bluuebunny/crossref_metadata_2025 huggingface dataset:
Target Heart Failure Populations for Newer Therapies
Authors: Stevenson Lynne Warner , Couper Gregory , Natterson Barbara , Fonarow Gregg , Hamilton Michele A. , Woo Mary , Creaser Julie W.
Published: June 2012

Background
The scarcity of donor hearts has created a large population of heart failure patients who are unlikely to undergo transplantation. Newer surgical therapies that might sustain such patients at home previously have been applied in critical situations in which early outcome is jeopardized by multiorgan failure. The optimal population for studies of extended support would be ambulatory patients with low operative risk but high risk of later unfavorable outcome.

Methods and Results
Baseline clinical, echocardiographic, and hemodynamic data were collected prospectively between 1988 and 1993 in 500 patients who were discharged on tailored medical therapy after evaluation for transplantation. Specific criteria were examined to identify high risk of death or need for urgent transplantation during the next 2 years. In 265 patients with ejection fraction ≤25% and initial New York Heart Association class IV symptoms, survival at 2 years was 55% (without urgent transplantation, 45%). Lower cardiac index or higher filling pressures at the time of referral did not confer higher risk, which was predicted by persistence of higher pressures after therapy. Serum sodium below 133 was associated with 34% 2-year survival without urgent transplantation, and ventricular dimension >80 mm with a rate of 25%. Patients with initial peak oxygen consumption >10 mL/kg per minute had a 2-year event-free rate of 72% compared with 48% for those with <10 mL/kg per minute and 32% for those unable to exercise at referral. Demonstration of a 30% decrease in mortality with a controlled trial of new therapy in patients with ejection fraction ≤25% would require 600 patients with class III symptoms or almost 300 patients with class IV symptoms unless another criterion were added.

Conclusions
Ambulatory populations with high predicted event rates can be identified at initial evaluation, when hemodynamic criteria may be less useful than ventricular dimension, serum sodium, and ability to exercise. The use of outcome data from previous eras may lead to overestimation of benefits from newer therapies and underestimation of the sample size required in a prospective trials.
Generation of Tumor-Specific T Lymphocytes for the Treatment of Posttransplant Lymphoma
Authors: DiMaio J. Michael , Van Trigt Peter , Gaynor J. William , Davis R. Duane , Coveney Eamonn , Clary Bryan M. , Lyerly H. Kim
Published: June 2012

Background
The incidence of lymphoproliferative disease, including B-cell lymphomas (BCL) in patients who have undergone heart or combined heart-lung transplants, has been reported to be as high as 15%. The majority of these tumors contain Epstein-Barr virus (EBV) DNA and regress when immunosuppressive agents are discontinued. This tumor regression is thought to be secondary to cytotoxic T lymphocytes (CTL) reactive to EBV-infected cells whose function is impaired in patients receiving immunosuppressive agents. We hypothesize that EBV-CTL expanded in the absence of these agents may demonstrate an antitumor effect against an EBV-expressing human BCL in vitro and in vivo.

Methods and Results
An EBV-expressing BCL from a heart transplant recipient was isolated and expanded in culture. EBV-CTL were generated by stimulation of peripheral blood leukocytes with irradiated autologous tumor cells in low-dose interleukin-2. Autologous BCL, HLA-mismatched BCL, lymphokine-activated killer target cell line (Daudi), and the natural killer target cell line (K562) were used in a standard 4-hour cytotoxicity assay using
51
CrO
4
after 7, 14, and 28 days of stimulation. There was significant percent specific lysis of autologous BCL targets (78%) at an effector-to-target ratio as low as 20:1 as compared with control cells. EBV-CTL were then adoptively transferred into SCID mice (provided by Duke University Vivarium) that had been engrafted with autologous BCL 7 days before. There was a significant survival advantage to those mice engrafted with EBV-CTL as compared with control cells.

Conclusions
The results indicate that ex vivo expansion of EBV-CTL in the absence of immunosuppressive agents results in a population that has significant antitumor activity. This strategy may be useful in the generation of EBV-CTL that might be effective antitumor agents in transplant recipients with EBV-associated lymphomas.
Genetic Linkage of the
ACE
Gene to Plasma Angiotensin-Converting Enzyme Activity but Not to Blood Pressure
Authors: Kreutz R. , Hübner N. , Ganten D. , Lindpaintner K.
Published: June 2012

Background
An allelic variant of the
ACE
gene has been found to be linked to plasma angiotensin-converting enzyme (ACE) activity in humans and has been implicated in the etiology of some common cardiovascular disorders. Previously, we have shown significant genetic linkage of blood pressure to a region on rat chromosome 10 that contains
ACE
in an experimental F
2
-intercross between the stroke-prone spontaneously hypertensive rat (SHRSP
HD
) and the normotensive Wistar-Kyoto (WKY
HD
-0) reference strain. Subsequent investigations revealed marked differences in plasma ACE activity among the SHRSP
HD
and WKY
HD
-0 strains. Nonetheless, the physiological relevance of these findings remained obscure. We therefore investigated the genetic determination of plasma ACE activity and its relation to blood pressure and dietary NaCl exposure in a model of experimental genetic hypertension, the SHRSP
HD
.

