bluuebunny/crossref_metadata_2025 huggingface dataset:
Mechanism of Ventricular Rate Control After Radiofrequency Modification of Atrioventricular Conduction in Patients With Atrial Fibrillation
Authors: Markowitz Steven M. , Stein Kenneth M. , Lerman Bruce B.
Published: June 2012

Background
Modification of atrioventricular (AV) conduction during atrial fibrillation (AF) may be achieved by radiofrequency ablation in the posteroseptal region of the tricuspid annulus. We tested the hypothesis that elimination of the posterior atrionodal input rather than direct damage to the compact AV node accounts for the decrease in ventricular rate after AV nodal modification.

Methods and Results
Twenty-four patients with the typical form of AV nodal reentrant tachycardia (AVNRT) underwent selective radiofrequency ablation of the slow AV nodal pathway in the posteroseptal tricuspid annulus. AF was induced before ablation (phase 1), 30 minutes after ablation (phase 2), and during follow-up 24 hours after ablation (phase 3), both with and without concurrent infusion of isoproterenol (4 μg/min). Successful elimination of AVNRT was achieved in all patients. During phase 3, 11 patients (46%) had residual dual pathway physiology. AV nodal Wenckebach cycle length (AVNW-CL) increased progressively during each phase of the protocol (356±72 versus 371±78 ms versus 432±104 ms,
P
<.0001), as did the effective refractory period of the AV node (279±60 versus 304±67 ms versus 372±56 ms,
P
<.0001). Minimal, mean, and maximal RR intervals during AF progressively increased immediately after ablation and 24 hours later (485±88 versus 533±116 ms versus 637±142 ms for mean RR,
P
<.0001). The changes in AVNW-CL, AV nodal effective refractory period, and ventricular response during AF were independent of residual dual pathway physiology after ablation. Similar observations were observed during isoproterenol infusion.

Conclusions
Modification of AV nodal conduction during AF by radiofrequency ablation in the posteroseptal tricuspid annulus is independent of the presence or absence of a residual slow AV nodal pathway. On the basis of these observations, the mechanism of AV nodal modification is consistent with elimination of the posterior atrionodal input.
Mechanism of Action Potential Prolongation by RP 58866 and Its Active Enantiomer, Terikalant
Authors: Jurkiewicz Nancy K. , Wang Jixin , Fermini Bernard , Sanguinetti Michael C. , Salata Joseph J.
Published: June 2012

Background
The class III antiarrhythmic agent RP 58866 and its active enantiomer, terikalant, are reported to selectively block the inward rectifier K
+
current, I
K1
. These drugs have demonstrated efficacy in animal models of cardiac arrhythmias, suggesting that block of I
K1
may be a useful antiarrhythmic mechanism. The symmetrical action potential (AP)–prolonging and bradycardic effects of these drugs, however, are inconsistent with a sole effect on I
K1
.

Methods and Results
We studied the effects of RP 58866 and terikalant on AP and outward K
+
currents in guinea pig ventricular myocytes. RP 58866 and terikalant potently blocked the rapidly activating delayed rectifier K
+
current, I
Kr
, with IC
50
s of 22 and 31 nmol/L, respectively. Block of I
K1
was ≈250-fold less potent; IC
50
s were 8 and 6 μmol/L, respectively. No significant block of the slowly activating delayed rectifier, I
Ks
, was observed at ≤10 μmol/L. The phenotypical I
Kr
currents in mouse AT-1 cells and
Xenopus
oocytes expressing
HERG
were also blocked 50% by 200 to 250 nmol/L RP 58866 or terikalant, providing further conclusive evidence for potent block of I
Kr
. RP 58866 ≤1 μmol/L and dofetilide increased AP duration symmetrically, consistent with selective block of I
Kr
. Only higher concentrations (≥10 μmol/L) of RP 58866 slowed the rate of AP repolarization and decreased resting membrane potential, consistent with an additional but substantially less potent block of I
K1
.

Conclusions
These data demonstrate that RP 58866 and terikalant are potent blockers of I
Kr
and prompt a reinterpretation of previous studies that assumed specific block of I
K1
by these drugs.
Pacing-Induced Chronic Atrial Fibrillation Impairs Sinus Node Function in Dogs
Authors: Elvan Arif , Wylie Kevin , Zipes Douglas P.
Published: June 2012

Background
We assessed the effects of pacing-induced chronic atrial fibrillation (AF) on sinus node function, intra-atrial conduction, and atrial refractoriness.

Methods and Results
In 15 mongrel dogs (20 to 30 kg), AV nodal block was produced by radiofrequency catheter ablation, and a ventricular-inhibited (VVI) pacemaker (Minix 8330, Medtronic) was implanted and programmed to pace at 80 pulses per minute. In 11 of these dogs, right atrial endocardial pacing leads were connected to a pulse generator (Itrel 7432, Medtronic) and set at a rate of 20 Hz to induce AF. Corrected sinus node recovery time, P-wave duration, 24-hour Holter ECG to assess AF duration, maximal heart rate in response to isoproterenol (10 μg/min), intrinsic heart rate after administration of atropine (0.04 mg/kg) and propranolol (0.1 mg/kg), and atrial effective refractory periods (ERPs) were obtained at baseline (EPS-1) and after 2 to 6 weeks (EPS-2) of VVI pacing alone (n=4) or VVI pacing and rapid atrial pacing (n=11). At EPS-2, corrected sinus node recovery time and P-wave duration were prolonged, maximal heart rate and intrinsic heart rate were decreased, atrial ERPs were shortened, and the duration of AF was increased significantly compared with EPS-1. These changes partially reversed toward baseline 1 week after conversion to sinus rhythm. Sinus node function and AF inducibility observed in the control dogs that underwent ventricular pacing alone (n=4) did not change.

