg]
i
in 22 AMI patients was 30.7±0.4 mEq/L, which was significantly lower than in 21 ICU patients and 15 healthy individuals (35.0±0.5 mEq/L and 34.5±0.7 mEq/L, respectively,
P
<.001). Intravenous magnesium sulfate was administered to most of the AMI patients (mean dose, 36±6 mmol). [Mg]
i
rose significantly in the AMI patients over the first 24 hours, and the magnitude of the increase was greater in those who received higher doses of intravenous magnesium sulfate.

Conclusions
Sublingual epithelial cell [Mg]
i
correlates well with atrial [Mg]
i
but not with serum magnesium. [Mg]
i
levels are low in patients undergoing cardiac surgery and those with AMI. Intravenous magnesium sulfate corrects low [Mg]
i
levels in AMI patients. Energy-dispersive x-ray analysis determination of sublingual cell [Mg]
i
may expedite the investigation of the role of magnesium deficiency in heart disease.
Abnormal Forearm Vascular Responses During Dynamic Leg Exercise in Patients With Vasovagal Syncope
Authors: Thomson Helen L. , Lele Suhas S. , Atherton John J. , Wright Karen N. , Stafford Wayne , Frenneaux Michael P.
Published: June 2012

Background
We have reported previously that in some patients with normal hearts who present with exercise syncope, abnormal forearm vasodilation is seen during leg exercise and tilt table tests are positive. This suggests that exercise syncope may be a variant of vasovagal syncope. In this study we tested the hypothesis that there is loss of the normal forearm vasoconstrictor response during dynamic leg exercise in an unselected population of patients with classic vasovagal syncope.

Methods and Results
We evaluated forearm vascular responses during maximal semierect cycle exercise in 28 consecutive patients with vasovagal syncope and compared them with 30 age-matched control subjects. We also evaluated blood pressure responses during erect treadmill exercise (Bruce protocol). While forearm vascular resistance at rest was similar in the patients with vasovagal syncope and the control group, forearm vascular resistance was markedly lower in the patients than in control subjects at peak exercise (85±54 versus 149±94 units,
P
=.002). Forearm vascular resistance fell by 3±48% during exercise in patients versus an increase of 135±103% in control subjects (
P
<.0001). Systolic blood pressure during erect exercise was lower in patients versus control subjects (155±32 versus 188±17 mm Hg,
P
<.0001). Six of the vasovagal patients complained of exercise syncope or presyncope on specific inquiry, and 4 of these 6 exhibited exercise hypotension during erect treadmill exercise testing.

Conclusions
Patients with vasovagal syncope exhibit a failure of the normal vasoconstrictor response in the forearm during dynamic leg exercise. Exercise syncope and presyncope are not uncommon in unselected patients with classic vasovagal syncope, as is exercise hypotension.
Neutrophil Sequestration and Pulmonary Dysfunction in a Canine Model of Open Heart Surgery With Cardiopulmonary Bypass
Authors: Dreyer William J. , Michael Lloyd H. , Millman Ellen E. , Berens Kurt L. , Geske Robert S.
Published: June 2012

Background
Previous studies documented an inflammatory reaction to cardiopulmonary bypass with neutrophil (PMN) sequestration in the lungs, contributing to microvascular injury and postoperative pulmonary dysfunction. This study explored the hypothesis that the β
2
integrin CD18, a leukocyte adhesion molecule, mediates this response.

Methods and Results
Fifteen adult, mixed-breed dogs underwent 90 minutes of cardiopulmonary bypass with 3 hours of subsequent recovery. Seven additional dogs were treated before cardiopulmonary bypass with a 1-mg/kg IV bolus of R15.7 IgG, a monoclonal antibody to CD18. Both groups were compared with 5 sham bypass control dogs. Bypassed dogs demonstrated an increased number of PMNs sequestered in the lungs 3 hours after bypass compared with sham bypass control dogs (1466±75 versus 516±43 PMN/mm
2
alveolar surface area, mean±SEM,
P
<.001). Also, when PMNs from bypass dogs were compared with those from sham dogs, they produced more H
2
O
2
(305±45 versus 144±48 amol H
2
O
2
per phagocyte per 20 minutes,
P
<.05). Bypass dogs had significantly decreased arterial oxygenation 3 hours after the procedure compared with shams (457±20 versus 246±49 mm Hg,
P
<.05), and they had a significantly increased lung wet-to-dry weight ratio (5.38±0.14 versus 4.54±0.15,
P
=.003), demonstrating a significant increase in lung water. R15.7 markedly attenuated pulmonary PMN accumulation in bypass dogs (412±73 PMN/mm
2
,
P
<.001) and significantly inhibited PMN production of H
2
O
2
(146±18 amol H
2
O
2
per phagocyte per 20 minutes,
P
<.05) Bypass dogs pretreated with R15.7 also had improved oxygenation (445±28 mm Hg,
P
<.05) and tended to have less lung water accumulation after bypass (4.99±0.20).

