bluuebunny/crossref_metadata_2025 huggingface dataset:
Cyclosporine impairs release of endothelium-derived relaxing factors in epicardial and resistance coronary arteries.
Authors: Sudhir K , MacGregor J S , DeMarco T , De Groot C J , Taylor R N , Chou T M , Yock P G , Chatterjee K
Published: June 2012

BACKGROUND

Cyclosporin A is reported to impair endothelium-mediated vasorelaxation and induce endothelin release in some noncoronary vascular beds. We wished to determine whether acute cyclosporine administration induces endothelial dysfunction in coronary conductance or resistance arteries.

METHODS AND RESULTS

We examined the effect of intracoronary acetylcholine, N omega-nitro-L-arginine methyl ester (L-NAME), L-arginine, nitroglycerin, and adenosine before and after acute cyclosporine administration (3 mg/kg IV over 30 minutes) in anesthetized dogs. Flow velocity was measured with a 0.014-in Doppler wire to assess resistance vessel responses, and epicardial coronary lumen area was simultaneously measured with a 4.3F, 30-MHz imaging catheter inserted over the Doppler wire. In 6 dogs, acetylcholine-induced increase in flow velocity was attenuated by cyclosporine in vehicle (137% to 55% at 10(-5) mol/L, P < .001), as was acetylcholine-induced epicardial vasodilation (14.1% to 6.7% at 10(-5) mol/L, P < .001). Vasodilation in response to intracoronary nitroglycerin (200 micrograms) and adenosine (6 mg) were unchanged by cyclosporine. Epicardial vasoconstriction with L-NAME (10(-4) mol/L) was reduced by cyclosporine (Pre, 7.4 +/- 0.9%; Post, 2.6 +/- 1.2%; P = .04), but L-arginine (10(-4) mol/L) had no effect after cyclosporine. In another 5 dogs, pure cyclosporine impaired acetylcholine-induced vasodilatation to the same degree as cyclosporine in vehicle (Cremophor); vehicle infusion did not impair endothelial function. In 5 more dogs, cyclosporine did not increase either arterial or coronary sinus concentrations of endothelin-1.

CONCLUSIONS

The present study shows that cyclosporine acutely impairs release of endothelium-derived relaxing factor in canine conductance and resistance coronary arteries and provides evidence for decreased epicardial nitric oxide release after cyclosporine. The potential contribution of acute cyclosporine-induced coronary endothelial dysfunction to posttransplant vasculopathy needs further study.
Effect of exercise on left ventricular mechanical efficiency in conscious dogs.
Authors: Nozawa T , Cheng C P , Noda T , Little W C
Published: June 2012

BACKGROUND

We studied the effect of exercise (7.2 to 8.0 km/h) on the efficiency of the conversion of metabolic energy to external work or stroke work (SW) by the left ventricle (LV).

METHODS AND RESULTS

Energy use was calculated from LV myocardial oxygen consumption per beat (MVO2). LV volume was calculated from orthogonal dimensions and coronary flow measured with ultrasonic flow probes. The total mechanical energy of the LV was calculated as the pressure-volume area (PVA). At rest, the MVO2-PVA point fell on the MVO2-PVA relation determined by steady-state changes in arterial pressure produced by graded infusions of phenylephrine. Exercise increased the slope (Ees) of LV end-systolic pressure-volume (PV) relation by 29%. During exercise, the MVO2-PVA point shifted to the right only slightly above the control MVO2-PVA relation by 0.007 +/- 0.005 mL O2.beat-1.100 g LV-1. Despite the increase in ventricular contractility with exercise, the PVA/MVO2 ratio was unchanged because of the marked increase in PVA. During exercise, the transmission of total mechanical energy to external work (SW/PVA) increased from 65 +/- 5% to 72 +/- 4% (P < .01) as the ratio of the arterial end-systolic elastance to Ees decreased from 1.1 +/- 0.2 to 0.8 +/- 0.1 (P < .05). Thus, LV mechanical efficiency (SW/MVO2 = SW/PVA.PVA/MVO2) improved from 12.9 +/- 1.5% to 14.3 +/- 1.1% (P < .05) during exercise.

CONCLUSIONS

Exercise increases the efficiency of conversion of metabolic energy to external work by the LV due to alteration in LV arterial coupling resulting in increased production of mechanical energy and enhanced transmission of mechanical energy to external work, which more than offsets any increased metabolic cost of the enhanced contractility.
Observations of ventilation during resuscitation in a canine model.
Authors: Chandra N C , Gruben K G , Tsitlik J E , Brower R , Guerci A D , Halperin H H , Weisfeldt M L , Permutt S
Published: June 2012

BACKGROUND

Fear of infection limits the willingness of laymen to do cardiopulmonary resuscitation (CPR). This study assessed the time course of change in arterial blood gases during resuscitation with only chest compression (no ventilation) in an effort to identify the time for which ventilation could be deferred.