Conclusions
Pacing-induced chronic AF induces sinus node dysfunction, prolongs intra-atrial conduction time, shortens atrial refractoriness, and perpetuates AF, changes that reverse gradually after termination of AF.
Common Mutation in Methylenetetrahydrofolate Reductase
Authors: Deloughery Thomas G. , Evans Adam , Sadeghi Abbas , McWilliams Jeffrey , Henner W. David , Taylor Lloyd M. , Press Richard D.
Published: June 2012

Background
Increased homocysteine levels are a risk factor for atherosclerosis and its sequelae. A common genetic mutation in methylenetetrahydrofolate reductase (MTHFR), an enzyme required for efficient homocysteine metabolism, creates a thermolabile enzyme with reduced activity. We determined the prevalence of this mutation in many subjects with and without vascular disease and related it to homocysteine and folate levels.

Methods and Results
DNA from 247 older subjects with vascular disease and 594 healthy subjects without vascular disease (in three different control groups) was screened for the MTHFR 677 C-to-T mutation. Within each group, 9% to 17% of the subjects were homozygous for this mutation, and the mutant allele frequency was 31% to 39%. The genotype distributions, homozygote frequencies, and allele frequencies did not differ significantly between the study groups. In the vascular disease subjects, despite significantly lower folate levels in MTHFR homozygotes, there was no significant difference in homocysteine levels among the MTHFR genotype groups. The negative slope of the regression line relating homocysteine and folate was significantly steeper for those with a homozygous MTHFR mutation compared with those without this mutation.

Conclusions
Although the thermolabile MTHFR mutation is very common, it does not appear to be a significant genetic risk factor for typical late-onset vascular disease. Because MTHFR homozygotes have increased homocysteine with low folate levels, this mutation may contribute to early-onset or familial vascular disease. The genotype dependence of the folate-homocysteine correlation further suggests that homozygotes for this mutation may have both an exaggerated hyperhomocysteinemic response to folic acid depletion and a better response to folic acid therapy.
Intimal Thickening Develops Without Humoral Immunity in a Mouse Aortic Allograft Model of Chronic Vascular Rejection
Authors: Chow Lawrence H. , Huh Susanna , Jiang Jifu , Zhong Robert , Pickering J. Geoffrey
Published: June 2012

Background
The major threat to the long-term survival of cardiac allograft recipients is the development of diffuse intimal thickening in the allograft coronary arteries through mechanisms that are poorly understood. Although antidonor antibodies have been associated with the development of this condition, a causal relationship has not been established.

Methods and Results
To determine whether humoral immune responses are necessary for the development of graft vascular disease, we performed abdominal aortic allografts from normal donor mice into different immunodeficient recipient mice: those lacking all donor-specific immune responses (severe combined immunodeficient [SCID] mice and recombination activating gene-1 [RAG-1]–deficient mice) and those lacking humoral immune responses alone owing to a targeted deletion of the joining region (J
H
) gene segments for the immunoglobulin heavy chain. At 6 to 9 weeks after transplantation, aortic allografts in normal immunocompetent recipients showed concentric intimal thickening extending the full length of the graft (percent luminal reduction, [%LR], 31.2±9.1 [mean±SD] and 38.5±3.6 in different donor-recipient strain combinations). In contrast, syngeneic (histocompatible) aortic grafts showed a normal-appearing vessel wall (%LR, 1.6±0.7). In both SCID and RAG-1–deficient recipients, aortic allografts showed a virtual absence of neointimal formation (%LR, 3.7±2.1 and 3.8±1.6 in SCID and RAG-1–deficient recipients, respectively), indicating a critical etiological role for alloimmune responses in this model. Importantly, allografts in J
H
-deficient mice showed marked intimal thickening (%LR, 35.7±7.9), with an appearance histologically indistinguishable from that of normal immunocompetent recipients.

Conclusions
Neointimal formation in graft vascular disease is critically dependent on alloimmune responses of the host. Humoral effector mechanisms, however, may not be required.
Depression, Psychotropic Medication, and Risk of Myocardial Infarction
Authors: Pratt Laura A. , Ford Daniel E. , Crum Rosa M. , Armenian Haroutune K. , Gallo Joseph J. , Eaton William W.
Published: June 2012

Background
There is suggestive evidence that depression increases risk of myocardial infarction (MI), but there are no prospective studies in which the measure of depression corresponds to clinical criteria. This study examines prospectively whether a major depressive episode increases the risk of incident MI and evaluates the role of psychotropic medication use in this relationship.

Methods and Results
The study is based on a follow-up of the Baltimore cohort of the Epidemiologic Catchment Area Study, a survey of psychiatric disorders in the general population. A history of major depressive episode, dysphoria (2 weeks of sadness), and psychotropic medication use were assessed in 1981, and self-reported MI was assessed in 1994. Sixty-four MIs were reported among 1551 respondents free of heart trouble in 1981. Compared with respondents with no history of dysphoria, the odds ratio for MI associated with a history of dysphoria was 2.07 (95% CI, 1.16 to 3.71), and the odds ratio associated with a history of major depressive episode was 4.54 (95% CI, 1.65 to 12.44), independent of coronary risk factors. In multivariate models, use of barbiturates, meprobamates, phenothiazines, and lithium was associated with an increased risk of MI, whereas use of tricyclic antidepressants and benzodiazepines was not. Among individuals with no history of dysphoria, only lithium use was significantly associated with MI.

