bluuebunny/crossref_metadata_2025 huggingface dataset:
Heterogeneity of Retrograde Fast-Pathway Conduction Pattern in Patients With Atrioventricular Nodal Reentry Tachycardia
Authors: Anselme Frederic , Hook Bruce , Monahan Kevin , Frederiks Joost , Callans David , Zardini Marco , Epstein Laurence M. , Zebede Joseph , Josephson Mark E.
Published: June 2012

Background
Selective ablation of either the fast or the slow pathway resulting in cure of AV nodal reentry tachycardia (AVNRT) has led to the concept that these pathways are discrete, anatomically defined structures. We hypothesized that if a discrete retrograde fast pathway exists, it should be possible to record a single focus of early atrial activation near the apex of Koch’s triangle, with sequential spread of depolarization to the rest of the atria.

Methods and Results
We evaluated 46 patients (33 women, 13 men; mean age, 45±17 years) undergoing electrophysiology study and catheter ablation for typical AVNRT. Retrograde atrial activation during AVNRT (337±43 ms) and ventricular pacing at a similar cycle length (352±51 ms) was recorded in the region of Koch’s triangle with a decapolar catheter in the His bundle position, a multipolar catheter in the coronary sinus, and a deflectable quadripolar catheter along the tricuspid annulus anterior to the coronary sinus ostium. Earliest atrial activation was recorded at the apex of the triangle of Koch in 38 patients during ventricular pacing and in 43 patients during AVNRT. A broad wave front of atrial activation was recorded in 17 patients during ventricular pacing and in 26 patients during AVNRT. During AVNRT, only 2 patients had a single early site with focal and sequential activation along the tendon of Todaro. There was concordance in the pattern of atrial activation between ventricular pacing and AVNRT in only 21 of 46 patients.

Conclusions
Retrograde atrial activation over the fast pathway is heterogeneous within Koch’s triangle and the coronary sinus, both for the entire population and for individual patients during different modes of activation. These data do not support the concept of an anatomically discrete retrograde fast pathway.
Angiotensin-Converting Enzyme Inhibition Suppresses Plasminogen Activator Inhibitor-1 Expression in the Neointima of Balloon-Injured Rat Aorta
Authors: Hamdan Allen D. , Quist William C. , Gagne Jennifer B. , Feener Edward P.
Published: June 2012

Background
Plasminogen activator inhibitor-1 (PAI-1), an important regulator of fibrinolysis and extracellular matrix turnover, has been implicated in a number of vascular diseases. Studies demonstrating angiotensin II (Ang II) to be a potent stimulator of PAI-1 expression in cultured vascular cells suggests that the renin-angiotensin system may modulate vascular PAI-1 expression.

Methods and Results
We examined the effects of the ACE inhibitor captopril on PAI-1 expression in control and balloon-injured rat aorta. Northern blot analysis demonstrated that aortic PAI-1 mRNA expression was 7.6-fold elevated 3 hours (
P
<.05) after balloon injury, back to baseline at 2 days, increased again at 4 days, and by 7 days after balloon injury was 3.2-fold elevated (
P
<.05) when compared with control. In captopril-treated rats, the induction of PAI-1 expression by balloon injury was significantly suppressed by 44% (
P
<.05) in the 7-day group but was not altered in the 3-hour group. Captopril also reduced baseline aortic PAI-1 mRNA. In situ hybridization and immunohistochemistry revealed dense PAI-1 staining of 7-day neointima in untreated rats and a dramatic decrease in PAI-1 in neointima of captopril-treated rats.

Conclusions
This report demonstrates that balloon injury results in both a rapid ACE inhibitor–independent induction of aortic PAI-1 expression and a later increase in PAI-1 in the neointima that is significantly suppressed by captopril. This provides the first evidence that the renin-angiotensin system regulates neointimal PAI-1 expression and that ACE inhibitors can reduce PAI-1 in the vessel wall in vivo.
Distribution of Hyaluronan During Extracellular Matrix Remodeling in Human Restenotic Arteries and Balloon-Injured Rat Carotid Arteries
Authors: Riessen Reimer , Wight Thomas N. , Pastore Christopher , Henley Courtney , Isner Jeffrey M.
Published: June 2012

Background
The glycosaminoglycan hyaluronan (HA) is present in developing tissues and healing wounds and forms a loose, hydrated extracellular matrix (ECM) that promotes processes such as cell migration. To investigate the potential contribution of HA to the pathogenesis of restenosis, we studied (1) human lesions obtained by directional atherectomy and (2) experimentally induced neointima formation in balloon-injured rat carotid arteries.

Methods and Results
A biotinylated proteoglycan fragment that binds specifically to HA was used to stain atherectomy specimens from 29 human restenotic lesions (mean restenosis interval, 6.0±4.4 months) and 8 human primary lesions. The loose myxoid ECM typical of human restenotic arteries demonstrated intense, diffuse staining for HA. The intensity was inversely related to the density of immunostaining for collagen types I and III and was lowest in hypocellular primary atherosclerotic plaque. Among 24 rat carotid arteries retrieved 3, 7, 14, 28, 42, or 56 days after balloon injury and immunostained as well for proliferating cell nuclear antigen, staining for HA in the neointima reached a maximum 7 days after balloon injury and was associated with the presence of proliferating, PCNA-positive smooth muscle cells.