Methods and Results
We conducted a further crossbreeding experiment between SHRSP
HD
and a congenic reference strain, WKY
HD
-1, that carries a 6-centimorgan (cM) long, SHRSP-homologous segment introgressed in chromosome 10, 26 cM remote from
ACE
. This allowed us to contrast effects on blood pressure and ACE activity conferred by the
ACE
locus with other more remote loci within the congenic chromosomal region. Genetic analysis in this F
2
(WKY
HD
-1×SHRSP
HD
) cross revealed that plasma ACE activity was determined almost entirely by genetic effects of the
ACE
gene locus (lod score=43). However, neither plasma ACE nor the
ACE
locus showed any cosegregation with blood pressure before or after dietary NaCl exposure.

Conclusions
These results demonstrate that a molecular variant of the
ACE
gene determines plasma ACE activity but exhibits no direct effect on blood pressure. Moreover, the findings also exclude the possibility that plasma ACE is secondarily affected by blood pressure or excess dietary NaCl exposure. Our results reconcile the previous discrepancy between findings in human and experimental hypertension.
Coronary Arterial Flow-Velocity Dynamics in Children With Angiographically Normal Coronary Arteries
Authors: Hamaoka Kenji , Onouchi Zenshiro , Ohmochi Yutaka , Sakata Kohichi
Published: June 2012

Background
There have been few reports about coronary hemodynamics in children during the process of growth. In the present study, to assess the characteristics of coronary flow dynamics in children, we examined the phasic coronary flow-velocity (CFV) patterns at rest and during peak hyperemic responses in children with angiographically normal coronary arteries.

Methods and Results
Spectral Doppler phasic coronary flow velocity was recorded with a 0.018-in intracoronary Doppler guidewire at rest and during peak responses after intracoronary bolus injection of ATP in 30 patients with Kawasaki’s disease (age, 8.2±5.1 years; 24 boys and 6 girls) without angiographic coronary lesions. Average peak velocity (APV), maximum peak velocity (MPV), and diastolic-to-systolic velocity ratio (DSVR) were evaluated in the left anterior descending coronary artery (LAD), left circumflex artery (LCx), and right coronary artery (RCA). Coronary vasodilator reserve (coronary flow reserve [CFR]) was calculated as the ratio of ATP-induced hyperemic to baseline APV. Flow-velocity parameters in RCA were significantly lower than those in the LAD and LCx in both proximal and distal portions. Although the distal LCx had significantly lower values of APV and MPV than did the proximal LCx, there was no significant difference between the proximal and distal portions of the LAD and RCA for APV and MPV. All three coronary vessels showed a diastolic dominant flow pattern in each segment. This coronary flow pattern was less marked in the RCA than in the LCA. All three coronary vessels showed a significant increase in APV and a significant decrease in DSVR after ATP administration. CFR was significantly lower in the LCx than in the LAD or RCA (
P
<.01: 1.93±0.34 in LCx versus 2.32±0.42 in LAD and 2.37±0.44 in RCA). From the view of aging, it was revealed that APV values in three vessels were higher in the younger group than in the older group. CFR values in the LAD and LCx were significantly lower in the younger group than in the older group (
P
<.001 in LAD: 2.01±0.28 in the younger versus 2.53±0.37 in the older;
P
<.01 in LCx: 1.61±0.15 in the younger versus 2.06±0.31 in the older). In addition, intracoronary injection of ATP did not increase the absolute angiographic coronary luminal diameter.

Conclusions
With the use of an intracoronary Doppler guidewire, we demonstrated that there are some characteristic findings in CFV dynamics in childhood. These physiological characteristics in CFV dynamics that occur with aging and occur in each vessel must be taken into consideration in the study of the coronary circulation in children.
Natural History of Hypertrophic Cardiomyopathy
Authors: Cannan Charles R. , Reeder Guy S. , Bailey Kent R. , Melton L. Joseph , Gersh Bernard J.
Published: June 2012

Background
Hypertrophic cardiomyopathy is a disease entity characterized by marked heterogeneity in morphology and natural history. Most of our knowledge of the natural history of this disorder derives from the study of hospital-based populations and is influenced by referral bias. Therefore, this population-based study was undertaken to examine the natural history of hypertrophic cardiomyopathy among unselected residents of Olmsted County, Minnesota.

Methods and Results
Patients with hypertrophic cardiomyopathy, confirmed by echocardiography, were identified by use of the resources of the Rochester Epidemiology Project. Patients with the echocardiographic features of hypertrophic cardiomyopathy but with long-standing hypertension requiring drug therapy were categorized as having hypertensive hypertrophic cardiomyopathy. Baseline clinical details and follow-up events were obtained by retrospective chart review. Thirty-seven patients were diagnosed with hypertrophic cardiomyopathy and 24 with hypertensive hypertrophic cardiomyopathy. Eight additional patients were first diagnosed at autopsy. The mean age of the 37 patients with hypertrophic cardiomyopathy was 59±20 years (range, 1 week to 92 years); the mean ventricular septal thickness was 17.5±3 mm. Follow-up was obtained for a median of 7.7 years (range, 45 days to 17.2 years). The 1- and 5-year survival rates were 95% and 92%, respectively; these rates did not differ from those of an age- and sex-matched population (
P
=NS). The annual risk of cardiac death was 0.7%. The mean age of patients with hypertensive hypertrophic cardiomyopathy was 79±8 years (range, 62 to 91 years), and the mean ventricular septal thickness was 19±2.5 mm. Follow-up was obtained for a median of 2.8 years (range, 4 days to 16.7 years). The 1- and 5-year survival rates were 75% and 43%, respectively, which differed sharply from the expected rates of 94% and 70% (
P
=.0028). The annual risk of cardiac death was 5%. Atrial fibrillation and evidence for myocardial infarction on ECG, use of digoxin and diuretics, and a high New York Heart Association functional class at presentation were all associated with decreased survival by multivariate analysis for both groups combined. A history of myocardial infarction, atrial fibrillation, and mitral annular calcification at presentation were associated with cardiac death.