Conclusions
These data suggest that a history of dysphoria and a major depressive episode increase the risk of MI. The association between psychotropic medication use and MI is probably a reflection of the primary relationship between depression and MI.
Effects of Dobutamine Stimulation on Myocardial Blood Flow, Glucose Metabolism, and Wall Motion in Normal and Dysfunctional Myocardium
Authors: Sun Karl T. , Czernin Johannes , Krivokapich Janine , Lau Yuk-Kong , Bo¨ttcher Morten , Maurer Gerald , Phelps Michael E. , Schelbert Heinrich R.
Published: June 2012

Background
This investigation examines the effects of inotropic stimulation on myocardial blood flow (MBF) and glucose metabolism (MRGlc) in dysfunctional myocardium through the use of positron emission tomography (PET).

Methods and Results
Nineteen patients with chronic coronary artery disease and 12 normal volunteers were studied with
13
N-ammonia,
18
F-deoxyglucose, and PET and with two-dimensional echocardiography at baseline and during intravenous dobutamine (5 to 10 μg/kg per minute). At rest, MBF in mismatch regions (n=10) averaged 0.53±0.19 mL/g per minute and increased by 41.4±46.6% (
P
=.01) during dobutamine, whereas in match regions (n=16) MBF was 0.28±0.09 mL/g per minute at rest without an increase during dobutamine (26.4±47.3%; NS). Myocardium with normal rest MBF was classified as normal remote (normal wall motion, n=8) or abnormal remote (abnormal wall motion, n=11). Dobutamine raised MBF similarly in normal subjects and in normal remote regions (by 82±85% and 84±42%,
P
<.01) but by only 33±34% in abnormal remote regions. MRGlc declined by 49±28% (
P
<.005) with dobutamine in the normal subjects, remained unchanged in normal and abnormal remote regions of the patients, but increased in mismatch and match regions (by 49±74% and 46±77%;
P
<.05). Wall motion improved with dobutamine only in mismatch and abnormal remote regions but not in match regions.

Conclusions
Blood flow–metabolism mismatch patterns are not consistently associated with a fixed downregulation of MBF; the increased contractile work in response to dobutamine stimulation is associated with an increase in MBF and a greater reliance on glucose utilization, possibly reflecting acute ischemia or alterations in substrate selection by chronically dysfunctional myocardium. Importantly, functionally impaired though normally perfused myocardium frequently exists in chronic coronary artery disease patients and may represent repetitively stunned or, more likely, remodeled left ventricular myocardium.
Hemodynamic Exercise Testing
Authors: Chomsky Don B. , Lang Chim C. , Rayos Glenn H. , Shyr Yu , Yeoh Tiong-Keat , Pierson Richard N. , Davis Stacy F. , Wilson John R.
Published: June 2012

Background
Peak exercise oxygen consumption (V̇
o
2
), a noninvasive index of peak exercise cardiac output (CO), is widely used to select candidates for heart transplantation. However, peak exercise V̇
o
2
can be influenced by noncardiac factors such as deconditioning, motivation, or body composition and may yield misleading prognostic information. Direct measurement of the CO response to exercise may avoid this problem and more accurately predict prognosis.

Methods and Results
Hemodynamic and ventilatory responses to maximal treadmill exercise were measured in 185 ambulatory patients with chronic heart failure who had been referred for cardiac transplantation (mean left ventricular ejection fraction, 22±7%; mean peak V̇
o
2
, 12.9±3.0 mL·min
−1
·kg
−1
). CO response to exercise was normal in 83 patients and reduced in 102. By univariate analysis, patients with normal CO responses had a better 1-year survival rate (95%) than did those with reduced CO responses (72%) (
P
<.0001). Survival in patients with peak V̇
o
2
of >14 mL·min
−1
·kg
−1
(88%) was not different from that of patients with peak V̇
o
2
of ≤14 mL·min
−1
·kg
−1
(79%) (
P
=NS). However, survival was worse in patients with peak V̇
o
2
of ≤10 mL·min
−1
·kg
−1
(52%) versus those with peak V̇
o
2
of >10 mL·min
−1
·kg
−1
(89%) (
P
<.0001). By Cox regression analysis, exercise CO response was the strongest independent predictor of survival (risk ratio, 4.3), with peak V̇
o
2
dichotomized at 10 mL·min
−1
·kg
−1
(risk ratio, 3.3) as the only other independent predictor. Patients with reduced CO responses and peak V̇
o
2
of ≤10 mL·min
−1
·kg
−1
had an extremely poor 1-year survival rate (38%).

Conclusions
Both CO response to exercise and peak exercise V̇
o
2
provide valuable independent prognostic information in ambulatory patients with heart failure. These variables should be used in combination to select potential heart transplantation candidates.
Epicardial Neodymium
Authors: Pfeiffer Dietrich , Moosdorf Rainer , Svenson Robert H. , Littmann Laszlo , Grimm Wolfram , Kirchhoff Paul G. , Lu¨deritz Berndt
Published: June 2012

Background
Surgical ablation of ventricular tachycardia (VT) after myocardial infarction has been reported by different endocardial approaches. The ventriculotomy may increase mortality of the procedure.

Methods and Results
We report on nine patients who suffered from recurrent VT in the late post–myocardial infarction period. Significant stenoses were detected in all patients. The mean left ventricular ejection fraction was 43.1±8.3%. Left ventricular scar (n=9) was seen. The mean NYHA class was 2.2±0.4. Sustained VT (mean cycle length, 293±52 ms) occurred spontaneously (n=9) and could be induced reproducibly. Catheter mapping detected a prematurity of −42±13 ms in six patients. Clinical VT was inducible during surgery in seven patients. Middiastolic potentials were detected from the epicardial surface (n=3), and premature potentials were found (n=8 with prematurity of −108±46 ms). Application of neodymium/yttrium/argon/garnet (Nd:YAG) laser energy to early epicardial activation terminated the arrhythmia (n=7). Ventriculotomy was not performed. Seven patients have been free of VT for a mean follow-up period of 17±11 months; one patient relapsed and was treated with an implantable cardioverter-defibrillator, as was a second patient with inducible VT after surgery.