METHODS AND RESULTS

Aortic pressures and arterial blood gases were monitored in seven 20- to 30-kg dogs in ventricular fibrillation (VF) at 2-minute intervals during chest compression alone (no ventilation) at 80 to 100 compressions per minute. Before the induction of ventricular fibrillation, all animals were intubated and ventilated with room air, 10 mL/kg. The endotracheal tube was removed when VF was induced. Pre-VF arterial pH, PCO2, and O2 saturation were (mean +/- SEM) 7.39 +/- 0.02, 27.0 +/- 1.5 mm Hg, and 97.5 +/- 0.5%, respectively, with aortic pressures being 143.2 +/- 5.7/116.2 +/- 4.6 mm Hg. At 4 minutes of chest compression alone, the corresponding values were 7.39 +/- 0.03, 24.3 +/- 3.1 mm Hg, and 93.9 +/- 3.0%, with an arterial pressure of 48.1 +/- 7.7/22.6 +/- 3.9 mm Hg. Mean minute ventilation during the fourth minute of CPR, measured with a face mask-pneumotachometer, was 5.2 +/- 1.1 L/min.

CONCLUSIONS

These data suggest that in the dog model of witnessed arrest, chest compression alone during CPR can maintain adequate gas exchange to sustain O2 saturation > 90% for > 4 minutes. The need for immediate ventilation during witnessed arrest should be reexamined.
Suppression of thrombolysis in a canine model of pulmonary embolism.
Authors: Marsh J J , Konopka R G , Lang I M , Wang H Y , Pedersen C , Chiles P , Reilly C F , Moser K M
Published: June 2012

BACKGROUND

The brisk fibrinolytic response of canines has impaired efforts to develop a canine model of chronic thromboembolic pulmonary hypertension. Difficulties in retaining chronic embolic residuals were partially overcome by administration of tranexamic acid (TXA) (Circulation. 1991;83:1272-1279.). In this study, we used type 1 plasminogen activator inhibitor (PAI-1), a major inhibitor of the endogenous fibrinolytic system, to determine its efficacy in the suppression of thrombolysis in canines.

METHODS AND RESULTS

Thrombus was induced in the inferior vena cava of anesthetized mongrel dogs with thrombin and a special double-balloon catheter; 2 hours later, the thrombus was embolized. In one group of dogs, activated type 1 plasminogen activator inhibitor (PAI-1) (130 micrograms) was delivered directly into the forming thrombus; in another, TXA (110 mg/kg) was given intravenously before thrombus formation; in controls, thrombus was induced without inhibitors. Cross-linked fibrin degradation product (D-dimer) appeared in the blood of control animals within 1 hour of thrombus induction (176 +/- 62.5 versus 1.02 +/- 0.39 ng/mL baseline; mean +/- SEM), was maximal by 4 hours (413 +/- 110 ng/mL) and remained elevated at 24 hours (90.8 +/- 19.5 ng/mL). Compared with controls, PAI-1 and TXA suppressed D-dimer release by 80% and 85%, respectively, over the first 24 hours. One week later, animals were killed, and residual emboli were harvested. Perfusion scan defects persisted in all animals at this time, but there were no scan defect differences among groups. However, emboli recovered from animals receiving PAI-1 still harbored immunoreactive PAI-1 and were, on average, more than twofold greater in mass (393 +/- 56 mg) than emboli recovered from either controls (183 +/- 76 mg) or animals receiving TXA (180 +/- 80 mg).

CONCLUSIONS

Intravenous TXA and intrathrombus PAI-1 effectively suppress thrombolysis for 24 hours in canines. Thromboemboli enriched with PAI-1 appear to resist lysis for longer periods of time (up to 1 week). These findings are consistent with the hypothesis that PAI-1 remains associated with the embolus, where it continues to inhibit lysis, whereas TXA eventually diffuses out of the embolus, allowing lysis to ensue.
Value of physical signs in the diagnosis of ventricular tachycardia.
Authors: Garratt C J , Griffith M J , Young G , Curzen N , Brecker S , Rickards A F , Camm A J
Published: June 2012

BACKGROUND

Although the use of physical signs for the diagnosis of ventricular tachycardia (VT) was described in the early 1900s, their value in this role has never been systematically assessed.