Conclusions
Hypertrophic cardiomyopathy is a more benign disease than previously reported from tertiary referral centers. Patients assessed as having hypertensive hypertrophic cardiomyopathy represent a subset at higher risk for cardiac and noncardiac death, with an overall decreased survival rate.
Effect of Ryanodine on Sarcoplasmic Reticulum Ca
2+
Accumulation in Nonfailing and Failing Human Myocardium
Authors: Nimer Lynn R. , Needleman Dolores H. , Hamilton Susan L. , Krall Judith , Movsesian Matthew A.
Published: June 2012

Background
The purpose of this study was to determine whether abnormal Ca
2+
release through ryanodine-sensitive Ca
2+
channels in the sarcoplasmic reticulum might contribute to the abnormal [Ca
2+
]
i
homeostasis that has been described in failing human myocardium.

Methods and Results
Occupancy of low-affinity ryanodine binding sites on ryanodine-sensitive Ca
2+
channels stimulates oxalate-supported, ATP-dependent Ca
2+
accumulation in sarcoplasmic reticulum–derived microsomes by inhibiting concurrent Ca
2+
efflux through these channels. We examined the effects of 0.5 mmol/L ryanodine on
45
Ca
2+
accumulation in microsomes prepared from nonfailing (n=8) and failing (n=10) human left ventricular myocardium. In the absence of ryanodine,
45
Ca
2+
accumulation reached similar levels in microsomes from nonfailing and failing hearts. Incubation with 0.5 mmol/L ryanodine caused a 52.2±6.5% increase in peak
45
Ca
2+
accumulation in microsomes from nonfailing hearts and a 24.3±4.1% increase in microsomes from failing hearts. The density of high-affinity ryanodine binding sites and the inhibition of [
3
H]ryanodine dissociation from these sites by 0.1 mmol/L ryanodine were similar in microsomes from nonfailing and failing hearts.

Conclusions
These results, which demonstrate a diminished stimulation of Ca
2+
accumulation by ryanodine in sarcoplasmic reticulum–derived microsomes from failing human myocardium that could be explained by an uncoupling of the occupancy of low-affinity ryanodine binding sites from the reduction in the open probability of these channels or by concurrent Ca
2+
efflux through a ryanodine-insensitive mechanism, are evidence that increased efflux of Ca
2+
from the sarcoplasmic reticulum may contribute to the abnormal [Ca
2+
]
i
homeostasis described in failing human myocardium.
Magnesium Cardioplegia Enhances mRNA Levels and the Maximal Velocity of Cytochrome Oxidase I in the Senescent Myocardium During Global Ischemia
Authors: Faulk Elizabeth A. , McCully James D. , Hadlow Narelle C. , Tsukube Takuro , Krukenkamp Irvin B. , Federman Micheline , Levitsky Sidney
Published: June 2012

Background
The aged myocardium accumulates significantly more cytosolic calcium [Ca
2+
]
i
during ischemia, and functional recovery is more severely compromised as compared with the mature heart. Cardioplegia ameliorates these phenomena. The mechanism by which increased calcium accumulation reduces functional recovery in the senescent myocardium is unknown, but it has been suggested that futile calcium cycling in the mitochondria leading to depletion of ATP stores during normothermic global ischemia may be involved.

Methods and Results
To investigate the effect of cardioplegia on mitochondrial calcium ([Ca
2+
]
mt
) accumulation and the expression of cytochrome oxidase I (COX I) during global ischemia, mitochondria were isolated from mature (age, 15 to 20 weeks) and aged (age >130 weeks) rabbit hearts after Langendorff perfusion. Five perfused heart groups were investigated: 30 minutes of global ischemia without treatment (control), with potassium (K, 20 mmol/L), magnesium (Mg, 20 mmol/L), or potassium and magnesium (K/Mg) cardioplegia. No significant difference in [Ca
2+
]
mt
was evident in mature hearts with any protocol. In aged hearts, [Ca
2+
]
mt
was increased in global ischemia but was ameliorated with Mg and K/Mg cardioplegia. COX I mRNA levels in aged hearts were lower in both control and global ischemia but were increased with cardioplegia. Maximal velocities for COX I were significantly increased with Mg cardioplegia both in the mature and the aged myocardium.

Conclusions
K and/or Mg cardioplegia ameliorates [Ca
2+
]
mt
accumulation in aged hearts during normothermic global ischemia and increases COX I mRNA levels to a level not significantly different from that found in mature hearts.
Improved 4- and 6-Hour Myocardial Preservation by Hypoxic Preconditioning
Authors: Engelman Daniel T. , Chen Chang-zhi , Watanabe Masazumi , Engelman Richard M. , Rousou John A. , Flack Joseph E. , Deaton David W. , Maulik Nilanjana , Das Dipak K.
Published: June 2012

Background
A brief hypoxic episode can precondition myocardium against a subsequent ischemic-reperfusion injury. The present study sought to determine whether intracellular ionic alterations, induced expression of heat-shock proteins (hsps), and/or catalase are involved in the cellular mechanisms by which hypoxic preconditioning can preserve postischemic function in a model of prolonged hypothermic storage.