Conclusions
Surgical Nd:YAG laser photocoagulation of VT on the epicardial surface of the heart in post–myocardial infarction patients without ventriculotomy is safe and has a high success rate. At the present time, this method is recommended in patients with sustained and tolerated VT who need bypass surgery. This is the first report on epicardial laser ablation of VT in post–myocardial infarction VT.
Quantitative Detection of Outlet Strut Separations in Bjo¨rk-Shiley Convexo-concave Mitral Valves
Authors: Powell Kimerly A. , Obuchowski Nancy A. , Mueller Klaus D. , LaPresto Eric , Hwang Charles G. , Hirsch Jamie Lee , Nissen Steven E. , Cornhill J. Fredrick
Published: June 2012

Background
As of January 31, 1995, 564 outlet strut fractures (OSFs) of Bjo¨rk-Shiley convexo-concave (BSCC) heart valves had been reported to the Shiley Heart Valve Research Center, of which approximately two thirds resulted in the death of the patient. Previous studies indicate that one leg of the outlet strut separates (single-leg separation, SLS) from the valve before the second leg breaks, which results in complete OSF. To identify those valves at risk of complete OSF, an in vivo radiographic imaging technique is being developed to evaluate the strut leg integrity. The goal of the present study was to develop an objective postprocessing technique to evaluate outlet strut leg integrity quantitatively in these cineradiographic images.

Methods and Results
Twenty-two sets (12 intact valves, 10 SLS valves) of cineangiographic images were obtained from individuals whose valve status was subsequently verified ex vivo. Several quantitative measures of SLS were evaluated to identify possible loss of metal or gaps in the SLS legs. Two of these measures, decrease in pixel intensity (DIPI) ratio and gap half-width, are diagnostic metrics of SLS: ie, the maximum likelihood estimate of the area under the receiver operating characteristic curve was 0.892 (SD, 0.066) for a model based on DIPI ratio and 0.802 (SD, 0.093) for gap half-width.

Conclusions
We have developed a postprocessing technique that can be used to objectively evaluate outlet strut integrity in cineradiographic images of BSCC heart valves. At an estimated specificity of 1.0, the estimated sensitivity of the objective review was comparable to that of a subjective expert review panel.
Echocardiographic and Radionuclide Pulmonary Blood Flow Patterns After Transcatheter Closure of Patent Ductus Arteriosus
Authors: Dessy Hugues , Hermus Joris P.S. , van den Heuvel Freek , Oei H.Y. , Krenning Eric P. , Hess John
Published: June 2012

Background
Transcatheter occlusion of patent ductus arteriosus (PDA) has been associated with protrusion of the occluder device into the left pulmonary artery (LPA). This study was conducted to evaluate the significance of occluder protrusion and its implications for potential obstruction of the LPA and associated decrease of left lung perfusion.

Methods and Results
Fifty-two patients underwent successful transcatheter PDA occlusion over a period of 5 years. In this study, 49 were reexamined between March and June 1995. In addition to clinical and echocardiographic examination, lung scintigraphy was performed. Protrusion into the LPA was present in 5 of 49 patients (10%). In these patients, maximal flow velocity in the LPA was significantly (
P
<.01) increased. Decreased left lung perfusion, defined as <40% of total pulmonary blood flow, was found in 7 of 49 patients (14%). Although mean left pulmonary perfusion was significantly (
P
=.02) decreased in patients with protrusion, there was considerable overlap with patients without protrusion, and only a weak correlation was found (
r
=−.35,
P
=.01) between flow-velocity and left lung perfusion.

Conclusions
Our results demonstrate that protrusion of the device in the LPA is an infrequent finding. If present, it is associated with increased maximal flow velocity in the LPA and diminished left lung perfusion. However, echocardiography and lung scintigraphy are weakly correlated: Increased maximal blood flow velocities in the proximal LPA proved to be a poor indicator of impaired left lung perfusion. Also, decreased perfusion occurs in the absence of echocardiographic evidence of device protrusion.
Beneficial Effects of RheothRx Injection in Patients Receiving Thrombolytic Therapy for Acute Myocardial Infarction
Authors: Schaer Gary L. , Spaccavento Leo J. , Browne Kevin F. , Krueger Karol A. , Krichbaum Daniel , Phelan John M. , Fletcher William O. , Grines Cindy L. , Edwards Suzanne , Jolly Michael K. , Gibbons Raymond J.
Published: June 2012

Background
RheothRx (poloxamer 188) is a surfactant with hemorheological and antithrombotic properties that reduces myocardial reperfusion injury in animal models of myocardial infarction. The purpose of the present study was to evaluate the safety and efficacy of adjunctive therapy with poloxamer 188 in patients receiving thrombolytic therapy for acute myocardial infarction.

Methods and Results
In this multicenter trial, we randomized 114 patients to a 48-hour infusion of poloxamer 188 or vehicle placebo beginning immediately after the initiation of thrombolytic therapy. Tomographic imaging with
99m
Tc sestamibi before reperfusion and again 5 to 7 days after the infarction was used to determine myocardium at risk for infarction, infarct size, and myocardial salvage. Radionuclide angiography at 5 to 7 days after infarction was used to measure left ventricular ejection fraction. The treated and control groups had comparable baseline characteristics, time to thrombolytic administration, and time to treatment with poloxamer 188 or placebo. Poloxamer 188−treated patients demonstrated a 38% reduction in median myocardial infarct size (25th and 75th percentile) compared with placebo (16% [7, 30] versus 26% [9, 43];
P
=.031), greater median myocardial salvage (13% [7, 20] versus 4% [1, 15];
P
=.033), and a 13% relative improvement in median ejection fraction (52% [43, 60] versus 46% [35, 60];
P
=.020). Poloxamer 188 treatment also resulted in a reduced incidence of reinfarction (1% versus 13%;
P
=.016). Poloxamer 188 was well tolerated without adverse hemodynamic effects or significant organ toxicity.