METHODS AND RESULTS

Using a blinded, randomized protocol, we examined the ability of 26 clinicians to detect ventriculoatrial (VA) dissociation during cardiac pacing in 21 patients with both atrial and ventricular pacing wires in situ after successful ablation of accessory pathways. In protocol 1 (10 patients), pacing was randomized to either ventricular pacing alone (simulating VT) or to atrioventricular sequential pacing (simulating supraventricular tachycardia or VT with intact VA conduction) at rates of 150 or 180 beats per minute. Each patients was examined by four clinicians blinded to the pacing mode. Clinicians were asked to make a diagnosis of "VA association" or "VA dissociation" after examining the patient for variability of the arterial pulse, jugular venous pulse (JVP), and first heart sound. In protocol 2 (11 patients), randomization of pacing mode was performed between examination of each of the three physical signs so that the value of each sign was assessed individually. In protocol 1, a diagnosis of VA dissociation (VT) was made in 21 of 40 observations, with a specificity of 75%, sensitivity of 70%, and a positive predictive value (PPV) of 71%. In protocol 2, from a total of 132 observations (44 for each sign), the sensitivity, specificity, and PPV for a diagnosis of VT were as follows: arterial pulse, 61%, 71%, 70%; JVP, 96%, 75%, 82%; and first heart sound, 58%, 100%, 100%.

CONCLUSIONS

It is concluded that, in patients with a regular tachycardia of uncertain origin, clinically detectable variations in the first heart sound and JVP are highly specific and sensitive indicators, respectively, of a diagnosis of VT. Assessment of the arterial pulse is of little value in this role.
Effects of Chronic Systemic Administration of Basic Fibroblast Growth Factor on Collateral Development in the Canine Heart
Authors: Lazarous Daisy F. , Scheinowitz Mickey , Shou Matie , Hodge Everett , Rajanayagam M. A. Sharmini , Hunsberger Sally , Robison W. Gerald , Stiber Jonathan A. , Correa Rosaly , Epstein Stephen E. , Unger Ellis F.
Published: June 2012

Background
Recently we reported that intracoronary administration of basic fibroblast growth factor (bFGF), a potent angiogenic peptide, increases collateral blood flow in dogs subjected to progressive left circumflex coronary artery (LCx) occlusion. The aim of the present study was to examine the effect of systemically administered bFGF on collateral blood flow and to assess its pharmacokinetics and potential side effects.

Methods and Results
Forty-seven dogs were subjected to progressive ameroid-induced occlusion of the LCx, an intervention known to induce the development of collateral vessels. In phase I of the investigation, dogs were randomized to receive bFGF 1.74 mg/d (n=10) or saline (n=9) as a left atrial injection for 4 weeks. Relative collateral blood flow was assessed serially with radiolabeled microspheres in the conscious state during maximal coronary vasodilatation. Initiation of bFGF treatment was temporally associated with a marked acceleration of collateral development; however, collateral flow in control dogs improved toward the end of the study, approaching that of bFGF-treated dogs at the 38-day end point. Phase II of the investigation was a three-armed study of extended duration to determine whether bFGF caused a sustained increase in collateral function. Dogs were randomized to receive bFGF 1.74 mg/d for 9 weeks (n=7), bFGF 1.74 mg/d for 5 weeks followed by placebo for 4 weeks (n=11), or placebo for 9 weeks (n=10). Relative and absolute collateral blood flow were assessed serially with microspheres during maximal coronary vasodilatation. Between the 10th and 17th days after ameroid placement, bFGF-treated dogs exhibited marked improvement in collateral flow such that maximal collateral conductance exceeded that of controls by 24% at the 5-week crossover point. Final collateral conductance was similar in dogs receiving bFGF for 5 and 9 weeks despite withdrawal of treatment in the former group. bFGF administration was associated with a 21% increase in final collateral conductance as well as a 49% increase in collateral zone vascular density. Prolonged bFGF administration was also associated with a decrease in arterial pressure, moderate thrombocytopenia, and moderate, reversible anemia.

Conclusions
Systemic administration of bFGF enhanced collateral conductance in dogs with progressive single-vessel coronary occlusion. The beneficial effect of bFGF occurred primarily between the 7th and 14th days of therapy, and regression of collateral development was not noted after withdrawal of treatment. The present investigation provides impetus to the concept that collateral development can be enhanced pharmacologically–specifically by bFGF–raising the possibility that such an intervention might eventually be applied clinically.
Myocarditis in β-Thalassemia Major
Authors: Kremastinos Dimitrios Th. , Tiniakos George , Theodorakis George N. , Katritsis Demosthenes G. , Toutouzas Pavlos K.
Published: June 2012

Background
Although acute pericarditis is a common complication of β-thalassemia major, the prevalence and consequences of myocarditis in this disease have not been investigated.

