bluuebunny/crossref_metadata_2025 huggingface dataset:
Plasma Endothelin Correlates With Antiendothelial Antibodies in Patients With Mixed Connective Tissue Disease
Authors: Filep János G. , Bodolay Edit , Sipka Sándor , Gyimesi Edit , Csipö István , Szegedi Gyula
Published: June 2012

Background
Elevated circulating levels of the vasoactive peptide endothelin-1 have been reported in various cardiovascular disorders. Because these conditions are frequently associated with endothelial dysfunction and damage and the vasoconstrictor effect of endothelin-1 is believed to be produced at the local vascular level, it is uncertain whether circulating endothelin-1 is a causal factor in enhanced vascular tone or instead a marker of endothelial injury.

Methods and Results
We tested whether elevated immunoreactive endothelin-1 could be detected by radioimmunoassay in plasma and whether endothelin-1 levels correlated with antiendothelial autoantibodies in patients with mixed connective tissue disease. Venous blood samples were collected from 21 patients in the morning after an overnight fast and before medication. The plasma immunoreactive endothelin-1 level was 2.7±0.5 pg/mL (range, 1.1 to 5.2 pg/ml; n=9) and 7.3±1.5 pg/mL (range, 2.8 to 20.7 pg/mL; n=12) in patients who had no antiendothelial antibodies and in patients with antiendothelial antibodies, respectively. These latter values were significantly (
P
<.001) increased compared with 10 age-matched healthy volunteers (2.0±0.3 pg/mL; range, 0.5 to 3.0 pg/mL). Plasma endothelin-1 level strongly correlated with antiendothelial antibodies (
r
s
=.836, n=21,
P
<.001), whereas there was no correlation between age, systolic and diastolic blood pressures, antinuclear antibodies, and duration of the disease and endothelin-1 values. The incidence of Raynaud’s phenomenon and angina did not differ significantly in patients with low and high endothelin-1 levels.

Conclusions
This study showed that mixed connective tissue disease is associated with elevated plasma immunoreactive endothelin-1 and that endothelin-1 levels significantly correlate with antiendothelial autoantibodies. These findings suggest that increases in plasma endothelin-1 concentration may be secondary to vascular injury and do not necessarily represent enhanced susceptibility to vasoconstriction.
New Variant of Human Tissue Plasminogen Activator (TPA) With Enhanced Efficacy and Lower Incidence of Bleeding Compared With Recombinant Human TPA
Authors: Benedict Claude R. , Refino Canio J. , Keyt Bruce A. , Pakala Rajbabu , Paoni Nicholas F. , Thomas G. Rodger , Bennett William F.
Published: June 2012

Background
The thrombolytic properties of a new variant of tissue plasminogen activator (TPA) (T103N, N117Q, KHRR 296-299 AAAA, or TNK-TPA) with longer plasma half-life, greater fibrin specificity, and increased resistance to inhibition by plasminogen activator inhibitor (PAI-1) were investigated in a rabbit thrombosed carotid artery model.

Methods and Results
After 60 minutes of arterial occlusion, TPA (1.5, 3.0, 6.0, or 9.0 mg/kg as a front-loaded IV infusion for 90 minutes; n=22) or TNK-TPA (0.38, 0.75, or 1.5 mg/kg as IV bolus; n=16) was administered. Blood flow through the artery was monitored for an additional 120 minutes. Bleeding was assessed by weighing the amount of blood absorbed in a gauze pad placed in a subcutaneous muscular incision. Recanalization rates and duration of recanalization were dose dependent. The doses that produced >80% recanalization rates with the longest duration of recanalization were 9.0 mg/kg for TPA and 1.5 mg/kg for TNK-TPA. At these doses, time to reperfusion (mean±SEM) was significantly faster (11±2 versus 23±7 minutes) and duration of recanalization longer (77±9 versus 51±18 minutes) for TNK-TPA compared with TPA (
P
<.025). Weights of the residual thrombi of the TPA group were greater than those of the TNK-TPA group (
P
=.004). Concentrations of fibrinogen, plasminogen, and α
2
-antiplasmin at 120 minutes were significantly higher for TNK-TPA–treated animals compared with TPA-treated animals (
P
<.001). ANOVA of the blood loss data determined that there were significant differences between thrombolytic agents but not between doses. After correction for saline controls, total blood loss for pooled doses of TPA and TNK-TPA was 82±6 mg and 40±4 mg, respectively (
P
<.01).

Conclusions
From these data, we conclude that TNK-TPA, given as a bolus, produces faster and more complete recanalization of occluded arteries in a rabbit experimental model compared with TPA, without increasing systemic plasmin generation or peripheral bleeding. In addition, we observed that TNK-TPA, unlike TPA, did not potentiate collagen-induced aggregation of platelets obtained from human plasma. This lack of effect on platelet aggregation by TNK-TPA potentially could be associated with a decreased risk of reocclusion after successful thrombolysis.
Radiofrequency Catheter Modification of Sinus Pacemaker Function Guided by Intracardiac Echocardiography
Authors: Kalman Jonathan M. , Lee Randall J. , Fisher Westby G. , Chin Michael C. , Ursell Phillip , Stillson Carol A. , Lesh Michael D. , Scheinman Melvin M.
Published: June 2012

Background
The sinus P wave arises from a pacemaker complex distributed along the crista terminalis. We investigated the feasibility of modification of sinus pacemaker function using graded applications of radiofrequency energy along the crista terminalis in dogs to achieve sinus rate control.