Conclusions
Adjunctive therapy with poloxamer 188 resulted in substantial benefit in this randomized trial, including significantly smaller infarcts, greater myocardial salvage, better left ventricular function, and a lower incidence of in-hospital reinfarction. Although the mechanisms are unproven, poloxamer 188 treatment may accelerate thrombolysis, reduce reocclusion, and ameliorate reperfusion injury.
Acute Hemodynamic Responses to Inhaled Nitric Oxide in Patients With Limited Scleroderma and Isolated Pulmonary Hypertension
Authors: Williamson D.J. , Hayward C. , Rogers P. , Wallman L.L. , Sturgess A.D. , Penny R. , Macdonald P.S.
Published: June 2012

Background
Inhaled nitric oxide (NO) is a selective pulmonary vasodilator that reduces pulmonary vascular resistance (PVR) in patients with primary pulmonary hypertension. Their responses to inhaled NO predict their responses to other vasodilators, such as prostacyclin, and provide an estimate of the “fixed” component of their increased PVR. Some patients with limited cutaneous systemic sclerosis develop isolated pulmonary hypertension with a similar clinical course. Therefore, we have measured the acute hemodynamic response to inhaled NO in such patients.

Methods and Results
Seven patients were studied during inhalation of increasing concentrations of NO (0 to 80 ppm). Complete hemodynamic data were collected on five patients. They demonstrated a selective, dose-dependent, and rapidly reversible fall in PVR (34%) and mean pulmonary artery pressure (17%). There was a nonsignificant increase in cardiac index but no change in mean arterial pressure or systemic vascular resistance. The mean right atrial pressure fell (27%), but there was no change in pulmonary artery occlusion pressure. Of the seven patients, five responded to inhaled NO (≤40 ppm) with a decrease in total pulmonary resistance of at least 20%.

Conclusions
Inhaled NO is an effective and selective pulmonary vasodilator in a significant number of patients with pulmonary hypertension associated with limited cutaneous systemic sclerosis. It may be useful in determining the potentially reversible contribution to the increased PVR and should be considered for patients with acute pulmonary vascular crisis.
Pleural and Pericardial Pressures Limit Fetal Right Ventricular Output
Authors: Grant Daniel A. , Walker Adrian M.
Published: June 2012

Background
The chest wall, lungs, and pericardium limit diastolic filling of the left ventricle in the fetus, neonate, and adult. To determine the effect that these tissues have on the fetal right ventricle (RV), we studied six fetal lambs (142 days of gestation).

Methods and Results
Pregnant ewes were anesthetized (ketamine and α-chloralose), and the fetuses were partially delivered by cesarean section. Fetuses were instrumented to record RV stroke volume, RV end-diastolic pressure (Prved), intrapericardial pressure (Pip), and pleural pressure. Prved was varied between 2 and 20 mm Hg under three conditions: initially with a closed chest and a closed pericardium (CCCP); subsequently with an open chest (chest wall and lungs retracted) and a closed pericardium (OCCP); and finally after the chest wall, lungs, and pericardium were retracted (OCOP). At equal Prved, stroke volume increased substantially when the chest wall and lungs were retracted from the heart and increased further on subsequent retraction of the pericardium (eg, at Prved of 9 mm Hg, stroke volume increased from 1.2±0.2 mL [mean±SEM] in the CCCP condition to 2.9±0.4 and 4.2±0.3 mL in the OCCP and OCOP conditions, respectively,
P
≤.05). The limitation of stroke volume in the CCCP and OCCP conditions occurred because Pip increased in an almost one-to-one fashion as Prved increased; as a consequence, RV preload (RV end-diastolic transmural pressure, Prved minus Pip) was relatively unchanged.

Conclusions
The chest wall–lung combination and the pericardium each significantly constrain the fetal RV and together limit RV stroke volume.
Class III Antiarrhythmic Effects of Zatebradine
Authors: Valenzuela Carmen , Delpo´n Eva , Franqueza Laura , Gay Pilar , Pe´rez One´sima , Tamargo Juan , Snyders Dirk J.
Published: June 2012

Background
Zatebradine is a bradycardic agent that inhibits the hyperpolarization-activated current (I
f
) in the rabbit sinoatrial node. It also prolongs action potential duration in papillary muscles in guinea pigs and in Purkinje fibers in rabbits. The underlying mechanism by which zatebradine induces this effect has not been explored, but it is likely to involve K
+
channel block.

Methods and Results
Cloned human cardiac K
+
delayed rectifier currents (hKv1.5) were recorded in
Ltk
−
cells transfected with their coding sequence. Zatebradine 10 μmol/L did not modify the initial activation time course of the current but induced a subsequent decline to a lower steady-state current level with a time constant of 109±16 ms. Zatebradine inhibited hKv1.5 with an apparent
K
D
of 1.86±0.14 μmol/L. Block was voltage dependent (electrical distance δ=0.177±0.003) and accumulated in a use-dependent manner during 0.5- and 1-Hz pulse trains because of slower recovery kinetics in the presence of the drug. Zatebradine reduced the tail current amplitude, recorded at −30 mV, and slowed the deactivation time course, which resulted in a “crossover” phenomenon when control and zatebradine tail currents were superimposed.