Conclusions
Pulmonary dysfunction after cardiopulmonary bypass is caused, at least in part, by a neutrophil-mediated, CD18-dependent mechanism.
The Cellular Basis of Pacing-Induced Dilated Cardiomyopathy
Authors: Kajstura Jan , Zhang Xun , Liu Yu , Szoke Ervin , Cheng Wei , Olivetti Giorgio , Hintze Thomas H. , Anversa Piero
Published: June 2012

Background
Rapid ventricular pacing leads to a cardiac myopathy consisting of an increase in chamber dimension, mural thinning, elevation in ventricular wall stress, and congestive heart failure, mimicking dilated cardiomyopathy in humans. However, contrasting results have been obtained concerning the mechanisms of ventricular dilation and the existence of myocardial hypertrophy. Moreover, questions have been raised regarding the occurrence of myocardial damage and cell loss in the development of the experimental myopathy.

Methods and Results
The functional and structural characteristics of the heart were studied in conscious dogs subjected to left ventricular pacing at 210 beats per minute for 3 weeks and 240 beats per minute for an additional week. At the time the animals were killed, measurements of myocardial structural integrity and myocyte shape, size, and number were determined by morphometric analysis of the myocardium in situ and enzymatically dissociated cells. The experimental protocol used was associated with overt cardiac failure documented by an increase in left ventricular end-diastolic pressure and a decrease in left ventricular systolic pressure and +dP/dt in combination with tachycardia, ascites, and pulmonary congestion. Although cardiac weights were not altered, cavitary diameter was increased and wall thickness was decreased from the base to the apex of the heart. Multiple foci of replacement fibrosis, comprising 6% of the myocardium, were detected across the left ventricular wall. Measurements of myocyte size and number documented a 39% loss of cells in the entire ventricle and a 61% increase in volume of the remaining viable myocytes. Myocyte hypertrophy was characterized by a 33% increase in cell length and a 23% increase in transverse area, resulting in a 23% increase in the cell length–to–cell diameter ratio. Pacing did not alter the relative proportion of mononucleated, binucleated, and multinucleated myocytes in the myocardium.

Conclusions
Myocyte cell loss and myocyte reactive hypertrophy are the major components of ventricular remodeling in pacing-induced dilated cardiomyopathy.
Distribution, Morphology, and Neurochemistry of Endocardial and Epicardial Nerve Terminal Arborizations in the Human Heart
Authors: Marron K. , Wharton J. , Sheppard M.N. , Fagan D. , Royston D. , Kuhn D.M. , de Leval M.R. , Whitehead B.F. , Anderson R.H. , Polak J.M.
Published: June 2012

Background
The heart contains a variety of morphologically distinct nerve terminals known to influence cardiac function. Little is known about the distribution, morphology, and neurochemistry of these terminals in the human heart.

Methods and Results
We examined the entire endocardial and epicardial surfaces of infant and adult hearts obtained postmortem and at transplantation using immunohistochemical and histochemical staining of whole-mount preparations in conjunction with confocal and fluorescence microscopy. Terminals arising from nerve fibers (diameter, 6 to 10 μm) immunoreactive for myelin basic protein were identified in the atrial endocardium, epicardium, and coronary sinus, and four types were distinguished by differences in immunostained nerve area (range, 358 to 797 μm
2
) and dispersion (range, 620 to 4684 μm
2
). These terminals displayed immunoreactivity for tyrosine hydroxylase, neuropeptide Y, and the general neural marker protein gene product 9.5. Acetylcholinesterase (AChE) activity was detected in <5% of endocardial terminals and in no epicardial terminals arising from myelinated fibers. The latter were observed in close proximity to mesothelial cells, and nerve fibers supplying these terminals were found to be associated with local ganglia. A distinct population of terminals (mean stained area, 35 μm
2
; 18 to 53 μm
2
, 95% CI; and mean dispersion, 59 μm
2
; 38 to 80 μm
2
, 95% CI) was demonstrated to arise from nonmyelinated fibers (mean diameter, 2.5 μm; 2.2 to 2.8 μm, 95% CI) in the endocardial plexus of the atria and left ventricle and were predominantly AChE-positive.