Methods and Results
Modification of sinus pacemaker function (30±5% reduction in intrinsic heart rate with retention of a normal P-wave axis) was performed in 11 dogs (group 1). Total sinus pacemaker ablation (>50% reduction in intrinsic heart rate with development of a low ectopic atrial or a junctional rhythm) was performed in 4 dogs (group 2). Intracardiac echocardiography was used to identify the crista terminalis as an anatomic marker of sinus node location. Sinus pacemaker modification caused a significant decrease in intrinsic heart rate (31% reduction,
P
<.001), heart rate responsiveness to isoproterenol (30% reduction,
P
<.0001), and average (20% reduction,
P
=.0002) and maximal (22% reduction,
P
=.0007) heart rates during 24-hour Holter monitoring. In 6 of the 11 animals, the targeted rate reduction of 30±5% was accurately achieved (mean, 31.6±4.3%;
P
<.001), and in the other 5, significant reduction of intrinsic heart rate was achieved but with greater variation (28.0±17.3%,
P
<.005). Corrected sinus node recovery time was not prolonged. After modification, earliest activation was mapped to the crista terminalis inferior to the lesion in all animals. In long-term follow-up (3.7±1.0 months), effects were maintained. After total sinus pacemaker ablation, junctional and low atrial escape pacemakers were unstable.

Conclusions
This study demonstrates the feasibility of modification of sinus pacemaker function for sinus rate control using catheter-based radiofrequency ablation guided by intracardiac echocardiography. This can be done while pacemaker stability and attenuated responsiveness to autonomic influences are preserved. Intracardiac echocardiography accurately defined the crista terminalis and provided a reliable means to anatomically localize catheter position in relation to the sinus node.
Influence of Epicardial Patches on Defibrillation Threshold With Nonthoracotomy Lead Configurations
Authors: Fotuhi Parwis C. , Ideker Raymond E. , Idriss Salim F. , Callihan Richard L. , Walker Robert G. , Alt Eckhard U.
Published: June 2012

Background
In previous studies, epicardial patch electrodes decreased transthoracic defibrillation efficacy. We studied the effects of two inactive epicardial 14-cm
2
titanium mesh patches on defibrillation energy requirements with nonthoracotomy internal lead configurations.

Methods and Results
A 6/6-millisecond biphasic shock waveform was delivered via several electrode configurations 10 seconds after ventricular fibrillation was initiated with a 60-Hz generator. In two series, a total of 16 dogs (weight, 23.3±2.4 kg) underwent an up-down defibrillation protocol. In the first series, the defibrillation threshold (DFT) was determined for each electrode configuration in the presence of two inactive epicardial patches. In the second series, DFTs were determined in the presence of an inactive right ventricular (RV) or left ventricular (LV) patch alone. For several nonthoracotomy lead configurations tested in the first 8 dogs, the mean±SD DFT energy increased 49% to 97% with two inactive patches on the heart compared with no patches on the heart as follows: RV to superior vena caval (SVC) electrode, from 8.9±2.6 to 18.0±14.3 J; RV to SVC plus subcutaneous array electrode, from 7.0±2.4 to 10.7±5.3 J; RV to subcutaneous pectoral plate electrode, from 6.2±1.3 to 11.4±4.0 J (
P
≤.05). The lowest DFT was achieved by defibrillating between the epicardial patches (3.8±3.3 J). The second series showed that DFT voltage requirements increased significantly for all three nonthoracotomy lead configurations with the inactive LV patch alone (
P
≤.05) but not with the inactive RV patch alone.

Conclusions
Inactive epicardial patches can significantly increase the defibrillation energy requirements for nonthoracotomy lead configurations. This negative impact may be due to an insulating effect of the patches and to a disturbance of the potential gradient field under the patches. If the same holds true in patients, these results have clinical implications. Functioning epicardial patch leads should be incorporated in the defibrillation lead system if already present. If the LV patch is nonfunctioning, such as because of a lead fracture, the marked increase in DFT due to an inactive LV patch calls for thorough DFT testing during surgery and, in selected patients, may necessitate patch removal to produce an effective transvenous-based system.
Identification of Anomalous Coronary Arteries and Their Anatomic Course by Magnetic Resonance Coronary Angiography
Authors: McConnell Michael V. , Ganz Peter , Selwyn Andrew P. , Li Wei , Edelman Robert R. , Manning Warren J.
Published: June 2012

Background
Anomalous coronary arteries are a rare but recognized cause of myocardial ischemia and sudden death. Identification currently requires x-ray angiography, which may have difficulty defining the three-dimensional course of the anomalous vessel. Magnetic resonance coronary angiography (MRCA) has been shown to image coronary artery anatomy noninvasively. We hypothesize that MRCA may be useful in the identification of anomalous coronary arteries and their anatomic course.

Methods and Results
Sixteen patients (9 men, 7 women, age 44 to 81 years) with anomalous aortic origins of the coronary arteries by conventional x-ray angiography underwent MRCA. Multiple images of the major epicardial coronary arteries were obtained by use of a breathhold, fat-suppressed, segmented–k space, gradient-echo technique by investigators blinded to all patient data. Anomalous coronary artery pathology, by x-ray angiography, included right-sided left main coronary artery (n=3), right-sided left circumflex artery (n=6), separate left-sided left anterior descending and left circumflex arteries (n=2), left-sided right coronary artery (n=4), and an anteriorly displaced right coronary artery (n=1). MRCA correctly identified the anomalous coronary vessel(s) in 14 of 15 patients. In 1 patient, the anomalous vessel was incorrectly identified, and in 2 patients the course of the anomalous vessel was not clearly seen; one of these was a nondominant, anomalous right coronary artery.

Conclusions
MRCA is a useful technique for the noninvasive identification of anomalous coronary arteries and their anatomic course.
Endothelial Control of Arterial Distensibility Is Impaired in Chronic Heart Failure
Authors: Ramsey M.W. , Goodfellow J. , Jones C.J.H. , Luddington L.A. , Lewis M.J. , Henderson A.H.
Published: June 2012

Background
Vascular tone is a determinant of conduit artery distensibility. The aim of this study was to establish whether endothelium-derived relaxing factor (EDRF) influences the distensibility of conduit arteries and whether endothelium-mediated increases in distensibility are impaired in chronic heart failure (CHF).