Conclusions
These results indicate that (1) zatebradine is an open-channel blocker of hKv1.5, (2) binding occurs in the internal mouth of the ion pore, (3) unbinding is required before the channel can close, and (4) zatebradine-induced block is use dependent because of slower recovery kinetics in the presence of the drug. These effects may explain the prolongation of the cardiac action potential and could be clinically relevant.
Modulation of the Hyperpolarization-Activated Current (I
f
) by Adenosine in Rabbit Sinoatrial Myocytes
Authors: Zaza Antonio , Rocchetti Marcella , DiFrancesco Dario
Published: June 2012

Background
Modulation of sinoatrial pacemaking by adenosine (Ado) in the absence of concomitant adrenergic stimulation (direct modulation) has been attributed to activation of a K
+
conductance. In the present study, we evaluated the direct effects of Ado on the pacemaking current I
f
and tested their interaction with those of acetylcholine (ACh).

Methods and Results
Rabbit sinoatrial myocytes were patch-clamped at 35°C in the presence of 1 mmol/L BaCl
2
and 2 mmol/L MnCl
2
. Ado (1 μmol/L) reversibly reduced I
f
by 33.1±5.7% of control (n=5;
P
<.05). Ado (1 μmol/L) reversibly shifted I
f
midactivation potential by −6.63±1.18 mV (n=4;
P
<.05). Fully activated I
f
conductance (0.262±0.037 versus 0.254±0.036 nS/pF; n=6, NS) and reversal potential (−17.35±0.99 versus −18.01±1.42 mV; n=6, NS) were not changed by 10 μmol/L Ado. The Ado receptor antagonist 8-PST (10 μmol/L) reversed the effect of 0.3 μmol/L Ado by 64.9±4.2% (n=6;
P
<.05). Ado maximally shifted the I
f
activation curve by −5.85 mV, with a half-maximal concentration of 0.0796 μmol/L (n=93). The shifts in I
f
activation induced by Ado (0.3 μmol/L) and ACh (1 μmol/L) separately were −4.89±0.05 and −8.84±0.51 mV, respectively; concomitant Ado and ACh superfusion shifted activation by −9.7±0.45 mV (NS versus ACh alone; n=9). Threshold Ado concentrations dose-dependently reduced the rate of spontaneous pacemaker activity (eg, −18.8±3.4% at Ado 0.03 μmol/L).

Conclusions
Submicromolar Ado directly inhibits I
f
and slows pacemaking in sinoatrial myocytes; the mode of I
f
inhibition is similar to that previously described for ACh. Thus, Ado may exert local modulation of sinus rate through signaling pathways similar to those used by ACh.
Computer Simulation of Systemic Circulation and Clot Lysis Dynamics During Thrombolytic Therapy That Accounts for Inner Clot Transport and Reaction
Authors: Anand Sriram , Diamond Scott L.
Published: June 2012

Background
We developed a computer model to predict lysis rates of thrombi for intravenous thrombolytic regimens based on the convective/diffusive penetration of reacting and adsorbing fibrinolytic species from the circulation into the proximal face of a dissolving clot.

Methods and Results
Solution of a one-compartment plasma model provided the dynamic concentrations of fibrinolytic species that served as inlet conditions for simulation of the one-dimensional spatiodynamics within a dissolving fibrin clot of defined composition. The model predicted the circulating levels of tissue plasminogen activator (TPA) and plasminogen levels found in clinical trials for various intravenous therapies. To test the model predictions under in vitro conditions, plasma clots were perfused with TPA (0.1 μmol/L) and plasminogen (1.0 μmol/L) delivered at constant permeation velocity of 0.1 or 0.2 mm/min. The model provided an accurate prediction of the measured lysis front movement. For TPA administration regimens used clinically, simulations predicted clot dissolution rates that were consistent with observed reperfusion times. For unidirectional permeation, the continual accumulation of adsorbing species at the moving lysis front due to prior rounds of solubilization and rebinding was predicted to provide for a marked concentration of TPA and plasmin and the eventual depletion of antiplasmin and macroglobulin in an advancing (≈0.25 mm thick) lysis zone.

Conclusions
Pressure-driven permeation greatly enhances and is a primary determinant of the overall rate of clot lysis and creates a complex local reaction environment at the plasma/clot interface. With simulation of reaction and transport, it becomes possible to quantitatively link the administration regimen, plasminogena activator properties, and thrombolytic outcome.
Selective Functional Properties of Dual Atrioventricular Nodal Inputs
Authors: Amellal Farid , Billette Jacques
Published: June 2012

Background
The atrioventricular node receives its activation signal from the low crista terminalis and low interatrial septum, the summation of which is believed to favor conduction. A functional asymmetry between the inputs is also believed to be involved in nodal reentrant rhythms. We studied the selective functional characteristics of nodal inputs and determined their role in nodal conduction, refractoriness, summation, and rate-dependent function.

Methods and Results
The nodal properties of recovery, facilitation, and fatigue were characterized with stimulation protocols applied with varying phases between the two inputs in isolated rabbit heart preparations. The effects of the input phase, nodal functional state, and input reference on the nodal conduction time, recovery time, and refractory periods were assessed with multifactorial ANOVAs. It was found that the phase of stimulation significantly affected nodal conduction time but not the refractory periods or the time constant of the recovery. Each input could show longer and shorter conduction time than the other depending on the stimulation phase, input reference, and coupling interval. These effects were similar for different nodal functional states. However, pacing and recording from the low crista resulted in similar conduction and refractory values than did pacing and recording from the low septum. Input summation did not increase the otherwise equal efficacy of individual input in activating the node. Nodal surface recordings confirmed this functional symmetry and equivalent efficacy of the inputs and showed that input effects were confined to the proximal node.