Conclusions
Hyaluronan is a characteristic constituent of the loose myxoid ECM in human restenotic arteries and of the neointima in experimentally injured arteries. The presence of hyaluronan may be a marker for an initial phase of the extracellular matrix remodeling that occurs during the development of a fibroproliferative lesion and could facilitate biological processes such as cell migration.
Myocardial Contractile Response to Nitric Oxide and cGMP
Authors: Mohan Puneet , Brutsaert Dirk L. , Paulus Walter J. , Sys Stanislas U.
Published: June 2012

Background
Cardiac endothelium releases a number of factors that may modulate performance of underlying cardiac muscle. Nitric oxide (NO), which accounts for the biological activity of the vascular endothelium-derived relaxing factor and relaxes vascular smooth muscle by elevating intracellular cGMP, may be involved in this cardiac modulation.

Methods and Results
We examined the myocardial contractile effects of the NO-releasing nitrovasodilators sodium nitroprusside (SNP), 3-morpholino-sydnonimine (SIN-1), and
S
-nitroso-
N
-acetyl-penicillamine (SNAP); of a cGMP analogue, 8-bromo-cGMP; and of the cGMP-phosphodiesterase inhibitor zaprinast in isolated cat papillary muscle. Modulation of these effects by endocardial endothelium (EE) and by cholinergic and adrenergic stimulation was also investigated. Concentration-response curves with addition of NO-releasing nitrovasodilators (SNP, SIN-1, SNAP) and 8-bromo-cGMP resulted in a biphasic inotropic response. Although administration of low concentrations induced a positive inotropic effect, higher concentrations induced a negative inotropic effect. Both NO-induced positive and negative inotropic effects were attenuated by methylene blue, suggesting a role for cGMP. The response to high concentrations of 8-bromo-cGMP was shifted to the right in muscles with damaged EE, whereas cholinergic stimulation shifted the curve leftward. Zaprinast caused a monophasic concentration-dependent positive inotropic effect; damaging the EE shifted the terminal portion of the curve upward. Concomitant cholinergic or adrenergic stimulation modified the response to zaprinast into a negative inotropic response.

Conclusions
NO and cGMP induced a concentration-dependent biphasic contractile response. The myocardial contractile effects of NO and cGMP were modulated by the status of EE and by concomitant cholinergic or adrenergic stimulation.
Endothelial Nitric Oxide Production and Insulin Sensitivity
Authors: Petrie John R. , Ueda Shinichiro , Webb David J. , Elliott Henry L. , Connell John M.C.
Published: June 2012

Background
Insulin sensitivity varies up to threefold in apparently healthy individuals, but the mechanism for this is unknown. We have examined the hypothesis that vascular endothelial nitric oxide production and insulin sensitivity are directly related in humans.

Methods and Results
Nineteen healthy male subjects were studied on 3 separate days 1 week apart during which time they underwent measurement of insulin sensitivity by the euglycemic hyperinsulinemic clamp technique (soluble insulin 1.5 mU·kg
−1
·min
−1
) and measurement of in vivo basal and stimulated endothelial nitric oxide production by forearm venous occlusion plethysmography. There was a correlation between insulin sensitivity and forearm vasoconstrictor responses to
N
G
-monomethyl-
l
-arginine, the substrate inhibitor of nitric oxide synthase (
r
=.52,
P
<.05). No correlations were observed between insulin sensitivity and noradrenaline, acetylcholine, or sodium nitroprusside responses.

Conclusions
Endothelial nitric oxide synthesis and insulin sensitivity are positively related in healthy humans, which suggests a direct physiological link.
Cigarette Smoking Potentiates Endothelial Dysfunction of Forearm Resistance Vessels in Patients With Hypercholesterolemia
Authors: Heitzer Thomas , Ylä-Herttuala Seppo , Luoma Jukka , Kurz Sabine , Münzel Thomas , Just Hanjörg , Olschewski Manfred , Drexler Helmut
Published: June 2012

Background
Risk factors for atherosclerosis such as hypercholesterolemia and hypertension are associated with endothelial dysfunction of conduit and resistance vessels; however, the interaction of these risk factors and underlying mechanisms affecting endothelial function remain to be determined. The present study investigated the role of long-term smoking and hypercholesterolemia and their impact on endothelial function of peripheral resistance vessels in relation to plasma levels of autoantibodies against oxidized LDL, which has been implicated in the development of endothelial dysfunction and atherosclerosis.

Methods and Results
The vascular responses to the endothelium-dependent agent acetylcholine (7.5, 15, 30, and 60 μg/min) and the endothelium-independent agent sodium nitroprusside (1, 3, and 10 μg/min) were studied in normal control subjects (n=10), patients with hypercholesterolemia (n=15), long-term smokers (n=15), and hypercholesterolemic patients who smoked (n=15). Drugs were infused into the brachial artery, and forearm blood flow (FBF) was measured by venous occlusion plethysmography. The FBF responses to acetylcholine were significantly blunted in all three patient groups compared with normal control subjects (
P
<.05). The acetylcholine-induced increase in FBF was significantly attenuated in patients with hypercholesterolemia who smoked compared with hypercholesterolemic nonsmokers and normocholesterolemic smokers (
P
<.05 for both). The response to sodium nitroprusside was not statistically different in all four groups. Plasma levels of autoantibody titer against oxidized LDL were inversely related to acetylcholine-induced changes in FBF (
r
=−.53,
P
<.002) and were substantially increased in the group with both risk factors.