Methods and Results
Conduit artery distensibility was measured by two methods in healthy subjects and in nine patients with CHF caused by dilated cardiomyopathy. In the first method, pulse-wave velocity (PWV) was measured in the right common iliac artery at rest and during local infusions of acetylcholine (10
−7
to 10
−5
mol/L) or adenosine (2×10
−7
to 2×10
−5
mol/L), with correction for systemic effects. Acetylcholine induced concentration-dependent local reductions of PWV in healthy subjects (−5%, −15%, and −26%) but not in CHF patients (3%, 1% , −4%,
P
<.01), whereas adenosine induced similar reductions of PWV in healthy subjects and CHF patients. In the second method, brachial artery diameter, blood flow, and blood pressure were measured noninvasively by high-resolution ultrasound, continuous-wave Doppler, and photoplethysmography during reactive hyperemia in the hand and after sublingual glyceryl trinitrate (GTN, 400 μg). Hyperemic flow, similar in healthy subjects and CHF patients, was associated with increases in diameter and distensibility in healthy subjects (8.8% and 18.4%, respectively) but not in CHF patients (0.3% and −4.5%), whereas GTN induced similar effects in healthy subjects and CHF patients.

Conclusions
These data indicate that conduit artery distensibility is increased by acetylcholine and increased blood flow in healthy subjects but not in CHF patients, whereas the effects of adenosine and GTN on distensibility are preserved in CHF patients. This implies that EDRF-mediated increases in distensibility are impaired in CHF patients, thus adding to cardiac work.
Unchanged Protein Levels of SERCA II and Phospholamban but Reduced Ca
2+
Uptake and Ca
2+
-ATPase Activity of Cardiac Sarcoplasmic Reticulum From Dilated Cardiomyopathy Patients Compared With Patients With Nonfailing Hearts
Authors: Schwinger Robert H.G. , Böhm Michael , Schmidt Ulrich , Karczewski Peter , Bavendiek Udo , Flesch Markus , Krause Ernst-Georg , Erdmann Erland
Published: June 2012

Background
The aim of the present study was to investigate whether Ca
2+
uptake into the sarcoplasmic reticulum (SR) is altered in failing human myocardium resulting from dilated cardiomyopathy.

Methods and Results
Ca
2+
-ATPase (SERCA II) activity and Ca
2+
-dependent
45
Ca
2+
uptake (oxalate supported, steady state) in isolated vesicles from the SR (VSR) and in crude membrane preparations (CSR) (free Ca
2+
, 0.01 to 100 μmol/L) from nonfailing (donor hearts, n=13) and terminally failing (heart transplants, dilated cardiomyopathy, n=17) human myocardium were studied. In the same hearts, protein levels (Western blot analysis) and mRNA levels (Northern blot analysis) of SERCA II and phospholamban were measured. Increasing concentrations of Ca
2+
were followed by an increased Ca
2+
-ATPase activity and Ca
2+
uptake. Ca
2+
uptake activity and Ca
2+
-ATPase activity in CSR preparations from failing myocardium were significantly reduced compared with nonfailing hearts (Ca
2+
-ATPase, 163±8 and 125±7 nmol ATP/mg protein per minute for nonfailing tissue and failing tissue in New York Heart Association [NYHA] class IV, respectively; Ca
2+
uptake, 7.1±0.8 and 3.5±0.3 nmol/mg protein per minute in CSR from nonfailing and NYHA class IV hearts, respectively;
P
<.05). In contrast, no significant difference was measured in VSR. In the same preparations (CSR and VSR), both SERCA II and phospholamban levels (Western blot technique with monoclonal antibodies) were unchanged in failing compared with nonfailing tissue. mRNA expression relative to GAPDH mRNA for SERCA IIa and for phospholamban was significantly reduced in failing human myocardium (
P
<.05).

Conclusions
These findings provide evidence that in failing human myocardium caused by dilated cardiomyopathy, protein levels of SERCA II and phospholamban are unchanged even though mRNA levels for SERCA II and phospholamban and the SERCA II function are reduced compared with nonfailing myocardium.
Pericardial Effusion in AIDS
Authors: Heidenreich Paul A. , Eisenberg Mark J. , Kee Laura L. , Somelofski Carolyn A. , Hollander Harry , Schiller Nelson B. , Cheitlin Melvin D.
Published: June 2012

Background
Although pericardial effusion is known to be common among patients infected with HIV, the incidence of pericardial effusion and its relation to survival have never been described.

Methods and Results
To evaluate the incidence of pericardial effusion and its relation to mortality in HIV-positive subjects, 601 echocardiograms were performed on 231 subjects recruited over a 5-year period (inception cohort: 59 subjects with asymptomatic HIV, 62 subjects with AIDS-related complex, and 74 subjects with AIDS; 21 HIV-negative healthy gay men; and 15 subjects with non-HIV end-stage medical illness). Echocardiograms were performed every 3 to 6 months (82% had follow-up studies). Sixteen subjects were diagnosed with effusions (prevalence of effusion for AIDS subjects entering the study was 5%). Thirteen subjects developed effusions during follow-up; 12 of these were subjects with AIDS (incidence, 11%/y). The majority of effusions (80%) were small and asymptomatic. The survival of AIDS subjects with effusions was significantly shorter (36% at 6 months) than survival for AIDS subjects without effusions (93% at 6 months). This shortened survival remained significant (relative risk, 2.2,
P
=.01) after adjustment for lead time bias and was independent of CD4 count and albumin level.