Conclusions
The two nodal inputs have equivalent functional properties and are equally effective in activating the rate-dependent portion of the node. Input interaction affects perinodal activation but not the rate-dependent nodal function.
Ventricular Rate During Atrial Fibrillation Before and After Slow-Pathway Ablation
Authors: Strickberger S. Adam , Weiss Raul , Daoud Emile G. , Goyal Rajiva , Bogun Frank , Man K. Ching , Morady Fred
Published: June 2012

Background
Radiofrequency catheter modification of AV conduction can be used to control the ventricular rate during atrial fibrillation both in the baseline state and during exercise. Slow-pathway ablation has been suggested to be the mechanism for this response. The purpose of this study was to determine the effect of slow-pathway ablation on the ventricular rate in atrial fibrillation during autonomic blockade and sympathetic stimulation in patients with AV nodal reentrant tachycardia (AVNRT).

Methods and Results
Thirty-five patients undergoing slow-pathway radiofrequency ablation for AVNRT were assigned to autonomic blockade (0.2 mg/kg propranolol and 0.04 mg/kg atropine; n=14) or isoproterenol (2 μg/min; n=21). Atrial fibrillation was induced before and after slow-pathway radiofrequency ablation. During autonomic blockade, the mean ventricular cycle length (448±34 versus 525±103 ms,
P
<.01) and maximum ventricular cycle length (640±105 versus 798±226 ms,
P
=.04) were prolonged after ablation, whereas the minimum ventricular cycle length did not change significantly (361±42 versus 403±83 ms,
P
=.05). During isoproterenol infusion, the mean ventricular cycle length (375±52 versus 390±61 ms,
P
=.2), maximum ventricular cycle length (520±88 versus 537±106 ms,
P
=.3), and minimum ventricular cycle length (307±59 versus 298±33 ms,
P
=.4) did not change significantly after slow-pathway ablation.

Conclusions
Slow-pathway ablation slows the ventricular rate during atrial fibrillation under conditions of autonomic blockade but not during sympathetic stimulation. Therefore, slow-pathway ablation alone cannot account for the clinical results obtained with radiofrequency modification of AV conduction in patients with atrial fibrillation.
Perioperative and Long-term Results With Mapping-Guided Subendocardial Resection and Left Ventricular Endoaneurysmorrhaphy
Authors: Rastegar Hassan , Link Mark S. , Foote Caroline B. , Wang Paul J. , Manolis Antonis S. , Estes N.A. Mark
Published: June 2012

Background
Surgical ablation of the arrhythmogenic focus in patients with life-threatening ventricular tachyarrhythmias can be curative. However, the surgical techniques have been plagued by a high perioperative mortality rate (averaging ≈12%). Reconstruction of the left ventricle may reduce mortality.

Methods and Results
Reconstruction of the left ventricle with a pericardial patch, or endoaneurysmorrhaphy, was performed with mapping-guided subendocardial resection for recurrent ventricular tachycardia in 25 patients over a 5-year period. Postoperatively, electrophysiological studies were conducted to assess the results of surgery, which were further evaluated during long-term follow-up with survival analyses. The study included 25 patients, 60±9 years of age, with coronary artery disease, discrete left ventricle aneurysms, and malignant ventricular tachyarrhythmias. Left ventricular ejection fraction was 24±6% preoperatively. Left ventricular endocardial mapping, endocardial resection, and endoaneurysmorrhaphy were performed in all patients. There was no operative or postoperative (30-day) mortality. Postoperative ventricular tachycardia was induced in 2 of the 25 patients (8%); left ventricular function increased to 32±9% (range, 19% to 52%). At a mean follow-up of 37±16 months (range, 6 to 65 months), there had been 6 deaths, including 1 sudden cardiac death, 2 congestive heart failure deaths, and 3 noncardiac deaths. Analysis of multiple variables failed to identify predictors of postoperative inducibility, sudden cardiac death, cardiac death, or total mortality.

Conclusions
Endoaneurysmorrhaphy with a pericardial patch combined with mapping-guided subendocardial resection frequently cures recurrent ventricular tachycardia with low operative mortality and improvement of ventricular function. Long-term follow-up demonstrates low sudden cardiac death rates.
Cycle Length Dependence of the Electrophysiological Effects of Increased Load on the Myocardium
Authors: Horner S.M. , Dick D.J. , Murphy C.F. , Lab M.J.
Published: June 2012

Background
Mechanoelectric feedback, the process by which changes in mechanical activity change the electrophysiology of the myocardium, has been linked to the genesis of arrhythmias. We investigated possible arrhythmogenic mechanisms by measuring changes in steady-state action potential duration and, more particularly, electrical restitution on a transiently applied load change, because action potential recovery may provide clues to arrhythmogenesis.

Methods and Results
Pigs were anesthetized and their hearts exposed. A snare was placed around the aorta, and the right atrium was paced. Ventricular pressure, monophasic action potential, and segment motion were recorded from the left ventricle. The action potential duration was measured before and during transient aortic occlusion. Electrical restitution curves were constructed from the records obtained during normal loading or during transient aortic occlusion. The degree of shortening of action potential duration on aortic occlusion decreased with decreases in the steady-state beat-to-beat interval (
P
=.0008). Control restitution curves had the typical configuration, with a rapid initial, usually monotonic, rise toward a plateau. Some curves showed a marginal “supernormal” section. Increased load reduced the action potential duration at the plateau of the restitution curve (9.4 ms,
P
<.0001) but increased the action potential duration at the start of the restitution curve (8.7 ms,
P
=.03). Increased loading increased the maximum slope of the electrical restitution curve by 32 ms/100 ms (
P
=.04). Increased load also increased the supernormal period of the electrical restitution curves.