Conclusions
These results demonstrate that cigarette smoking and hypercholesterolemia synergistically impair endothelial function and that their combined presence is associated with increased plasma levels of autoantibodies against oxidized LDL. These observations raise the possibility that long-term smoking potentiates endothelial dysfunction in hypercholesterolemic patients by enhancing the oxidation of LDL.
Coronary Plaque Erosion Without Rupture Into a Lipid Core
Authors: Farb Andrew , Burke Allen P. , Tang Anita L. , Liang Youhui , Mannan Poonam , Smialek John , Virmani Renu
Published: June 2012

Background
Coronary thrombosis has been reported to occur most frequently in lipid-rich plaques with rupture of a thin fibrous cap and contact of the thrombus with a pool of extracellular lipid. However, the frequency of coronary artery thrombosis with or without fibrous cap rupture in sudden coronary death is unknown. In this study, we compared the incidence and morphological characteristics of coronary thrombosis associated with plaque rupture versus thrombosis in eroded plaques without rupture.

Methods and Results
Fifty consecutive cases of sudden death due to coronary artery thrombosis were studied by histology and immunohistochemistry. Plaque rupture of a fibrous cap with communication of the thrombus with a lipid pool was identified in 28 cases. Thrombi without rupture were present in 22 cases, all of which had superficial erosion of a proteoglycan-rich plaque. The mean age at death was 53±10 years in plaque rupture cases versus 44±7 years in eroded plaques without rupture (
P
<.02). In the plaque-rupture group, 5 of 28 (18%) were women versus 11 of 22 (50%) with eroded plaques (
P
=.03). The mean percent luminal area stenosis was 78±12% in plaque rupture and 70±11% in superficial erosion (
P
<.03). Plaque calcification was present in 69% of ruptures versus 23% of erosions (
P
<.002). In plaque ruptures, the fibrous cap was infiltrated by macrophages in 100% and T cells in 75% of cases compared with 50% (
P
<.0001) and 32% (
P
<.004), respectively, in superficial erosions. Clusters of smooth muscle cells adjacent to the thrombi were present in 95% of erosions versus 33% of ruptures (
P
<.0001). HLA-DR expression was more often seen in macrophages and T cells in ruptures (25 of 28 cases) compared with expression in macrophages in superficial erosion arteries (8 of 22 cases,
P
=.0002).

Conclusions
Erosion of proteoglycan-rich and smooth muscle cell–rich plaques lacking a superficial lipid core or plaque rupture is a frequent finding in sudden death due to coronary thrombosis, comprising 44% of cases in the present study. These lesions are more often seen in younger individuals and women, have less luminal narrowing and less calcification, and less often have foci of macrophages and T cells compared with plaque ruptures.
Body Weight, Cardiovascular Risk Factors, and Coronary Mortality
Authors: Jousilahti Pekka , Tuomilehto Jaakko , Vartiainen Erkki , Pekkanen Juha , Puska Pekka
Published: June 2012

Background
Body weight is closely related to several known cardiovascular risk factors, but it may also have an independent effect on the risk of coronary heart disease (CHD). In this study, we analyzed the association between body mass index (BMI) and smoking, serum cholesterol, and blood pressure at baseline, as well as how BMI and the other risk factors are related to CHD mortality.

Methods and Results
A total of 16 113 men and women aged 30 to 59 years were examined in eastern Finland in either 1972 or 1977. Serum cholesterol and blood pressure had a positive association and smoking had a negative association with BMI. During the 15-year prospective follow-up, mortality from CHD was positively associated with BMI. The BMI-associated risk ratio of CHD mortality, adjusted for age and study year, estimated from the Cox proportional hazards model was 1.04 (per kg/m
2
) (
P
<.001) among men. Inclusion of smoking in the model increased the risk ratio for BMI, whereas inclusion of serum cholesterol and blood pressure decreased it. In the model that included age, study year, and all three major cardiovascular risk factors, the BMI-associated risk ratio was 1.03 (
P
=.027). Among women, the BMI-associated risk ratio of CHD mortality adjusted for age and study year was 1.05 (
P
=.023) and the multifactorial adjusted risk ratio was 1.03 (
P
=.151).

Conclusions
Obesity is an independent risk factor for CHD mortality among men and also contributes to the risk of CHD among women. Part of the BMI-associated risk of CHD mortality is mediated through other known cardiovascular risk factors. By preventing overweight, a substantial part of CHD mortality may be prevented.
Insulin Modulation of β-Adrenergic Vasodilator Pathway in Human Forearm
Authors: Lembo Giuseppe , Iaccarino Guido , Vecchione Carmine , Rendina Virgilio , Parrella Lucia , Trimarco Bruno
Published: June 2012

Background
Insulin modulates sympathetic vasoconstriction, but the mechanisms underlying this effect are not completely elucidated. We have recently investigated the insulin effect on the α
1
- and α
2
-adrenergic vasoconstriction pathway, where it is still conflicting with the possible insulin influence on the β-adrenergic vasodilator pathway. The aim of the present study was to investigate this issue.

Methods and Results
The study was performed on the forearm of healthy humans, and all test substances were infused into the brachial artery at systemically ineffective rates. In five subjects, we evaluated isoproterenol-induced vasodilation (1, 3, 6, and 9 ng·kg
−1
·min
−1
) both under control conditions and during insulin infusion (0.05 mU·kg
−1
·min
−1
). In another group of five subjects, we tested whether the vasorelaxant effect of sodium nitroprusside (1, 2, 4, and 8 ng·kg
−1
·min
−1
) was modified by insulin. Moreover, to explore whether the interaction between insulin and forearm β-adrenergic pathway participates in insulin modulation of sympathetic-evoked vasoconstriction, we measured in six normal subjects the forearm vascular response to lower-body negative pressure under control conditions and during intrabrachial infusion of insulin alone and in combination with a selective β-adrenergic blocking agent (propranolol 10 μg/100 mL per minute). Finally, to verify whether insulin interaction with the β-adrenergic pathway may also account for insulin modulation of α
2
-adrenergic vasoconstriction, we assessed the vascular response to a selective α
2
-adrenergic agonist before and after propranolol administration. Insulin exposure potentiated the vascular responsiveness to isoproterenol but did not affect the vasodilator response to sodium nitroprusside. Furthermore, the insulin-induced attenuation of sympathetic vasoconstriction was partially corrected by propranolol. In contrast, the insulin modulation of α
2
-adrenergic vasoconstriction was not influenced by β-adrenergic blockade.