Conclusions
Specialized nerve terminals are distributed more widely in the human heart than has been described in experimental animals. These terminals express either AChE activity or tyrosine hydroxylase and neuropeptide Y immunoreactivity, suggesting that acetylcholine, catecholamines, and neuropeptide Y may be present in sensory and autonomic nerves in the human heart.
Coarctation of the Aorta
Authors: Backer Carl L. , Paape Kerry , Zales Vincent R. , Weigel Thomas J. , Mavroudis Constantine
Published: June 2012

Background
The first successful surgical repair of coarctation of the aorta (CoAo) was performed in 1944, but during the years that followed a high incidence of recoarctation was seen, ranging from 20% to 86%. In response to that problem, the patch aortoplasty was introduced in 1957; however, true aneurysms were found in the aortic wall opposite the patch after Dacron patch aortoplasty, particularly when the coarctation ridge was excised. The purpose of our review was to evaluate the results of patch aortoplasty for CoAo using a relatively new material, polytetrafluoroethylene (PTFE), and an operative technique that does not involve resection of the coarctation ridge.

Methods and Results
Between 1979 and 1993, 125 infants and children underwent PTFE patch aortoplasty for CoAo; 111 of the procedures were primary repairs, and 14 were reoperations. Diagnoses were isolated CoAo (96 patients), CoAo and ventricular septal defect (15 patients), and CoAo with complex intracardiac anomaly (14 patients). Patient age at the time of repair ranged from 4 days to 17 years (mean age, 5.1±4.5 years). There were no instances of intraoperative mortality or paraplegia. There were 4 deaths from 10 to 40 days postoperatively, all in neonates (mean age, 33 days) who received additional intracardiac procedures for complex associated anomalies. Follow-up has ranged from 6 months to 12.5 years (mean, 4.5±3.2 years). All children had postoperative chest roentgenograms, 80 (66%) patients have had a postoperative echocardiogram and 16 (13%) a cardiac catheterization. One patient had successful repair of a false aneurysm 4 months postoperatively. No patient has developed a late true aneurysm. Of the patients <1 month of age at the time of CoAo repair (12 patients), 6 patients had recurrent CoAo (gradient >20 mm Hg) compared with only 4 recurrences in 97 patients >1 month of age at the time of repair (
P
<.001).

Conclusions
For children >1 year of age, PTFE patch aortoplasty remains our procedure of choice for CoAo repair because of the low mortality rate, low recoarctation rate, and absence of late true aneurysms. We have stopped using this technique for infants <1 month of age because of the high recurrence rate.
Screening Scale Predicts Patients Successfully Receiving Long-term Implantable Left Ventricular Assist Devices
Authors: Oz Mehmet C. , Goldstein Daniel J. , Pepino Paolo , Weinberg Alan D. , Thompson Seth M. , Catanese Katherine A. , Vargo Rita L. , McCarthy Patrick M. , Rose Eric A. , Levin Howard R.
Published: June 2012

Background
Although use of long-term implantable left ventricular assist devices (LVAD) is becoming more popular, further reduction of the mortality rate accompanying device insertion through improved patient selection would make this alternative even more appealing. We sought to develop a scoring system that was based on criteria obtainable at the time of evaluation and predictive of successful early outcome and simple to apply.

Methods and Results
Patients (n=56) undergoing LVAD insertion between 1990 and 1994 were screened for easily obtainable preoperative risk factors. To test the association between survival and each risk factor, a χ
2
analysis was performed, and relative risks were estimated. Oliguria, ventilator dependence, elevated central venous pressure, elevated prothrombin time, and reoperation status had low probability values and high estimated relative risks. On the basis of these relations, a risk factor–selection scale (RFSS) (range, 0 to 10) was developed by computing appropriate weights for each risk factor. The distribution of patients for each scale score reveal that with RFSS ≥5, most device recipients will die (
P
<.001). The average RFSS (±SD) of survivors (n=42) was 2.45±1.73 compared with 5.43±2.85 in nonsurvivors (n=14) (
P
<.0001). Univariate logistical regression was also significant (score statistic, 16.2;
df
=1;
P
=.001).

Conclusions
The RFSS is simple, easy to apply, and statistically valid. Physicians could use the scale as a starting point in discussing the suitability for LVAD implantation in a specific patient and as a basis for comparing patient outcomes.
Influence of Intimal Thickening on Coronary Blood Flow Responses in Orthotopic Heart Transplant Recipients
Authors: Caracciolo Eugene A. , Wolford Thomas L. , Underwood R. Dent , Donohue Thomas J. , Bach Richard G. , Miller Leslie W. , Kern Morton J.
Published: June 2012

Background
Intravascular ultrasound imaging detects epicardial intimal thickening in the majority of heart transplant recipients with angiographically normal epicardial coronary arteries. Although coronary artery vasoreactivity is abnormal after cardiac transplantation, intimal thickening does not appear to affect conduit vessel responses. However, the effect of intimal thickening on both conduit and resistance vessel responses, as measured by changes in volumetric coronary blood flow (CBF), is unknown.