Methods and Results
Two groups of isolated working rat hearts were studied: control (CON) and hypoxically preconditioned (HP) hearts. Hearts were arrested at 4°C with St Thomas’ cardioplegic solution and immersion-stored for either a 4- or 6-hour period. Myocardial function (ie, heart rate, aortic flow, coronary flow, developed pressure, and its first derivative dP/dt
max
) was determined at baseline, after preconditioning, and during reperfusion. At similar time points, myocardial [Na
+
]
i
, [K
+
]
i
, [Mg
2+
]
i
, and [Ca
2+
]
i
were measured using an atomic absorption spectrophotometer, and the induction of hsp 70 and catalase mRNAs was assayed using Northern blot analysis. After 4 and 6 hours of hypothermic storage, aortic flow, dP/dt
max
, and [K
+
]
i
were increased, whereas [Na
+
]
i
and [Ca
2+
]
i
were decreased significantly in the HP group compared with the CON group. Steady state mRNA levels of catalase and hsp 70 were increased from baseline levels only in the HP group, with a peak (2.8- and 2.4-fold versus baseline) after 4 hours of storage.

Conclusions
Our results indicate that intracellular ionic alterations and upregulation of catalase and hsp 70 gene expression may contribute to the mechanisms underlying hypoxic preconditioning, leading to improved postischemic function during prolonged hypothermic storage of hearts.
Rapid Ventricular Pacing Produces Myocardial Protection by Nonischemic Activation of K
ATP
+
Channels
Authors: Koning Monique M.G. , Gho Ben C.G. , van Klaarwater Erik , Opstal René L.J. , Duncker Dirk J. , Verdouw Pieter D.
Published: June 2012

Background
Rapid ventricular pacing reduces the incidence of ventricular arrhythmias during a subsequent sustained period of ischemia and reperfusion. We investigated whether rapid ventricular pacing also limits myocardial infarction and determined the role of K
ATP
+
channels in the protection afforded by ventricular pacing.

Methods and Results
Myocardial infarction was produced by a 60-minute coronary artery occlusion in open chest pigs. Infarct size of pigs subjected to 10 minutes of ventricular pacing at 200 beats per minute followed by 15 minutes of normal sinus rhythm before the occlusion (79±3% of the area at risk, mean±SEM) was not different from control infarct size (84±2%). Thirty-minute pacing followed by 15-minute sinus rhythm resulted in modest reductions in infarct size (71±2%,
P
<.05 versus control). Thirty minutes of pacing immediately preceding the occlusion without intervening sinus rhythm resulted in considerable limitation of infarct size (63±4%,
P
<.05), which was abolished by pretreatment with the K
ATP
+
channel blocker glibenclamide (78±4%,
P
=NS). K
ATP
+
channel activation did not appear to involve ischemia: (1) myocardial endocardial/epicardial blood flow ratio was 1.07±0.08, (2) phosphocreatine and ATP levels and arterial-coronary venous differences in pH and P
co
2
were unchanged, (3) end-systolic segment length did not increase and postsystolic shortening was not observed during pacing, and (4) systolic shortening recovered immediately to baseline levels and coronary reactive hyperemia was absent after cessation of pacing. Administration of glibenclamide after 30 minutes of pacing at the onset of 15 minutes of normal sinus rhythm did not attenuate the protection (73±3%,
P
<.05 versus control), suggesting that K
ATP
+
channels did not contribute to the moderate degree of protection that was still present 15 minutes after cessation of pacing.

Conclusions
Rapid ventricular pacing protects the myocardium against infarction via nonischemic K
ATP
+
channel activation. Continued activation of K
ATP
+
channels does not appear mandatory for the protection that is still present 15 minutes after cessation of pacing.
Induction of DNA Synthesis by a Single Transient Mechanical Stimulus of Human Vascular Smooth Muscle Cells
Authors: Cheng George C. , Libby Peter , Grodzinsky Alan J. , Lee Richard T.
Published: June 2012

Background
Although mechanical vascular injury leads to smooth muscle cell proliferation that contributes to restenosis after balloon angioplasty, the role of the single transient mechanical stimulation of smooth muscle cells in this process is unknown.

Methods and Results
To test the hypothesis that a single transient mechanical stimulus can increase DNA synthesis, human vascular smooth muscle cells cultured in a three-dimensional collagen gel system were subjected to transient compression. Transient compression (5-minute duration) of smooth muscle cell–collagen gel cultures in defined serum-free conditions led to delayed increases in [
3
H]thymidine incorporation. At 12 to 24 hours after compression, there was a 3.3±0.5-fold (
P
<.001 versus control) and 3.0±0.6-fold (
P
<.002 versus control) increase for 60% and 80% strain, respectively; at 24 to 36 hours after compression, there was a 1.8±0.5-fold (
P
<.05 versus control) and 4.3±0.8-fold (
P
<.001 versus control) increase. Also, serum-free media conditioned by transiently compressed gel cultures induced DNA synthesis in control, unstimulated smooth muscle cell cultures, suggesting the release of growth factors by transient compression. Although neutralizing antibodies against platelet-derived growth factor did not affect the mechanical induction of DNA synthesis, a neutralizing monoclonal antibody against fibroblast growth factor–2 (FGF-2) decreased this induction by 89% and completely blocked the increase in DNA synthesis caused by media conditioned by transiently compressed gels. Media conditioned by transient compression contained elevated levels of FGF-2 (17±5 versus 2±2 pg/mL for control,
P
<.005) with no increase in lactate dehydrogenase activity, suggesting release of FGF-2 with sublethal cellular injury.