Conclusions
Taken together, our results suggest that insulin modulation of sympathetic-induced vasoconstriction is carried out through an interaction of the hormone with the pathways of both α
2
- and β-adrenergic receptors.
Apoptosis as a Possible Cause of Gradual Development of Complete Heart Block and Fatal Arrhythmias Associated With Absence of the AV Node, Sinus Node, and Internodal Pathways
Authors: James Thomas N. , St. Martin Edward , Willis Park W. , Lohr Thomas O.
Published: June 2012

Background
Gradually progressive development of complete heart block in young people often is associated with cardiac arrhythmia and sudden death, but the pathogenesis remains unexplained.

Methods and Results
A young woman with complete heart block died suddenly. Her mother had serological but no clinical evidence of antiphospholipid syndrome. Five brothers of another family had arrhythmia and heart block. Three died suddenly; the other two have automatic defibrillators and are alive. The hearts from the young woman and two of the three brothers who died were available for our histological examination of their cardiac conduction systems. In two of the three hearts, the AV node was absent; in the third heart, only fragments of the AV node remained. In all three hearts, the sinus node was nearly destroyed by a noninflammatory degeneration with no abnormal fibrosis or infiltrate. In each heart, the interatrial and internodal pathways were similarly involved, and in the young woman, there were no myocardial cells in which these pathways normally exist.

Conclusions
In these three subjects with progressive development of complete heart block and various arrhythmias, all of whom died suddenly, the histological abnormalities of their cardiac conduction systems are best interpreted as resulting from apoptosis. Programmed cell death is a logical explanation for the pathogenesis of this puzzling clinical picture.
Adverse Influence of Systemic Vascular Stiffening on Cardiac Dysfunction and Adaptation to Acute Coronary Occlusion
Authors: Kass David A. , Saeki Akio , Tunin Richard S. , Recchia Fabio A.
Published: June 2012

Background
Age is an independent risk factor for increased mortality from ischemic heart disease. Arterial stiffening with widening of the pulse pressure may contribute to this risk by exacerbating cardiac dysfunction after total coronary artery occlusion.

Methods and Results
To test the above hypothesis, 14 open-chest dogs underwent surgery in which the intrathoracic aorta was bypassed with a stiff plastic tube. Directing ventricular outflow through the bypass widened the arterial pulse pressure from 41 to 115 mm Hg at similar mean pressure and flow. Hearts ejecting into the native aorta (NA) exhibited only modest dysfunction after 2 minutes of mid–left anterior descending coronary artery occlusion. However, the same occlusion applied during ejection into the bypass tube (BT) induced far more severe cardiodepression (ie, systolic pressure fell by −41±10 mm Hg for BT versus −15±3 mm Hg for NA, and end-systolic volume rose by 15±3 versus 6±2 mL), with a threefold greater decline in ejection fraction. This disparity was not due to higher baseline work loads because total pressure-volume area was similar in both cases. Furthermore, marked increases in basal work load and wall stress induced by angiotensin II infusion (in four additional studies) did not reproduce this behavior. Although peak systolic chamber stress was greater with the BT, this did not increase systolic dyskinesis as measured in the central ischemic zone. However, the total mass of myocardium that was rendered severely ischemic (ie, flow reduced by ≥80%) was twice as large with BT ejection, likely expanding the region of dyskinesis. This disparity may relate to altered phasic coronary flow during BT ejection, which displays marked enhancement of systolic flow and renders the heart more vulnerable to diminished mean and systolic perfusion pressures.

Conclusions
Cardiac ejection into a stiff systemic vasculature augments cardiac dysfunction and ischemia due to coronary occlusion by tightening the link between cardiac systolic performance and myocardial perfusion. This may contribute to the higher mortality risk from ischemic heart disease due to age.
Neointimal Thickening After Severe Coronary Artery Injury Is Limited by Short-term Administration of a Factor Xa Inhibitor
Authors: Schwartz Robert S. , Holder Daniel J. , Holmes David R. , Veinot John P. , Camrud Allan R. , Jorgenson Michael A. , Johnson Robert G.
Published: June 2012

Background
Fibrin- and platelet-rich thrombus formations occur as the initial event after percutaneous transluminal coronary angioplasty. We therefore tested the hypothesis that short-term administration of the recombinant tick anticoagulant peptide (rTAP), a factor Xa inhibitor, would reduce the thickness of neointima at 28 days after injury in a porcine coronary balloon angioplasty model.

Methods and Results
Continuous intravenous infusion of rTAP (average dose, 194 μg·kg
−1
·min
−1
) or placebo (vehicle only) was given to the study pigs for 60 hours. The goal of anticoagulation was to maintain the activated clotting time at 200 seconds. A central venous catheter was inserted 2 days before the procedure. On the day of coronary injury, the animals were administered boluses of rTAP (6.5 mg) and then underwent injury with an oversized metallic coil by standard methods in the right, circumflex, or left anterior descending coronary artery. No significant difference in vascular injury between rTAP and vehicle control was observed after euthanasia at 28 days. Significantly less neointimal thickening occurred in the rTAP-treated animals (thickness, mean±SD: 0.30±0.08 mm) compared with the control (0.48±0.12 mm,
P
<.001).