Methods and Results
Epicardial coronary artery conductance and microvascular resistance vessel responses were studied after intracoronary adenosine and nitroglycerin administration in 36 orthotopic heart transplant recipients 1 month to 7 years after transplantation. Sequentially measured coronary flow average peak velocity ([APV, cm/s] 0.018 in Doppler guide wire) and epicardial luminal cross-sectional area ([CSA, mm
2
] 4.3F 30-MHz ultrasound catheter) data were obtained at baseline and during peak hyperemia after administration of 12 to 18 μg IC adenosine and 150 to 200 μg IC nitroglycerin. Volumetric CBF (mL/min) was calculated as CBF=APV (cm/s)×CSA (mm
2
)×60 seconds/1 min×1 cm
2
/100 mm
2
×0.5. Measurements were made from a discrete position in the proximal left anterior descending (LAD) artery (n=22), mid-LAD artery (n=7), proximal circumflex artery (n=6), and proximal right coronary artery (n=1). Intimal thickening was present in 19 of 32 patients (60%). Both adenosine and nitroglycerin increased APV (from 18.9±4.9 to 56.0±11.5 cm/s for adenosine and from 20.2±5.3 to 49.1±11.5 cm/s for nitroglycerin; both
P
<.05). Coronary flow velocity reserve was significantly higher for adenosine compared with nitroglycerin (3.1±0.6 versus 2.5±0.7, respectively;
P
<.001). Epicardial luminal CSA was unchanged during adenosine hyperemia compared with baseline (17.4±3.8 versus 17.3±4.0 mm
2
, respectively;
P
=NS) but was significantly greater during nitroglycerin hyperemia compared with baseline (18.7±3.8 versus 17.3±4.0 mm
2
, 6.2±3.6% change;
P
<.05). Baseline CBF was similar before drug administration. Hyperemic adenosine and nitroglycerin CBF responses (297±99 and 276±87 mL/min, respectively;
P
=NS) and CBF reserve (3.0±0.7 and 2.7±0.7, respectively;
P
=NS) were not significantly different. Importantly, intimal thickening did not diminish resting or hyperemic APV, coronary flow velocity reserve, luminal CSA, CBF, or CBF reserve responses.

Conclusions
In this study of angiographically normal heart transplant recipients, epicardial intimal thickening does not diminish conduit and resistance vessel responses during endothelial-independent vasodilator administration.
Standard Orthotopic Heart Transplantation Versus Total Orthotopic Heart Transplantation
Authors: Derumeaux Geneviève , Habib Gilbert , Schleifer Dominique Mouton , Ambrosi Pierre , Bessou Jean Paul , Metras Dominique , Cribier Alain , Luccioni Roger , Soyer Robert , Letac Brice
Published: June 2012

Background
After standard orthotopic heart transplantation (Sd HT), the enlarged resultant atria may promote atrial thrombosis. The purpose of this study was to compare the incidence of spontaneous echo contrast and left atrial thrombosis after Sd HT and total orthotopic (Tot HT) heart transplantation.

Methods and Results
Transesophageal echocardiography (TEE) was performed in 75 patients with Sd HT and in 20 patients with Tot HT. Despite the use of antiplatelet therapy, an acute arterial embolism occurred in 11 (15%) of the 75 patients with Sd HT but in none of the 20 Tot HT patients. All patients were in sinus rhythm. Left ventricular ejection fraction was similar in Sd HT and Tot HT patients. Left atrial diameter was smaller in Tot HT patients than in Sd HT patients (41±4 versus 58±6 mm,
P
<.001). In Sd HT patients, spontaneous echo contrast was present in 43 patients (57%) and was associated with left atrial thrombus in 20 patients (on the left atrial appendage in 12 patients, on the posterior wall in 6, and on the suture in 2). No thrombus was detected by transthoracic echocardiography; all thrombi were detected by TEE. On the other hand, no left atrial thrombus was observed in Tot HT patients, and only 1 patient had spontaneous echo contrast. Of the 11 Sd HT patients who experienced an arterial embolism, 5 had both spontaneous echo contrast and left atrial thrombus and 5 had only spontaneous echo contrast.

Conclusions
This study demonstrates a high rate of left atrial thrombus after Sd HT and emphasizes the role of TEE in the follow-up of these patients. The therapeutic implications are the need for a preventive anticoagulant therapy in the high-risk population receiving Sd HT diagnosed with TEE and the consideration of Tot HT as a better surgical approach as far as thrombotic complications are concerned.