Conclusions
A single transient mechanical stimulus increases DNA synthesis in human vascular smooth muscle cells, in part by autocrine or paracrine FGF-2 release.
Effectiveness of Revascularization in the Emory Angioplasty Versus Surgery Trial
Authors: Zhao Xue-Qiao , Brown B. Greg , Stewart Douglas K. , Hillger Lynn A. , Barnhart Huiman X. , Kosinski Andrzej S. , Weintraub William S. , King Spencer B.
Published: June 2012

Background
The Emory Angioplasty Versus Surgery Trial (EAST) was designed to determine whether percutaneous transluminal coronary angioplasty (PTCA) is as effective as coronary artery bypass graft surgery (CABG) in restoring arterial perfusion capacity in eligible patients with multivessel disease.

Methods and Results
Of 392 patients in EAST, 198 were randomized to PTCA and 194 to CABG. Index lesions (2.7±1.0 per patient) were those with ≥50% stenosis judged treatable by both angioplasty and surgery. Coronary segments jeopardized by these index lesions were designated as index segments (4.4±1.4 per patient). Percent stenosis was measured by quantitative angiography at the point of greatest obstruction in the main perfusion path of each index segment. The EAST primary arteriographic end point was the percent of a patient’s index segments with <50% stenosis in the main perfusion pathways at 1 and 3 years. At baseline, the percent of index segments for which revascularization was attempted was 85% for PTCA and 98% for CABG (
P
<.0001). At 1 year, PTCA patients had a smaller percentage of successfully revascularized index segments than CABG patients (59% versus 88%,
P
<.001). At 3 years, the findings were similar but less striking (70% versus 87%,
P
<.001). When only “high-priority” index segments (2.1±1.6 per patient) were considered, baseline attempts were comparable (96% versus 99%,
P
=NS); despite this, CABG remained more successful at 1 (64% versus 93%,
P
<.001) and 3 (76% versus 89%,
P
<.01) years. However, the mean percent of index segments free of severe stenosis (≥70%) did not differ between PTCA and CABG patients at 3 years (93% versus 95%,
P
=NS). Furthermore, the frequency of patients with all index segments free of severe stenosis did not differ between the two groups at 1 (76% versus 83%,
P
=NS) or 3 (82% for both PTCA and CABG) years.

Conclusions
In patients with multivessel disease, index segment revascularization was more complete with CABG than PTCA at both 1 and 3 years. However, when the physiological priority of the target lesion and the measured severity of the residual stenosis are taken into account, the advantage of CABG becomes less significant or nonsignificant. This may, in part, explain why these two strategies did not differ in terms of the EAST primary clinical end points over 3 years.
Longitudinal Clinical and Electrophysiological Assessment of Patients With Symptomatic Wolff-Parkinson-White Syndrome and Atrioventricular Node Reentrant Tachycardia
Authors: Chen Shih-Ann , Chiang Chern-En , Tai Ching-Tai , Lee Shih-Huang , Chiou Chuen-Wang , Ueng Kwo-Chang , Wen Zu-Chi , Cheng Chen-Chuen , Chang Mau-Song
Published: June 2012

Background
Functional changes of the accessory AV pathways and dual AV node pathways are very important for patients with Wolff-Parkinson-White syndrome or AV node reentrant tachycardia who refuse to receive long-term medication or radiofrequency catheter ablation. However, no studies of serial clinical and electrophysiological characteristics in these patients have been performed.

Methods and Results
One hundred thirteen patients with Wolff-Parkinson-White syndrome or AV node reentrant tachycardia were included in this study. The first and second follow-up electrophysiological studies were performed in years 5 and 10 after the baseline study, respectively. Conduction properties of the accessory pathways became poor over time. After a mean follow-up period of 9±1 years, antegrade ventricular preexcitation and retrograde accessory pathway conduction disappeared in 22.5% and 7.8% (
P
<.01), respectively; dual AV node pathway physiology persisted and retrograde fast pathway disappeared in 10.8% of the patients. Baseline conduction properties of the antegrade and retrograde accessory pathways and the retrograde fast pathway independently predicted late loss of conduction. Spontaneous disappearance of the original tachyarrhythmias occurred in 10.3% of all patients, and newly developed tachyarrhythmias in 15.2%. The incidence (38.5%) of newly developed atrial fibrillation was significantly higher in patients with manifest accessory pathways. Furthermore, symptom scores and attack frequency increased significantly over time in the patients with accessory pathways and AV node reentrant tachycardia.

Conclusions
Disappearance of the original tachycardia and changing patterns of tachycardia, also with an increase in symptom scores and attack frequency, suggested that a detailed evaluation of these events is important and early intervention with radiofrequency ablation would be helpful.
Endothelin-1 Is Involved in Norepinephrine-Induced Ventricular Hypertrophy In Vivo
Authors: Kaddoura Samer , Firth John D. , Boheler Kenneth R. , Sugden Peter H. , Poole-Wilson Philip A.
Published: June 2012

Background
Endothelin-1 (ET-1) has potent effects on cell growth and induces hypertrophy of cultured ventricular myocytes. Catecholamines increase expression of ET-1 mRNA by cultured myocytes. We investigated the role of endogenous ET-1 in catecholamine-induced hypertrophy in vivo by studying the effects of continuous norepinephrine infusion on physical and molecular markers of ventricular hypertrophy, ventricular and noncardiac expression of ET-1 mRNA, and the acute effects of bosentan, an orally active ET
A
and ET
B
receptor antagonist.