Conclusions
The specific factor Xa inhibitor rTAP, when given in fully anticoagulant doses for a short duration after coronary artery injury in the porcine model, resulted in a long-term decrease in neointimal thickness. These results implicate thrombin generation in neointimal formation and suggest that administration of a potent antithrombotic for several days immediately after the procedure may influence the long-term outcome of the coronary injury with a decrease in neointimal formation.
Calcium Responsiveness in Regional Myocardial Short-term Hibernation and Stunning in the In Situ Porcine Heart
Authors: Heusch Gerd , Rose Jochen , Skyschally Andreas , Post Heiner , Schulz Rainer
Published: June 2012

Background
We tested the hypothesis that decreased calcium responsiveness is responsible for the reduction in contractile function in regional hibernating and stunned myocardium in situ.

Methods and Results
In 19 anesthetized swine, the left anterior descending coronary artery flow was reduced to decrease anterior myocardial work index (sonomicrometry) by ≈60%. During 90 minutes of hypoperfusion, creatine phosphate recovered (as determined by biopsy specimens and bioluminescence) and no necrosis developed (as determined by staining with triphenyl tetrazolium chloride). In 10 swine, changes in the intracellular calcium concentration were induced by systematic variation of the postextrasystolic time interval at a constant prematurity. In 9 additional swine, a graded IC calcium infusion was performed. Under control conditions, anterior myocardial work increased with a fully compensated postextrasystolic time interval from 380±93 (mean±SD) to 523±98 mm Hg·mm. IC calcium infusion increased anterior myocardial work under control conditions from 356±85 to a maximum of 428±93 mm Hg·mm. Although the maximal responses were decreased during postextrasystolic potentiation (222±68 versus 523±98 mm Hg·mm) and calcium infusion (176±32 versus 428±93 mm Hg·mm) after 90 minutes of ischemia, the relationships between increases in anterior myocardial work and, respectively, postextrasystolic time interval and IC calcium were not different. The same was true after 30 minutes of reperfusion.

Conclusions
Both regional hibernating myocardium and stunned myocardium in situ are characterized by a decrease in overall myocardial calcium responsiveness; however, there appears to be no significant myocardial desensitization to calcium.
Leukocyte Depletion Attenuates Reperfusion Injury in Patients With Left Ventricular Hypertrophy
Authors: Sawa Yoshiki , Taniguchi Kazuhiro , Kadoba Keishi , Nishimura Motonobu , Ichikawa Hajime , Amemiya Akira , Kuratani Thoru , Matsuda Hikaru
Published: June 2012

Background
Reperfusion injury can occur after a long period of aortic cross-clamping in patients with left ventricular hypertrophy during open-heart surgery, even with the most up-to-date techniques of myocardial protection. In the present study, we examined whether leukocyte depletion as an adjunct to terminal blood cardioplegia (LDTC) attenuates reperfusion injury in patients with left ventricular hypertrophy (LV mass, >300 g; left ventricular end-systolic volume index, >100 mL/m
2
) in a group of 30 patients undergoing aortic valve replacement.

Methods and Results
We used basic cold potassium crystalloid cardioplegic solution. Terminal blood cardioplegic solution (TC) or LDTC was accomplished by mixing a cold potassium crystalloid cardioplegic solution with warm arterial blood obtained through cardiopulmonary bypass and administered to the aortic root for the first 10 minutes of reperfusion. During delivery of LDTC, warm arterial blood was passed through a leukocyte-removal filter. Patients were randomized into one of three groups for reperfusion: whole blood (WB) (n=10), TC (n=10), and LDTC (n=10). Left ventricular biopsies were obtained before ischemia, at the end of ischemia, and 15 minutes after reperfusion. Semiquantitative scoring for ultrastructural alterations indicated that the LDTC group achieved significantly better recoveries of both scores at reperfusion for myocyte damage and for endothelial cell damage of capillaries than did the WB and TC groups. The LDTC group had significantly fewer neutrophils adhering to endothelial cells at reperfusion and a lower level of malondialdehyde derived from myocardium than did the WB and TC groups. Regarding the clinical data, the LDTC group had a lower maximum creatine kinase–MB, a higher percentage of spontaneous defibrillation, a lower pulmonary capillary wedge pressure, and a lower requirement for dopamine than did the WB group, whereas the TC group failed to do better than the WB group.

Conclusions
These results demonstrate that leukocyte-depleted reperfusion is potentially beneficial as an adjunct to terminal cardioplegia during cardiac surgery to attenuate reperfusion injury in patients with left ventricular hypertrophy.
Endothelium-Dependent Coronary Vasomotion Relates to the Susceptibility of LDL to Oxidation in Humans
Authors: Anderson Todd J. , Meredith Ian T. , Charbonneau François , Yeung Alan C. , Frei Balz , Selwyn Andrew P. , Ganz Peter
Published: June 2012

Background
Oxidatively modified LDL has been shown to markedly impair endothelium-dependent dilation in experimental studies. The aim of the present study was to determine the relation between the coronary vasomotor response to the endothelium-dependent agonist acetylcholine and the in vitro susceptibility of LDL to oxidation in patients.