Conclusions
There is a high incidence of pericardial effusion in patients with AIDS, and the presence of an effusion is associated with shortened survival. The development of an effusion in the setting of HIV infection suggests end-stage HIV disease (AIDS).
Prolongation of RV-PA Conduit Life Span by Percutaneous Stent Implantation
Authors: Powell Andrew J. , Lock James E. , Keane John F. , Perry Stanton B.
Published: June 2012

Background
Right ventricle–to–pulmonary artery (RV-PA) homografts and bioprosthetic conduits are commonly used to palliate various types of complex congenital heart disease. These conduits frequently develop progressive obstruction and require surgical replacement. This report reviews our experience implanting balloon-expandable stents to relieve conduit obstruction and delay reoperation.

Methods and Results
A retrospective review identified 44 patients who underwent placement of 48 stents in obstructed RV-PA conduits. Median patient age was 6.9 years (range, 7 months to 30 years), and median follow-up time was 14.2 months (range, 0 to 48 months). Stent implantation initially decreased the RV-PA pressure gradient from 61.0±16.9 to 29.7±11.9 mm Hg (
P
≤.001) and the right ventricular–to–systemic arterial pressure ratio from 0.92±0.17 to 0.63±0.20 (
P
≤.001). The diameter of the stenotic region expanded from 9.3±3.5 to 12.3±3.3 mm in the anteroposterior view (
P
≤.001) and from 6.6±2.9 to 10.9±2.5 mm in the lateral view (
P
≤.001). During the follow-up period, 2 patients had their stents redilated, 7 had additional conduit stents deployed, and 14 underwent surgical replacement of their conduits. Actuarial freedom from conduit reoperation was 65% at 30 months postprocedure. Seven patients were found to have fractured stents on follow-up, suggesting an important role for external compressive forces in conduit failure. Recatheterization in 16 patients a median of 11.8 months (3 to 48 months) postprocedure demonstrated hemodynamic evidence of recurrent obstruction despite sustained enlargement at the previously stented sites. Complications included stent displacement (n=1), bacterial endocarditis (n=1), and false aneurysm formation (n=1). One patient died awaiting conduit replacement surgery.

Conclusions
Stent implantation in obstructed RV-PA conduits results in significant immediate hemodynamic and angiographic improvement. In a subgroup of patients, the procedure prolongs conduit life span by several years and increases the interval between conduit reoperations. Recurrent obstruction is caused by external compression and progressive stenosis outside the stented region.
Peptido-Leukotrienes Are Potent Agonists of von Willebrand Factor Secretion and P-Selectin Surface Expression in Human Umbilical Vein Endothelial Cells
Authors: Datta Yvonne H. , Romano Mario , Jacobson Brian C. , Golan David E. , Serhan Charles N. , Ewenstein Bruce M.
Published: June 2012

Background
The peptido-leukotrienes (LTs) and lipoxins (LX) are produced by platelets through the transcellular conversion of leukocyte-derived LTA
4
at sites of vascular inflammation and injury, such as during coronary artery balloon angioplasty. We studied the actions of these eicosanoids on vascular endothelium.

Methods and Results
We found that stimulation of cultured human umbilical vein endothelial cells (EC) with LTC
4
and LTD
4
resulted in the release of high-molecular-weight multimers of von Willebrand factor (vWF) in a concentration- and time-dependent fashion, as measured by ELISA. Neither LXA
4
nor LXB
4
stimulated vWF release. LTC
4
and LTD
4
also stimulated a rapid increase in the surface expression of P-selectin indicated by increased binding of anti–P-selectin monoclonal antibody–coated beads. Fluorescence cytometry detected prolonged peaks of [Ca
2+
]
i
in EC in response to concentrations of thrombin and LTD
4
that induce near-maximal vWF secretion. In contrast, concentrations of LTC
4
that induce similar levels of vWF secretion produced only asynchronous oscillations of [Ca
2+
]
i
in most EC and rarely induced prolonged peaks of [Ca
2+
]
i
. Depletion of external Ca
2+
had no apparent impact on LT-stimulated [Ca
2+
]
i
transients and vWF secretion, implicating an intracellular pool as the source of this response. Staurosporine, sphingosine, and H-7 each had only modest effects on peptido-LT–induced vWF secretion, suggesting that protein kinase C is not a primary mediator of peptido-LT–induced exocytosis. Inhibitors of cyclooxygenase and platelet-activating factor had no effect on peptido-LT–mediated vWF secretion.

Conclusions
Through the induction of vWF secretion and P-selectin surface expression, peptido-LTs are likely to play an important role in the interrelated processes of hemostasis and inflammation.
Endothelin at Pathophysiological Concentrations Mediates Coronary Vasoconstriction via the Endothelin-A Receptor
Authors: Cannan Charles R. , Burnett John C. , Brandt Roland R. , Lerman Amir
Published: June 2012

Background
Endothelin-1 (ET-1) is an endothelium-derived vasoconstrictor peptide. Controversy persists regarding the predominant ET receptor that mediates coronary vasoconstriction at pathophysiological concentrations. The aim of the present study was to test the hypothesis that ET mediates local coronary vasoconstriction via the ET-A receptor at low concentrations of exogenous ET-1 designed to mimic pathophysiological states compared with pharmacological concentrations.