Methods and Results
Seventy male Sprague-Dawley rats (175 to 200 g) were divided into four groups: (1) sham-operated rats, (2) norepinephrine-infused rats (600 μg·kg
−1
·h
−1
by subcutaneous osmotic pump, up to 7 days), (3) sham-operated rats given bosentan, and (4) norepinephrine-infused rats given bosentan. Bosentan (100 mg/kg once daily) was administered by gavage for 6 days starting 1 day before operation. Norepinephrine caused increases in absolute ventricular weight and ratios of ventricular weight to body weight and ventricular RNA to protein. Ventricular expression of mRNAs for atrial natriuretic factor, skeletal α-actin, and β-myosin heavy chain, which in adult rat ventricle are indicators of hypertrophy, also increased. Ventricular expression of ET-1 mRNA was elevated in the norepinephrine group at 1, 2, and 3 days. By 5 days, this had fallen to control levels. In lung, kidney, and skeletal muscle, norepinephrine did not significantly increase expression of ET-1 mRNA. Bosentan attenuated norepinephrine-induced increases in ventricular weight, ratio of RNA to protein, and expression of skeletal α-actin mRNA and β-myosin heavy chain mRNA at 5 days, but it did not attenuate increased ventricular expression of atrial natriuretic factor mRNA.

Conclusions
These data suggest that endogenous ET-1 plays a direct role in mediating norepinephrine-induced ventricular hypertrophy in vivo.
Maximal Blood Lactate Level Acts as a Major Discriminant Variable in Exercise Testing for Coronary Artery Disease Detection in Men
Authors: Barthélémy Jean-Claude , Roche Frédéric , Gaspoz Jean-Michel , Geyssant André , Minini Pascal , Antoniadis Anestis , Page Éric , Wolf Jean-Éric , Wilner Claude , Isaaz Karl , Cavallaro Chantale , Lacour Jean-René
Published: June 2012

Background
The interpretation of exercise stress testing for coronary artery disease detection is affected by the many differences in chosen variables and mathematical methods. We conducted a prospective trial to evaluate a global muscle fatigue parameter—the blood lactate level achieved at maximal exercise—as a method of distinguishing between diseased and nondiseased coronary status.

Methods and Results
We evaluated 236 consecutive male patients without previous myocardial infarction who had been referred for the diagnosis of coronary artery disease. None of the patients had cardiomyopathy, severe cardiac heart failure, or valvular heart disease. Blood lactate concentration at maximal exercise was measured as well as other classic variables. Correlations between variables and coronary status as assessed by coronary arteriography were described using receiver operating characteristic (ROC) curves and logistic regression analysis. The first four most powerful variables (lactate level, maximal power output, exercise duration, and percentage of maximal predicted heart rate), which are directly representative of the global functional capacity, showed values of 0.777, 0.775, 0.760, and 0.740, respectively, by ROC curve analysis. Mean±SD blood lactate level at peak exercise reached 7.68±2.70 mmol/L in the 153 diseased and 10.56±2.75 mmol/L in the 83 nondiseased patients (
P
<.0001). After adjustment for other variables, blood lactate level remained a significant predictor of coronary artery disease by logistic regression analysis (adjusted odds ratio, 1.2; confidence interval, 1.04 to 1.4).

Conclusions
Global muscle fatigue as assessed by lactate levels in the blood at maximal exercise appears to be a powerful distinguisher of diseased and nondiseased coronary status.
Time-Related Normalization of Maximal Coronary Flow in Isolated Perfused Hearts of Rats With Myocardial Infarction
Authors: Nelissen-Vrancken H.J. Marjorie G. , Debets Jacques J.M. , Snoeckx Luc H.E.H. , Daemen Mat J.A.P. , Smits Jos F.M.
Published: June 2012

Background
In the present study, we investigated the time dependency and regional differences of the vascular adaptation of the myocardium after myocardial infarction (MI) in rats.

Methods and Results
MI was induced by total occlusion of the left anterior descending coronary artery. Time-dependent adaptation of the coronary vasculature was determined by histological staining of endothelial cells and measurement of basal and maximal coronary flow at days 0, 4, 7, 21, 35, and 90 after surgery in isolated retrogradely perfused hearts of sham-operated and infarcted rats. Cardiac function was determined during anterograde perfusion. In a separate group of experiments, regional myocardial flow was measured with radiolabeled microspheres in sham-operated and infarcted hearts to determine local differences in adaptation. Basal coronary flow was completely normalized within 7 days, whereas maximal coronary flow was not normalized until 35 days after MI. Normal growth, as observed in sham-operated hearts, resulted in a parallel increase in coronary flow and tissue mass from day 7 to 35 after surgery. In contrast, the increase in coronary flow was lower than the hypertrophic response in the right ventricles and septa of infarcted hearts, whereas a parallel increase in tissue mass and coronary flow was observed in the left ventricles of these hearts. These functional data were supported by structural data that showed the presence of numerous and dilated vessels, especially in the border zone of the infarcted and noninfarcted tissue.

Conclusions
These observations demonstrate that vessel growth, predominantly in the region adjacent to the infarcted zone, results in complete normalization of coronary vasodilatory capacity within 35 days after MI.
Analysis and Comparison of Operator-Specific Outcomes in Interventional Cardiology
Authors: Ellis Stephen G. , Omoigui Nowamagbe , Bittl John A. , Lincoff Michael , Wolfe Mark W. , Howell Georgiana , Topol Eric J.
Published: June 2012

Background
Medical consumers are increasingly requesting methods to discriminate among the results of different providers. Standards for appropriate modeling, risk adjustment, and evaluation (“scorecarding”) in this setting are not well developed, although such evaluation is being performed by the medical insurance industry and by several states in the United States. Our objectives were to develop and examine clinically meaningful methodology for assessing the operator-specific results for percutaneous coronary revascularization.