Methods and Results
Endothelium-dependent coronary vasomotion in response to acetylcholine (10
−8
to 10
−6
mol/L) was assessed in 23 patients with hypercholesterolemia (mean age, 56±9 years) after 1 year of therapy with either an American Heart Association Step 1 diet (seven patients), lovastatin and cholestyramine (seven patients), or lovastatin and probucol (nine patients). The susceptibility of LDL to oxidation was determined by measuring the lag phase of conjugated diene formation induced by Cu
2+
. Patients treated with lovastatin and probucol had prolongation of the lag phase (263±64 minutes) compared with diet- (91±22 minutes) or lovastatin and cholestyramine– (118±57 minutes) treated patients (
P
<.0001). By univariate analysis, the coronary vasomotor response to acetylcholine was significantly related to the lag phase of conjugated diene formation (
P
=.002), cholesterol-lowering therapy (
P
=.002), and serum cholesterol (
P
=.02). By multivariate analysis, the lag phase remained a significant predictor of the acetylcholine vasomotor response, independent of the effect of cholesterol-lowering treatment.

Conclusions
In patients treated with lipid-lowering agents, the vasodilator response to acetylcholine is related to the susceptibility of LDL to oxidation. These findings suggest that oxidative stress is an important determinant of the coronary endothelial dysfunction observed in patients with atherosclerosis and hypercholesterolemia.
Relation Between Troponin T and the Risk of Subsequent Cardiac Events in Unstable Coronary Artery Disease
Authors: Lindahl Bertil , Venge Per , Wallentin Lars
Published: June 2012

Background
Early risk assessment is important in patients with unstable coronary artery disease, ie, unstable angina or non–Q-wave myocardial infarction. Some previous small studies have indicated that patients with unstable angina and elevation of troponin T (tn-T) have worse short-term and long-term prognoses. In this study, the prognostic value of tn-T was evaluated and compared with other early available risk indicators.

Methods and Results
Nine hundred seventy-six patients participating in a randomized study of low-molecular-weight heparin in unstable coronary artery disease were followed for 5 months after the index episode. The risk of cardiac events increased with increasing maximal levels of tn-T obtained in the initial 24 hours. The lowest quintile (<0.06 μg/L) constituted a low-risk group, the second quintile (0.06 to 0.18 μg/L) an intermediate-risk group, and the three highest quintiles (≥0.18 μg/L) a high-risk group, with 4.3%, 10.5%, and 16.1% risk of either myocardial infarction or cardiac death, respectively. Troponin T level was identified together with age, hypertension, number of antianginal drugs, and ECG changes at rest as independent prognostic variables for myocardial infarction or cardiac death in a multivariate analysis. The prognostic value of tn-T was independent of the classification of index event into unstable angina or myocardial infarction.

Conclusions
Troponin T determination is an inexpensive and widely applicable method for early risk assessment in patients with unstable coronary artery disease. The maximum tn-T value obtained during the first 24 hours provides independent and important prognostic information.
Glucose Uptake in the Chronically Dysfunctional but Viable Myocardium
Authors: Mäki Maija , Luotolahti Matti , Nuutila Pirjo , Iida Hidehiro , Voipio-Pulkki Liisa-Maria , Ruotsalainen Ulla , Haaparanta Merja , Solin Olof , Hartiala Jaakko , Härkönen Risto , Knuuti Juhani
Published: June 2012

Background
The regulation of glucose uptake in the dysfunctional but viable myocardium has not been studied previously in humans.

Methods and Results
Seven patients with an occluded major coronary artery but no previous infarction were studied twice with 2-[
18
F]fluoro-2-deoxy-
d
-glucose positron emission tomography, once in the fasting state and once during hyperinsulinemic euglycemic clamping. Myocardial blood flow was measured with [
15
O]H
2
O. The myocardial region beyond an occluded artery that showed stable wall-motion abnormality represented chronically dysfunctional but viable tissue. Six of the patients were later revascularized, and wall-motion recovery was detected in the corresponding regions, which confirmed viability. A slightly reduced myocardial blood flow was detected in the dysfunctional than in the remote myocardial regions (0.81±0.27 versus 1.02±0.23 mL·g
−1
·min
−1
,
P
=.036). In the fasting state, glucose uptake was slightly increased in the dysfunctional regions compared with normal myocardium (15±10 versus 11±10 μmol/100 g per minute,
P
=.038). During insulin clamping, a striking increase in glucose uptake by insulin was obtained in both the dysfunctional and the normal regions (72±22 and 79±21 μmol/100 g per minute, respectively;
P
<.001, fasting versus clamping).

Conclusions
Contrary to previous suggestions, glucose uptake can be increased strikingly by insulin in chronically dysfunctional but viable myocardium. This demonstrates that insulin control over glucose uptake is preserved in the dysfunctional myocardium and provides a rational basis for metabolic intervention.
Carnitine-Related Alterations in Patients With Intermittent Claudication
Authors: Brevetti Gregorio , di Lisa Fabio , Perna Sergio , Menabó Roberta , Barbato Roberta , Domenico Martone Vincenzo , Siliprandi Noris
Published: June 2012

Background
Carnitine metabolism is altered in peripheral arterial disease.
l
-carnitine supplementation may correct these alterations and improve walking performance.

Methods and Results
Plasma levels of carnitine and its esters were measured at rest and after maximally tolerated exercise in 22 claudicant patients and 8 normal subjects. One week later, this protocol was repeated in patients after random administration of placebo or
l
-carnitine (500 mg IV as a single bolus). Two groups of patients emerged. In 10 patients (group IC1), the plasma level of acetylcarnitine at rest was 3.7±0.2 μmol/L and increased significantly (
P
<.01) at maximally tolerated exercise. In 12 patients (group IC2), the resting level of plasma acetylcarnitine was elevated (7.9±0.7 μmol/L,
P
<.01) and decreased with exercise. Furthermore, group IC2 patients had a significantly lower walking capacity than group IC1 patients. In both groups, placebo did not affect the metabolic profile, nor did it improve exercise performance. Conversely, after
l
-carnitine administration, all but one patient in group IC2 (n=7) showed an increase in plasma acetylcarnitine concentration during exercise versus the decrease observed without
l
-carnitine. This metabolic effect was accompanied by a significant increase (
P
<.01) in walking capacity. Interestingly, in group IC1 patients (n=5),
l
-carnitine neither improved walking capacity nor modified the metabolic profile. Statistical analysis showed that changes in walking capacity with
l
-carnitine treatment were influenced exclusively by exercise-induced changes in plasma acetylcarnitine.