Methods and Results
ET-1 (group 1, n=5) or sarafotoxin, a specific ET-B receptor agonist (group 3, n=6) (each at 2 ng/kg per minute), was infused into the left circumflex coronary artery in the anesthetized dog. In group 2 dogs (n=5), the same dose of ET-1 was infused with 4 μg/kg per minute of the specific ET-A receptor antagonist FR-139317. In group 4 (n=5), the same dose of sarafotoxin was infused with 50 μg/kg per minute of the specific inhibitor of nitric oxide formation,
N
G
-monomethyl-
l
-arginine (L-NMMA). No difference in hemodynamics, coronary blood flow (CBF), coronary vascular resistance (CVR), or coronary artery diameter (CAD) was observed at baseline between the groups. In group 1, intracoronary ET-1 significantly decreased CBF and CAD in association with an increase in CVR. The percentage decrease in CBF and CAD in the group that received ET-1 and the ET-A receptor antagonist (group 2) was significantly less than that in the group that received ET-1 alone (group 1) (−12±3% versus −48±6% [
P
<.001] and −4.6±0.8 versus 1.0±0.3 [
P
<.05], respectively). The administration of the ET-A receptor antagonist (group 2) abolished the ET-mediated increase in CVR (7±5% versus 105±21%,
P
<.005). There was no significant effect on CBF, CVR, or CAD in the group receiving sarafotoxin alone (group 3). The administration of L-NMMA and sarafotoxin (group 4) resulted in a significant percentage decrease in CBF compared with the group that received sarafotoxin alone (−28±7% versus −8±2% [
P
<.05]).

Conclusions
The present study demonstrates that low concentrations of exogenous ET-1, which may mimic pathophysiological concentrations, result in coronary vasoconstriction mediated predominantly via the ET-A receptor because such vasoconstriction is significantly attenuated by blockade with FR-139317. The ET-B receptor may have a dual vasoconstrictive and vasodilatory effect.
Therapeutic Trial of Sympathomimetics in Three Cases of Complete Heart Block in the Fetus
Authors: Groves Alison M.M. , Allan Lindsey D. , Rosenthal Eric
Published: June 2012

Background
A total of 36 fetuses with isolated congenital complete heart block and structurally normal hearts have been seen in the department of fetal echocardiography since 1980. Although the prognosis is good in the majority of cases, those who develop intrauterine cardiac failure have a high mortality. The aim of this study was to investigate the contribution to management of sympathomimetic therapy by comparing two possible agents administered to the mothers.

Methods and Results
The effect of two sympathomimetic agents, isoprenaline and salbutamol, was compared in three patients with isolated complete heart block. Fetal heart rate and indexes of cardiac function were monitored during therapy. Maternal cardiovascular status was also regularly assessed. Dosage of isoprenaline increased from 1 to 12 μg/min, and salbutamol increased from 4 to 64 μg/min during the trial. No significant change was detected with isoprenaline therapy, but all fetuses showed an increase in heart rate and improvement in ventricular function with salbutamol. Salbutamol was maintained until delivery in one case with evidence of cardiac failure, with resolution of fetal hydrops. All three delivered in good condition close to term. Two of three required pacing in the neonatal period.

Conclusions
We conclude that salbutamol can be effective in the treatment of fetal complete heart block and should be considered in patients with this condition where there is evidence of deteriorating cardiac function.
Mechanisms of Lumen Enlargement After Excimer Laser Coronary Angioplasty
Authors: Mintz Gary S. , Kovach Julie A. , Javier Saturnino P. , Pichard Augusto D. , Kent Kenneth M. , Popma Jeffrey J. , Salter Lowell F. , Leon Martin B.
Published: June 2012

Background
The mechanisms of excimer laser coronary angioplasty (ELCA) have never been studied in human coronary arteries in vivo.

Methods and Results
ELCA was used to treat 202 lesions in 190 patients. Forty-nine lesions in 48 patients were studied by use of sequential (before and after ELCA and after adjunctive device therapy) intravascular ultrasound (IVUS). External elastic membrane (EEM), lumen, and plaque+media (P+M=EEM−lumen) cross-sectional areas (CSAs) and lesion arcs of calcium were measured before and after ELCA and after adjunct device use. Lumen improvement after ELCA (1.4±0.5 to 2.7±0.8 mm
2
) was the result of both tissue ablation (decrease in P+M CSA from 16.8±7.1 to 15.9±6.7 mm
2
,
P
<.0001) and vessel expansion (increase in EEM CSA from 18.2±7.1 to 18.6±6.8 mm
2
,
P
=.0245), with no change in calcium. The decrease in P+M CSA was 39% of the CSA of the laser catheter used. Dissections were present in 39% of lesions, 84% within superficial calcium; fibrocalcific deposits developed a “fragmented” appearance.

Conclusions
ELCA increased lumen CSA by both atheroablation and vessel expansion without calcium ablation. Superficial fibrocalcific deposits developed a characteristic fragmented appearance. These findings support both photoablation and forced vessel expansion as mechanisms of lumen enlargement and plaque dissection after ELCA.
Delayed Rectifier Channels in Human Ventricular Myocytes
Authors: Veldkamp Marieke W. , van Ginneken Antoni C.G. , Opthof Tobias , Bouman Lennart N.
Published: June 2012

Background
Previous studies have shown that in heart there are two kinetically distinct components of delayed rectifier current: a rapidly activating component (I

Kr

) and a more slowly activating component (I

Ks

). The presence of I

Kr

and/or I

Ks

appears to be species dependent. We studied the nature of the delayed rectifier current in human ventricle in whole-cell and single-channel experiments.

Methods and Results
Ventricular myocytes were obtained from hearts of patients with ischemic or dilated cardiomyopathy. Single-channel currents and whole-cell tail currents were recorded at negative potentials directly after return from a depolarizing step. Single-channel currents were measured in the cell-attached patch configuration with 140 mmol/L K
+
in the pipette. In the present study, we identified a voltage-dependent channel with a single-channel conductance of 12.9±0.8 pS (mean±SEM, n=5) and a reversal potential near to the K
+
equilibrium potential, suggesting that the channel is selective to K
+
ions. Channel activity was observed only after a depolarizing step and increased with the duration and amplitude of the depolarization, indicating time- and voltage-dependent activation. Activation at +30 mV was complete within 300 milliseconds, and the time constant of activation, determined in the whole-cell configuration, was 101±25 milliseconds (mean±SEM, n=4). The voltage dependence of activation could be described by a Boltzmann equation with a half-activation potential of −29.9 mV and a slope factor of 9.5 mV. The addition of the class III antiarrhythmic drug E-4031 completely blocked channel activity in one patch. No indications for the presence of I

Ks

were found in these experiments.