Methods and Results
From a multicenter database of patients treated since January 1, 1990, we used training and validation samples (n=4860) to develop several models for risk adjustment and applied them to 38 providers performing 25 to 523 procedures in the database. Models were developed using multivariable logistic regression techniques for combinations of the end points of death, myocardial infarction, bypass surgery, and procedural success. Models were evaluated for predictive accuracy by using receiver operating characteristic (ROC) analysis, for the capacity to discriminate between superior and inferior provider outcomes, and for subjectivity and concordance. Major complications occurred in 3.6% of patients. The area under the ROC curve (with perfect discriminatory accuracy, area=1.0; with no apparent accuracy, area=0.5) in the validation sample, and frequency of identification of operators with outcomes outside the 95% CI for the outcome in question for the models were for death, 0.85 and 7.9%; for death, Q-wave infarction, and bypass surgery, 0.77 and 13.2%; for death, all infarction, and bypass surgery, 0.66 and 10.5%; and for procedural success, 0.76 and 23.7%. For the models as a group, identification of outliers was inversely related to provider volume (
P
=.05). Models evaluating non–Q-wave infarction or requiring measurement of percent diameter stenosis were identified as being most susceptible to provider manipulation.

Conclusions
For percutaneous coronary revascularization, modeling to discriminate between provider outcomes is limited by the low incidence of major adverse events, subjectivity or susceptibility to manipulation of more frequently occurring adverse events, the generally modest predictive capacity of the models, and the low volume of individual provider treatments. Modeling will be most useful in the identification of providers with extremely poor outcomes and for discrimination between providers with very large procedural volume. Until improved understanding of the biological and mechanical correlates of major complications allows the development of more predictive models, interpretation of the results of scorecarding, particularly for low-volume providers, should be made with caution.
Clinical Significance of the Pulmonary Vasodilator Response During Short-term Infusion of Prostacyclin in Primary Pulmonary Hypertension
Authors: Raffy Olivier , Azarian Réza , Brenot François , Parent Florence , Sitbon Olivier , Petitpretz Patrick , Hervé Philippe , Duroux Pierre , Dinh-Xuan A. Tuan , Simonneau Gérald
Published: June 2012

Background
The short-term vasodilator response to prostacyclin (PGI
2
) in patients with primary pulmonary hypertension (PPH) is not only unpredictable but also extremely variable in magnitude. In this retrospective study, we attempted to evaluate in a nonselected population of patients with PPH the degree of vasodilatation achieved during short-term infusion of PGI
2
and to investigate whether patients with PPH differed in terms of baseline characteristics and prognoses, according to the level of vasodilatation achieved during initial testing with PGI
2
.

Methods and Results
Between 1984 and 1992, 91 consecutive patients with PPH underwent catheterization of the right side of the heart with a short-term vasodilator trial with PGI
2
(5 to 10 ng·kg
−1
·min
−1
). According to the level of vasodilatation achieved during PGI
2
infusion, patients were divided into three groups: nonresponding (NR, n=40), moderately responding (MR, n=42), and highly responding (HR, n=9) patients. All three groups were defined by a decrease in total pulmonary resistance index (TPRi) of <20%, between 20% and 50%, and >50%, respectively, relative to control values. Prolonged oral vasodilator therapy was subsequently started only in MR and HR patients. All patients had long-term oral anticoagulant therapy. The survival rate at 2 years (transplant recipients excluded) was significantly higher in HR patients compared with NR and MR patients (62% versus 38% and 47% survivors, respectively;
P
<.05). Comparisons between groups showed no significant differences in baseline hemodynamics or clinical characteristics except for a longer time between onset of symptoms and diagnosis (ie, first catheterization) of PPH in HR patients than in NR and MR patients (71±61 versus 35±34 and 21±21 months, respectively;
P
<.05).

Conclusions
In this study, patients with PPH exhibiting a decrease in TPRi >50% during short-term PGI
2
challenge at the time of diagnosis had longer disease evolutions and better prognoses than patients with a lower vasodilator response.
Ablation of ‘Incisional’ Reentrant Atrial Tachycardia Complicating Surgery for Congenital Heart Disease
Authors: Kalman Jonathan M. , VanHare George F. , Olgin Jeffrey E. , Saxon Leslie A. , Stark Stephen I. , Lesh Michael D.
Published: June 2012

Background
Intra-atrial reentrant tachycardia occurs frequently after surgery for congenital heart disease and is difficult to treat. We tested the hypotheses that intra-atrial reentrant tachycardia in patients who had undergone prior reparative surgery for congenital heart disease could be successfully ablated by targeting a protected isthmus of conduction bounded by natural and surgically created barriers and that entrainment techniques could be used to identify these zones.

Methods and Results
Eighteen consecutive patients with 26 intra-atrial reentrant tachycardias complicating surgery for congenital heart disease (9 atrial septal defect repair, 4 Fontan, 2 Mustard, 2 Senning, and 1 Rastelli procedure) underwent electrophysiological study and ablation attempts. Mapping of activation was facilitated by the deployment of catheters with multiple electrodes. Sites for ablation were sought that demonstrated entrainment with concealed fusion and at which the postpacing interval minus the tachycardia cycle length and the stimulus to P wave minus the activation time were <30 ms. These sites were considered to be within a narrow isthmus critical to the tachycardia mechanism. Anatomic barriers bordering the critical isthmus of conduction were identified on anatomic grounds, by the presence of areas of electrical silence or by the demonstration of split potentials signifying a line of block. Success was achieved in 15 patients with 21 arrhythmias. The median number of radiofrequency applications was 5. There was a wide range of activation times at successful sites (−30 to −250 ms). At a mean duration of follow-up of 17±8 months, 11 patients were asymptomatic and 9 did not require antiarrhythmia therapy.