Conclusions
In patients with intermittent claudication, assessment of plasma acetylcarnitine at rest and after exercise may be a means to select a target population for
l
-carnitine therapy.
Marked Discordance Between Dynamic and Passive Diastolic Pressure-Volume Relations in Idiopathic Hypertrophic Cardiomyopathy
Authors: Pak Peter H. , Maughan W. Lowell , Baughman Kenneth L. , Kass David A.
Published: June 2012

Background
Dynamic diastolic pressure-volume curves measured during filling (PVR
fill
) in patients with idiopathic hypertrophic cardiomyopathy (HCM) are often considerably shallower than would be anticipated if one assumed high chamber stiffness. We hypothesized that these curves deviate markedly from the passive end-diastolic pressure-volume relation (EDPVR) and explored the mechanisms for such a discordance.

Methods and Results
We used invasive pressure-volume analysis and conductance catheter methodology to study 42 patients. Nine had HCM, and the remaining patients comprised three comparison groups: 11 with normal left ventricular (LV) function, 13 with LV hypertrophy secondary to chronic hypertension (LVH-HTN), and 9 with idiopathic dilated cardiomyopathy (DCM). EDPVRs were recorded during balloon catheter obstruction of inferior vena cava inflow. In normal subjects, LVH-HTN patients, and DCM patients, PVR
fill
curves deviated only slightly from the passive EDPVR. In striking contrast, HCM patients displayed a flat PVR
fill
that was very different from the steep EDPVR. On reduction of preload, PVR
fill
relations in HCM shifted downward in parallel, with a net pressure decline at the same chamber volume of −10±4 mm Hg. This staircaselike shift was much less in the other patient groups (−2±2 mm Hg;
P
<.001). The unusual behavior in HCM could not be attributed directly to increased viscosity, enhanced pericardial constraint, or preload dependence of isovolumic relaxation. Regional heterogeneity of relaxation may play a role; however, we speculate that the major mechanism relates to the unique fiber and chamber architecture seen with HCM and possibly to enhanced ventricular interaction.

Conclusions
Elevated LV filling pressures in HCM are not due simply to a stiff cavity but also reflect a major influence of offset pressures that vary with chamber loading. The large disparity between flat pressure-volume relations during filling and steep end-diastolic relations appears unique to HCM. This indicates that caution should be used in the interpretation of stiffness results derived from steady-state data and suggests that therapies that alter cavity geometry and/or reduce interaction may markedly influence LV diastolic pressures in HCM.
Echocardiographic Evaluation of Patients With Acute Rheumatic Fever and Rheumatic Carditis
Authors: Vasan Ramachandran S. , Shrivastava Savitri , Vijayakumar Manam , Narang Rajiv , Lister Bradford C. , Narula Jagat
Published: June 2012

Background
Cardiac involvement is the most important component of acute rheumatic fever. The role of echocardiography in the evaluation of rheumatic carditis has not been adequately defined. We used echocardiography in a large sample of patients with acute rheumatic fever to describe morphological abnormalities associated with rheumatic carditis and to assess its role in the diagnosis of rheumatic carditis.

Methods and Results
Cross-sectional and color Doppler echocardiographic examination was performed in 108 consecutive patients with acute rheumatic fever within 24 to 48 hours of diagnosis. Twenty-eight patients had acute rheumatic fever without clinical evidence of carditis (group 1). Thirty-five patients had a presumed first episode of rheumatic carditis (group 2), and 45 patients had a recurrence of carditis (group 3). Patients in group 1 did not demonstrate any evidence of valvular regurgitation. Mitral regurgitation was the most common Doppler echocardiographic feature in groups 2 (94%) and 3 (84%). Valvular thickening with or without restriction of leaflet mobility was frequently seen in rheumatic carditis. One of every 4 patients with rheumatic carditis demonstrated echocardiographic presence of focal valvular nodules. These nodules were found on the body and the tips of the mitral valve leaflets and disappeared on follow-up. Ventricular dilatation (group 2, 54%; group 3, 74%) and restriction of leaflet mobility (group 3, 37%) were common mechanisms of mitral regurgitation in rheumatic carditis; valve prolapse (group 2, 9%; group 3, 16%) and annular dilatation (group 2, 12%; group 3, 21%) were infrequent. The majority of patients with rheumatic carditis had normal left ventricular systolic function. Congestive heart failure (group 2, 17%; group 3, 40%) was invariably associated with the presence of hemodynamically significant valve lesions. On follow-up, no patient in group 1 developed valvular regurgitation. In group 2 patients, a progressive decrease in left ventricular dimensions was observed without any change in ventricular fractional shortening. Valvular regurgitation remained unchanged in 69% of patients, decreased in 22%, and disappeared in 9%.