Conclusions
Mechanoelectric feedback produces changes in rate-dependent electrophysiology, which could favor a matrix conducive to arrhythmogenesis.
Interaction Between Exercise Training and Ejection Fraction in Predicting Prognosis After a First Myocardial Infarction
Authors: Specchia Giuseppe , De Servi Stefano , Scire` Aldo , Assandri Jole , Berzuini Carlo , Angoli Luigi , La Rovere Maria Teresa , Cobelli Franco
Published: June 2012

Background
Although recent meta-analysis trials have shown that exercise training may improve survival after myocardial infarction, the mechanism of this beneficial effect is still unknown. The purpose of this study was to detect possible interactions between exercise training and predictors of prognosis after a first myocardial infarction.

Methods and Results
Patients with uneventful clinical courses after a first myocardial infarction were randomly assigned to a 4-week training period (125 patients, group 1) or to a control group (131 patients, group 2). Before randomization, all patients underwent a symptom-limited exercise test (28±2 days after myocardial infarction), 24-hour Holter monitoring, and coronary arteriography (31±3 days after the acute episode). After a mean follow-up period of 34.5 months, 18 patients had cardiac deaths (5 in group 1 and 13 in group 2). Multivariate analysis by Cox regression model showed that ejection fraction was the only independent prognostic indicator (
P
=.03). Evidence existed of an interaction between ejection fraction and exercise training, showing an effect of physical training on survival that depended on the patient's ejection fraction. Among patients with ejection fractions <41%, the relative risk for an untrained patient was 8.63 times higher than for a trained patient (
P
=.04), whereas for ejection fractions >40%, the estimated risks for trained and untrained patients were similar.

Conclusions
These data show that exercise training may prolong survival in post-myocardial infarction patients with depressed left ventricular function. A randomized trial in such patients seems warranted.
Effects of A
1
Adenosine Receptor Agonism Using
N
6
-Cyclohexyl-2′-
O
-Methyladenosine in Patients With Left Ventricular Dysfunction
Authors: Bertolet Barry D. , Anand Inder S. , Bryg Robert J. , Mohanty Pramod K. , Chatterjee Kanu , Cohn Jay N. , Khurmi Nardev S. , Pepine Carl J.
Published: June 2012

Background
The role of adenosine as a neuromodulator in heart failure was studied with the use of a selective adenosine A
1
receptor agonist,
N
6
-cyclohexyl-2′-
O
-methyladenosine (SDZ-WAG 994).

Methods and Results
Fifty patients with heart failure symptoms and moderate left ventricular systolic dysfunction had a balloon flotation catheter inserted. Patients received placebo or a single oral dose of either 1, 2, or 5 mg SDZ-WAG 994. After baseline measurements were obtained, hemodynamic and electrophysiological recordings were repeated at 30-minute intervals for the next 4 hours, then every 6 hours for the next 24 hours. Blood samples for norepinephrine, epinephrine, aldosterone, atrial natriuretic peptide, and plasma renin activity were drawn at baseline and 2 hours after drug administration. A
1
adenosine receptor agonism produced no important effects on systemic, right atrial, pulmonary artery, or pulmonary capillary wedge pressures; cardiac index; respiratory rate; or heart rate. The PR interval (a reflection of A
1
receptor–mediated activity) increased significantly in a stepwise fashion. At the 5-mg dose of SDZ-WAG 994, significant increases in atrial natriuretic peptide (216±137 to 407±146 pg/mL) and norepinephrine (477±243 to 618±237 pg/mL) levels were noted.

Conclusions
A
1
adenosine receptor agonism with SDZ-WAG 994 resulted in no significant hemodynamic changes at rest in this subset of patients with left ventricular dysfunction. An increase in the PR interval and atrial natriuretic peptide level, consistent with adenosine A
1
receptor–mediated activity, was observed. In addition, an increase in the norepinephrine level was observed, suggesting a role for adenosine as a peripheral nervous system neuromodulator.
Angiotensin II Related to Sodium Excretion Modulates Left Ventricular Structure in Human Essential Hypertension
Authors: Schmieder Roland E. , Langenfeld Matthias R.W. , Friedrich Anja , Schobel Hans P. , Gatzka Christoph D. , Weihprecht Horst
Published: June 2012

Background
Urinary sodium excretion and angiotensin II (Ang II), which are linked in a physiological feedback mechanism, have both been described to be blood pressure-independent determinants of left ventricular hypertrophy in essential hypertension. We conducted a study to investigate the interaction of sodium excretion with Ang II and its potential impact on myocardial hypertrophy.

Methods and Results
Sixty-eight patients (46 men and 22 women; mean age, 52±10 years) with untreated World Health Organization stage I to II essential hypertension were examined in a cross-sectional study. Left ventricular structure and function (two-dimensionally guided M-mode echocardiography), dietary sodium intake (as estimated by 24-hour urinary sodium excretion), and noninvasive ambulatory blood pressure over 24 hours (Spacelab 90207) were determined in parallel with plasma renin activity and plasma Ang II and serum aldosterone concentrations (radioimmunoassay). Twenty-four-hour urinary sodium excretion emerged as a strong correlate of relative wall thickness independent of 24-hour ambulatory blood pressure (partial
r
=.49,
P
<.001). Ang II concentrations were weakly correlated with septal wall thickness (
r
=.27,
P
<.05) and left ventricular mass (
r
=.25,
P
<.05). Patients with high Ang II concentrations in relation to sodium excretion had a greater left ventricular mass (318±77 versus 257±54 g,
P
<.02), posterior wall thickness (11.8±1.9 versus 10.5±0.8 mm,
P
<.02), and septal wall thickness (13.6±1.8 versus 11.9±1.3 mm,
P
<.01) than those with “relatively low” Ang II levels in relation to sodium excretion.

Conclusions
Impaired suppression of the renin-Ang II system appeared to act as a stimulus for myocardial hypertrophy in hypertensive patients.