Conclusions
Successful ablation of intra-atrial reentrant tachycardia complicating surgery for congenital heart disease may be achieved by creation of an ablative lesion in a critical isthmus of conduction bounded by anatomic barriers. This isthmus may be identified by the presence of entrainment with concealed fusion and an analysis of the relationship between the postpacing interval and the tachycardia cycle length and between the activation time and the stimulus time. Because this isthmus is invariably confined on at least one aspect by a surgical repair site that is of central importance to the tachycardia mechanism, we suggest that this type of arrhythmia be given the descriptive designation of “incisional reentry.”
Effective Regurgitant Orifice Area by the Color Doppler Flow Convergence Method for Evaluating the Severity of Chronic Aortic Regurgitation
Authors: Shiota Takahiro , Jones Michael , Yamada Izumi , Heinrich Russell S. , Ishii Masahiro , Sinclair Brian , Holcomb Scott , Yoganathan Ajit P. , Sahn David J.
Published: June 2012

Background
The aim of the present study was to evaluate dynamic changes in aortic regurgitant (AR) orifice area with the use of calibrated electromagnetic (EM) flowmeters and to validate a color Doppler flow convergence (FC) method for evaluating effective AR orifice area and regurgitant volume.

Methods and Results
In 6 sheep, 8 to 20 weeks after surgically induced AR, 22 hemodynamically different states were studied. Instantaneous regurgitant flow rates were obtained by aortic and pulmonary EM flowmeters balanced against each other. Instantaneous AR orifice areas were determined by dividing these actual AR flow rates by the corresponding continuous wave velocities (over 25 to 40 points during each diastole) matched for each steady state. Echo studies were performed to obtain maximal aliasing distances of the FC in a low range (0.20 to 0.32 m/s) and a high range (0.70 to 0.89 m/s) of aliasing velocities; the corresponding maximal AR flow rates were calculated using the hemispheric flow convergence assumption for the FC isovelocity surface. AR orifice areas were derived by dividing the maximal flow rates by the maximal continuous wave Doppler velocities. AR orifice sizes obtained with the use of EM flowmeters showed little change during diastole. Maximal and time-averaged AR orifice areas during diastole obtained by EM flowmeters ranged from 0.06 to 0.44 cm
2
(mean, 0.24±0.11 cm
2
) and from 0.05 to 0.43 cm
2
(mean, 0.21±0.06 cm
2
), respectively. Maximal AR orifice areas by FC using low aliasing velocities overestimated reference EM orifice areas; however, at high AV, FC predicted the reference areas more reliably (0.25±0.16 cm
2
,
r
=.82, difference=0.04±0.07 cm
2
). The product of the maximal orifice area obtained by the FC method using high AV and the velocity time integral of the regurgitant orifice velocity showed good agreement with regurgitant volumes per beat (
r
=.81, difference=0.9±7.9 mL/beat).

Conclusions
This study, using strictly quantified AR volume, demonstrated little change in AR orifice size during diastole. When high aliasing velocities are chosen, the FC method can be useful for determining effective AR orifice size and regurgitant volume.
Incidence and Clinical Significance of Multiple Consecutive, Appropriate, High-Energy Discharges in Patients With Implanted Cardioverter-Defibrillators
Authors: Villacastı́n Julián , Almendral Jesús , Arenal Angel , Albertos José , Ormaetxe José , Peinado Rafael , Bueno Héctor , Merino Jose L. , Pastor Agustı́n , Medina Olga , Tercedor Luis , Jiménez Francisco , Luis Delcán Juan
Published: June 2012

Background
Some patients with an automatic implantable cardioverter-defibrillator (ICD) suffer multiple appropriate, consecutive, high-energy discharges (MCDs) during follow-up. Such events might represent resistant ventricular arrhythmias and might have prognostic significance.

Methods and Results
Eighty consecutive patients with an ICD were followed up for up to 82 months (mean, 21±19 months). Thirty-eight patients had survived an out-of-hospital cardiac arrest and 42 had recurrent ventricular tachycardia. During follow-up, 16 patients had MCD (group A), 26 patients had episodes of single appropriate discharges (group B), and 38 patients had no appropriate discharges (group C). Group A patients had worse functional status (
P
=.001), lower left ventricular ejection fractions (LVEFs) (
P
=.001), and lower survival rates (log rank,
P
=.003) than the remaining two groups of patients. Cox analysis showed LVEF (
P
=.001) to be an independent predictor of MCD. Independent predictors of death or heart transplant were MCD (
P
=.001), female sex (
P
=.001), age (
P
=.001), history of cardiac arrest (
P
=.003), and functional status (
P
=.003). The only independent predictor of total mortality was female sex (
P
=.002). Independent predictors of cardiac death were MCD (
P
=.007) and female sex (
P
=.018). Independent predictors of arrhythmic death were age (
P
=.001), female sex (
P
=.02), and MCD (
P
=.023).

Conclusions
In patients with an ICD, the development of MCD is an independent predictor of cardiac and arrhythmic mortality. If this finding is confirmed in larger studies, it may help to identify patients in whom other therapeutic alternatives, ie, heart transplantation, should be considered during follow-up after ICD implantation.