Conclusions
The conformity between the properties of I

Kr

and those of the K
+
channel in the present study strongly suggests that I

Kr

is present in human ventricle.
Nitric Oxide
Authors: Shen Weiqun , Hintze Thomas H. , Wolin Michael S.
Published: June 2012

Background
Nitric oxide (NO) is known to be an inhibitor of mitochondrial function. However, the physiological significance of endothelium-derived NO in the control of tissue respiration is not established.

Methods and Results
Tissue O
2
consumption by skeletal muscle slices of the triceps brachii of normal dogs was measured with a Clark-type O
2
electrode/tissue bath system at 37°C.
S
-Nitroso-
N
-acetylpenicillamine (SNAP), carbachol (CCh), or bradykinin (BK) decreased tissue O
2
consumption by 12±3% to 55±8%, 15±6% to 36±11%, or 21±5% to 42±4% at doses of 10
−7
to 10
−4
mol/L, respectively. The effects of both CCh and BK but not SNAP were eliminated by nitro-
l
-arginine (NLA, 10
−4
mol/L), consistent with SNAP decomposing to release NO and both CCh and BK stimulating endogenous NO production from
l
-arginine. Oxygen consumption was also decreased by 8-bromo-cGMP. The mitochondrial uncoupler dinitrophenol blocked the effects of 8-bromo-cGMP but only slightly altered those of SNAP, indicating that the major site of action of NO is the mitochondria. In normal, chronically instrumented, resting conscious dogs, blockade of NO synthase by NLA increased mean arterial pressure by 28±2.5 mm Hg and hind limb vascular resistance by 114±12% and decreased blood flow by 39±3%. Most important, NLA also increased O
2
uptake by 55±9% in hind limb skeletal muscle (
P
<.05), associated with decreases in P
o
2
and O
2
saturation and an increase in reduced hemoglobin in hind limb venous blood.

Conclusions
Our results indicate that NO release from vascular endothelial cells appears to play an important physiological role in the regulation of tissue mitochondrial respiration in skeletal muscle and perhaps other organ systems.
Prerequisite for Cardiac Aldosterone Action
Authors: Lombès Marc , Alfaidy Nadia , Eugene Emmanuel , Lessana Alessandro , Farman Nicolette , Bonvalet Jean-Pierre
Published: June 2012

Background
It has been proposed that aldosterone exerts direct effects on heart function, most notably on the development of myocardial fibrosis during ventricular hypertrophy in rat. Initial events in aldosterone action entail its binding to mineralocorticoid receptor (MR). Because MR displays similar affinities for aldosterone and glucocorticoids, the in vivo aldosterone selectivity of MR requires the presence of an enzyme, 11β-hydroxysteroid dehydrogenase (11-HSD), which metabolizes glucocorticoids into inactive derivatives. Although evidence exists for the presence of MR in rodent heart, no data are available for humans; moreover, the existence of cardiac 11-HSD is controversial.

Methods and Results
The heart samples used originated from tissue removed during cardiac surgery in nontransplant patients or from endocavitary biopsies done for the follow-up of heart transplantation. The expression of MR was examined at the mRNA and protein level by in situ hybridization with cRNA probes specific for human MR mRNA and by immunodetection with two specific anti-MR antibodies. 11-HSD catalytic activity was determined by measurement of the metabolic rate of tritiated corticosteroids by cardiac samples. In nontransplanted hearts, an in situ hybridization signal equivalent to that found in the whole kidney was present on cardiomyocytes. Specific immunolabeling of cardiomyocytes with anti-MR antibodies demonstrated the presence of the MR protein. Cardiac 11-HSD activity was detected (243±26 fmol · 30 min
−1
· mg protein
−1
) and was dependent on the cofactor NAD, not NADP, suggesting that it corresponds to the form of the enzyme specifically responsible for MR protection. In transplanted hearts that presented severe alterations, MR immunodetection was weaker and irregular, with no specific hybridization signal.

Conclusions
Our results demonstrate that MR is coexpressed with 11-HSD in human heart, which thus possesses the cellular machinery required for direct aldosterone action.
Adenosine-Induced Coronary Vasodilatation During Transesophageal Doppler Echocardiography
Authors: Redberg Rita F. , Sobol Youri , Chou Tony M. , Malloy Mary , Kumar Shantha , Botvinick Eli , Kane John
Published: June 2012

Background
Less invasive methods are replacing traditional invasive means of measuring coronary flow reserve (CFR). Transesophageal echocardiography (TEE) is becoming a useful tool for evaluation of coronary artery disease and has recently been used to measure CFR. This has always been done using dipyridamole, but adenosine has a greater vasodilator potency and more favorable kinetics than dipyridamole. This study was done to evaluate the hypothesis that adenosine is safe, rapid, and accurate in measuring coronary blood flow reserve by TEE Doppler.