Conclusions
In patients with rheumatic carditis, the mitral valve is most often involved and mitral regurgitation is the most common finding on color flow imaging. Mitral regurgitation in rheumatic carditis is related to ventricular dilatation and/or restriction of leaflet mobility. Rheumatic carditis does not result in congestive heart failure in the absence of hemodynamically significant valve lesions. In a quarter of patients with rheumatic carditis, we observed valve nodules that may represent echocardiographic equivalents of rheumatic verrucae. Our study failed to reveal any incremental diagnostic utility of echocardiography and Doppler color flow imaging in rheumatic fever without clinical evidence of carditis.
Stenting of Aortopulmonary Collaterals in Complex Pulmonary Atresia
Authors: Redington Andrew N. , Somerville Jane
Published: June 2012

Background
The optimal treatment of patients with complex pulmonary atresia remains controversial. Surgical unifocalization programs are increasing popular but have not previously or currently gained universal acceptance. Furthermore, not all patients are suitable for attempts at biventricular correction. These patients may become increasingly symptomatic and require palliation.

Methods and Results
We attempted to palliate 12 patients with progressive symptomatic hypoxemia. Each had at least one stenotic but balloon-dilatable collateral supplying at least three lung segments. It was impossible to traverse the stenotic area with the stent in 1 patient, despite two attempts. Twelve stents were thus deployed in 11 patients. There was no effect in 1 patient who had multiple stenoses distal to the stented area. There was excellent palliation in the remainder, arterial oxygen saturation 45% to 79% before stenting (mean, 64±12%) rising to 67% to 90% (mean, 78±10%,
P
<.01) at discharge from hospital. One patient was referred for surgery to secure blood flow to a nearly totally occluded side branch to the right upper lobe traversed by the stent. There was an excellent symptomatic response in the remainder, with an early increase in exercise duration (
P
<.01). Late arterial desaturation occurred in 2 patients. In 1, there was pulmonary arterial hypertension in the lung segments supplied by the stented vessel. A stenosis had developed within the stent in the other patient, who was noncompliant with anticoagulation therapy.

Conclusions
Stenting of stenotic aortopulmonary collaterals can achieve excellent palliation in the majority of this highly selected subgroup of patients with complex pulmonary atresia.
Multicenter Comparison of Truncated Biphasic Shocks and Standard Damped Sine Wave Monophasic Shocks for Transthoracic Ventricular Defibrillation
Authors: Bardy Gust H. , Marchlinski Francis E. , Sharma Arjun D. , Worley Seth J. , Luceri Richard M. , Yee Raymond , Halperin Blair D. , Fellows Christopher L. , Ahern Thomas S. , Chilson Donald A. , Packer Douglas L. , Wilber David J. , Mattioni Thomas A. , Reddy Ramakota , Kronmal Richard A. , Lazzara Ralph
Published: June 2012

Background
The most important factor for improving out-of-hospital ventricular fibrillation survival rates is early defibrillation. This can be achieved if small, lightweight, inexpensive automatic external defibrillators are widely disseminated. Because automatic external defibrillator size and cost are directly affected by defibrillation waveform shape and because of the favorable experience with truncated biphasic waveforms in implantable cardioverter-defibrillators, we compared the efficacy of a truncated biphasic waveform with that of a standard damped sine monophasic waveform for transthoracic defibrillation.

Methods and Results
The principal goal of this multicenter, prospective, randomized, blinded study was to compare the first-shock transthoracic defibrillation efficacy of a 130-J truncated biphasic waveform with that of a standard 200-J monophasic damped sine wave pulse using anterior thoracic pads in the course of implantable cardioverter-defibrillator testing. Pad-pad ECGs were also examined after transthoracic defibrillation. After the elimination of data for 24 patients who did not meet all protocol criteria, the results from 294 patients were analyzed. The 130-J truncated biphasic pulse and the 200-J damped sine wave monophasic pulse resulted in first-shock efficacy rates of 86% and 86%, respectively (
P
=.97). ST-segment levels measured 10 seconds after the shock in 151 patients in sinus rhythm were −0.26±1.58 and −1.86±1.93 mm for the 130- and 200-J shocks, respectively (
P
<.0001).

Conclusions
We found that 130-J biphasic truncated transthoracic shocks defibrillate as well as the 200-J monophasic damped sine wave shocks that are traditionally used in standard transthoracic defibrillators and result in fewer ECG abnormalities after the shock.
Sex Difference in Risk of Torsade de Pointes With
d,l-
Sotalol
Authors: Lehmann Michael H. , Hardy Sterling , Archibald Donald , Quart Barry , MacNeil Daniel J.
Published: June 2012

Background
The present study was undertaken to test the hypothesis that women are more prone than men to develop torsade de pointes (TdP) in a defined cohort of patients exposed to the QT-prolonging antiarrhythmic drug
d,l
-sotalol.

Methods and Results
In a database derived from 22 clinical trials involving 3135 adult patients who received oral
d,l
-sotalol (median follow-up, 164 days), TdP developed in 44 (1.9%) of 2336 men and in 33 (4.1%) of 799 women (
P
<.001). Logistic regression analysis identified female sex (
P
<.0001), presenting arrhythmia of sustained ventricular tachycardia or fibrillation (
P
<.0001), history of congestive heart failure (
P
<.001), and
d,l
-sotalol dose >320 mg/d (
P
<.001) as factors most predictive of TdP; in addition to these, a serum creatinine >1.4 mg/dL in women and >1.6 mg/dL in men was weakly predictive (
P
<.05). After adjustment for these risk factors, women had threefold greater odds of developing TdP than men. The sex difference in TdP risk was age independent and could not be explained by differential dose-related bradycardic responses in women versus men.

Conclusions
Women are at increased risk of developing TdP during administration of
d,l
-sotalol. This finding needs to be taken into account, together with other TdP risk factors, when patients are treated with this antiarrhythmic agent. Given the consistency between the present and other recent observations, greater caution in women regarding use of QT-prolonging drugs, in general, is advisable.