Methods and Results
Forty-nine patients who had recently undergone angiography had a transesophageal echocardiogram with visualization of the coronary arteries and measurement of blood flow velocity in the left anterior descending coronary artery (LAD) during adenosine infusion of 0.14 mg/kg per minute. Angiograms were analyzed by quantitative coronary angiography, and significant stenosis was defined as >70% lumenal diameter narrowing. Thirty-nine of the 49 patients did not have a significant LAD stenosis (group 1); the remainder had significant disease (group 2). Good spectral Doppler recordings of blood flow velocity in the LAD were obtained in 41 of 46 patients (89%). There were no significant differences in baseline coronary blood flow velocities between the two groups. Hyperemic to baseline flow ratios were significantly higher in patients without significant LAD stenosis for peak (2.83±1.04 versus 1.78±0.36) and mean (2.68±0.96 versus 1.75±0.39) diastolic velocity. A CFR ratio >2.1 had a sensitivity of 86%, a specificity of 79%, a positive predictive value of 46%, and a negative predictive value of 96% for the absence of critical LAD stenosis. The infusion was well tolerated. It had to be prematurely terminated in only 3 patients (6.5%), and they were asymptomatic. No patient experienced chest pain, palpitations, or flushing. Intraobserver and interobserver variabilities were low, and reproducibility of data was good (<4%).

Conclusions
Adenosine Doppler TEE is an effective, rapid, safe, and superior means of measuring CFR ratio. This method is convenient for serial measurements of CFR as well as in clinical settings such as evaluation of syndrome X, cardiomyopathy, and aortic regurgitation.
Cardiac Allograft Vasculopathy
Authors: Hosenpud Jeffrey D. , Everett John P. , Morris Tony E. , Mauck Kimberly A. , Shipley Gary D. , Wagner Cynthia R.
Published: June 2012

Background
Cardiac allograft vasculopathy (CAV) is an accelerated form of coronary artery disease responsible for the majority of late deaths after cardiac transplantation. Although most consider this complication a manifestation of chronic allograft rejection, it has not been established whether this disease is a consequence of humoral or cell-mediated alloreactivity.

Methods and Results
Human aortic endothelial cells (HAECs) were isolated from donor aortas obtained at the time of organ acquisition for 52 cardiac allograft recipients. Serum and peripheral blood mononuclear cells were obtained from these 52 allograft recipients at several time points during the first year after transplantation. Lymphocyte proliferation (LP) in response to donor-specific HAECs and alloantibody binding to interferon-γ–treated donor-specific HAECs were performed and correlated with clinical parameters, including HLA matching, acute cellular rejection, and coronary artery disease on surveillance angiography. Ten of the 52 patients studied had angiographic or autopsy evidence of coronary artery disease in the first posttransplantation year (CAV+ group). The CAV+ group had higher LP responses to their donor HAECs at 1 week, 3 months, and 6 months after transplantation compared with the CAV− group (1 week: 1439±222 versus 824±141 counts per minute [cpm],
P
=.026; 3 months: 1282±388 versus 884±94 cpm,
P
=.07; 6 months: 2504±635 versus 1540±209 cpm,
P
=.036; CAV+ versus CAV−, respectively). Only 8 of the 52 patients had donor-specific alloantibodies, and there was no relation between antibody presence and CAV. Other clinical parameters that correlated with CAV included the level of HLA-DR mismatch and the presence of late acute rejection.

Conclusions
CAV is associated with donor-specific cell-mediated alloreactivity to vascular endothelium. Humoral immunity does not appear to have a major role in this disease.
Mechanoelectrical Interaction in Tetralogy of Fallot
Authors: Gatzoulis Michael A. , Till Jan A. , Somerville Jane , Redington Andrew N.
Published: June 2012

Background
Life-threatening ventricular arrhythmia and sudden death remain serious late complications after tetralogy of Fallot repair. Nevertheless, there remains no clear way of predicting which patients are at risk.

Methods and Results
The study population included a total of 178 adult survivors (mean follow-up, 21.4 years) of tetralogy of Fallot repair who were currently attending our clinic. Mechanoelectrical relations were sought in 41 of the patients (mean follow-up, 23.6 years) who were operated on by one surgeon and who were prospectively studied with a 12-lead ECG, chest radiography, and two-dimensional and Doppler echocardiography. Nine patients (mean follow-up, 17 years) from the total group of 178 were identified as having had sustained ventricular tachycardia (8 with near-miss sudden death), and their ECGs, Holter monitor readings, electrophysiological studies, and chest radiographs were reviewed. The case notes of an additional 4 patients with postoperative sudden cardiac death also were available for review. QRS duration in the 41 patients in whom mechanoelectrical interaction was sought ranged between 90 and 200 milliseconds and correlated with cardiothoracic ratio (CTR) on chest radiography (
r
=.64,
P
<.001) and with right ventricular size on echocardiography (
r
=.43,
P
<.02). Twenty of the 41 patients had restrictive right ventricular Doppler physiology (reduced ventricular compliance) with mean QRS duration of 129.3±20 milliseconds and mean CTR of 0.51±0.03. The remaining 21 patients with no evidence of right ventricular restriction had prolonged QRS duration of 157.5±13.2 milliseconds (
P
<.001) and CTR of 0.55±0.04 (
P
<.04) compared with the restrictive. In the 9 patients with ventricular tachycardia, the QRS duration ranged from 180 to 230 milliseconds (mean, 198.9±17.6 milliseconds), and the CTR ranged from 0.54 to 0.9 (mean, 0.67±0.12) (
P
<.0001 and
P
<.01, respectively, compared with patients without life-threatening arrhythmias). All patients with documented sustained ventricular tachycardia and the 4 patients with sudden death had a QRS duration of ≥180 milliseconds (100% sensitivity).

Conclusions
Chronic right ventricular volume overload after tetralogy of Fallot repair is related to diastolic function and correlates with QRS prolongation. The risk of symptomatic arrhythmia is high when marked right ventricular enlargement and QRS prolongation develop. A QRS duration on the resting ECG of ≥180 milliseconds is the most sensitive predictor of life-threatening ventricular arrhythmias yet described.
Arrhythmias and Death After Coronary Artery Occlusion in the Rat
Authors: Opitz Christian F. , Mitchell Gary F. , Pfeffer Marc A. , Pfeffer Janice M.
Published: June 2012

Background
The onset of acute myocardial infarction (MI) is accompanied by a rapid increase in electrical instability and often fatal ventricular arrhythmias. The aim of this study was to assess the continuous arrhythmia profile during the initial 48 hours after coronary artery ligation in the rat in relation to time course, mortality, and infarct size.

Methods and Results
Continuous ECG recordings were obtained in 26 conscious, untethered rats for 24 hours before and 48 hours after coronary ligation by use of an implantable telemetry system. All episodes of ventricular tachycardia and fibrillation were counted and their durations summed. Infarct size was measured at 48 hours after MI or after spontaneous death. After ligation, two distinctly active arrhythmogenic periods developed (A1, 0 to 0.5 hours; A2, 1.5 to 9 hours), each followed by a quiescent phase of low ectopy (Q1, 0.5 to 1.5 hours; Q2, 10 to 48 hours). The total mortality rate of 65% was found within the two active periods, with 13 of 15 deaths occurring in A2. Rats with larger infarcts (≥50%) and nonsurvivors tended to have increased arrhythmia frequency and duration compared with both animals with smaller MIs (<50%) and survivors.

Conclusions
Two distinct arrhythmogenic periods occur in rats with acute MI that may be caused by different mechanisms and correspond to the bimodal arrhythmia time course seen in dogs and humans after acute MI. Telemetric monitoring of the ECG in the conscious rat after infarction will be useful in assessment of the differential effects of therapeutic interventions on these two arrhythmogenic periods and in the study of potential mechanisms for the spontaneous resolution of ventricular ectopy and risk of sudden death.
Elevation of Circulating and Ventricular Adrenomedullin in Human Congestive Heart Failure
Authors: Jougasaki Michihisa , Wei Chi-Ming , McKinley Linda J. , Burnett John C.
Published: June 2012

Background
Adrenomedullin (ADM) is a newly discovered vasodilating and natriuretic peptide that may play an important role in cardiorenal regulation. Although ADM was originally isolated from human pheochromocytoma, ADM-like immunoreactivity has also been widely detected in various tissues, including the cardiovascular system.

Methods and Results
In view of reports that ADM circulates in the body and that ADM gene and ADM-like immunoreactivity are present in the heart, the present study was designed to determine the plasma concentration of ADM in healthy subjects and in patients with congestive heart failure (CHF) and to investigate the immunohistochemical presence and localization of ADM in normal and failing human hearts. Plasma ADM concentration was 13.2±2.3 pg/mL in healthy subjects (n=11) and increased to 47.3±6.7 pg/mL in patients with CHF (n=11,
P
<.05 versus normal). Human cardiac tissues were obtained from five patients with end-stage CHF undergoing cardiac transplantation. Five normal donor hearts that were used for cardiac transplantation served as sources for normal atrial tissues. Normal ventricular myocardium was also obtained by endomyocardial biopsy from the right ventricles of these donor hearts immediately before cardiac transplantation. Positive immunostaining was detected within the myocardia in both atria and ventricles of healthy and severely failing human transplanted hearts and was more intense in the atria than in the ventricles. Although there were no significant differences in the intensity of immunoreactivity between normal and failing atria, ADM immunoreactivity was significantly more intense in the ventricular myocytes from failing hearts compared with normal hearts.

Conclusions
The present study demonstrates that plasma concentration of ADM is increased in patients with CHF and that ADM is present in the human heart. ADM immunoreactivity is markedly increased in the failing human ventricle, suggesting that ventricular ADM expression may be influenced by the circumstances associated with CHF. This supports a potential role for this newly identified vasoactive and natriuretic peptide, ADM, in the neurohumoral activation that characterizes human CHF.
Relation Between the Deletion Polymorphism of the Angiotensin-Converting Enzyme Gene and Late Luminal Narrowing After Coronary Angioplasty
Authors: Hamon Martial , Bauters Christophe , Amant Carole , McFadden Eugène P. , Helbecque Nicole , Lablanche Jean-Marc , Bertrand Michel E. , Amouyel Philippe
Published: June 2012

Background
The insertion/deletion
(I/D)
polymorphism of the angiotensin-converting enzyme
(ACE)
gene has been implicated in the pathogenesis of coronary artery disease. The deletion allele is strongly associated with the level of circulating ACE and is a potent risk factor for myocardial infarction. Recently, the deletion allele was also associated with the occurrence of visually diagnosed restenosis after percutaneous transluminal coronary angioplasty (PTCA) in a selected population of patients with acute myocardial infarction.

Methods and Results
We investigated the influence of the ACE
I/D
polymorphism on the occurrence of restenosis after PTCA with the use of quantitative coronary angiography. ACE
I/D
genotypes were characterized in 118 consecutive patients who had one-vessel disease and were undergoing systematic angiographic follow-up. Coronary angiograms were analyzed before and after PTCA and at follow-up (7.4±3.0 months). Before PTCA, there were no clinical or angiographic differences among the three groups of genotypes (
DD
, n=39;
ID
, n=62;
II
, n=17). After PTCA, the mean differences in minimal luminal diameter between post-PTCA and pre-PTCA angiograms (acute gain) were identical in the three groups, as was the mean percent residual stenosis. At follow-up angiography, the mean difference in minimal coronary luminal diameter between post-PTCA and follow-up angiograms (late loss) was not significantly different in the three groups of genotypes. The percentage of patients with restenosis defined as a >50% stenosis was identical in the three groups.

Conclusions
In this quantitative study, the
I/D
polymorphism of the
ACE
gene had no influence on the occurrence of restenosis after coronary angioplasty.