Methods and Results
A prospective 5-year follow-up study was carried out in all patients with β-thalassemia major in whom the diagnosis of acute infectious myocarditis could be established between 1977 and 1986. A similar number of age- and sex-matched control subjects with β-thalassemia and normal left ventricular function and no evidence of myocarditis were also followed for 5 years. Of 1048 patients with β-thalassemia major, 47 patients (age, 15±2.5 years) with precordial chest pain were diagnosed as having acute infectious myocarditis. Myocardial biopsy was diagnostic in 26 patients, borderline in 14 patients, and nondiagnostic in 7 patients. Acute heart failure with left ventricular dysfunction (left ventricular ejection fraction, 25±11%) developed in 11 patients (23.4%) with myocarditis, and 8 of them died within 1 month to 1 year after diagnosis. Thirteen patients with myocarditis (27.6%) developed chronic heart failure (left ventricular ejection fraction, 26±13%) within 3±1.3 years, and 10 of them died within 8±3 months. Left ventricular systolic and diastolic functions of the control subjects did not change significantly during the 5-year period (left ventricular ejection fraction, 63±11% versus 65±7%;
P
=NS). However, left ventricular restrictive abnormalities (early diastole/late diastole, >2.2; deceleration time, <110 milliseconds) combined with right ventricular dilatation (>30 mm internal diameter) and right-sided heart failure developed in 3 patients with extremely high mean serum ferritin levels. No significant difference was found in mean levels of serum ferritin and pretransfusion hemoglobin between patients with and those without myocarditis.

Conclusions
In patients with β-thalassemia, myocarditis appears to be involved in the pathogenesis of left ventricular systolic dysfunction, being the main cause of death. Iron overload appears to provoke left ventricular restrictive abnormalities combined with right ventricular enlargement and dysfunction.
Characterization of Junctional Rhythm After Atrioventricular Node Ablation
Authors: Alison Jeffrey F. , Yeung-Lai-Wah John A. , Schulzer Michael , Kerr Charles R.
Published: June 2012

Background
Catheter ablation of the atrioventricular (AV) node with radiofrequency current (RFC) is associated with the short-term onset of a junctional escape rhythm (JER) in nearly all patients. However, the origin of the JER and short-term thermal effects of RFC on this junctional pacemaker activity are ill defined.

Methods and Results
Short-term and noninvasive long-term follow-up studies were performed to examine the electrophysiological characteristics of the underlying JER in 45 patients who had undergone AV nodal ablation with RFC. Baseline characteristics and responses to overdrive ventricular pacing and intravenous atropine followed by an incremental isoproterenol infusion were determined. Short- and long-term responses were compared. HV intervals before and after ablation were 49±9 and 48±9 milliseconds, respectively (
P
=NS). Follow-up was 11±8.3 months. JER cycle length was 1526±298 milliseconds in the short-term setting and was present in 44 patients (98%) in the long-term setting, measuring 1426±223 milliseconds (
P
<.005). Junctional recovery times increased exponentially as overdrive pacing rates increased–there was no difference between short-term and long-term responses. Drug responses within each study were all significant when compared with baseline. However, there was no significant difference between short- and long-term responses, except at the highest dose of isoproterenol. Intravenous atropine (1 mg) caused an 8.6±9.3% decrease in JER cycle length in the short-term setting compared with a 7.6±7.3% decrease in the long-term setting. The decreases in JER cycle length with isoproterenol infusion (short-term versus long-term) were 10.1±9.6% versus 9.6±7.4% with 1 μg/min, 15.8±11.7% versus 17.4±8.5% with 2 μg/min, 17.9±11.2% versus 21.4±9.1% with 3 μg/min (all
P
=NS), and 20.6±12.1% versus 24.8±9.1% with 4 μg/min (
P
<.01).

Conclusions
Radiofrequency ablation of the AV node is associated with development of a JER that is stable in the long-term setting. The lack of change in HV interval after ablation locates the junctional pacemaker proximal to the central fibrous body. The pattern of drug responses suggests an origin within the proximal His bundle at its junction with the AV node rather than the AV node itself. The overall similarity between short- and long-term characteristics of junctional pacemaker activity mitigates against any reversible thermal effects of RFC on this pacemaker focus.
Effects of Lipid Lowering by Pravastatin on Progression and Regression of Coronary Artery Disease in Symptomatic Men With Normal to Moderately Elevated Serum Cholesterol Levels
Authors: Jukema J. Wouter , Bruschke Albert V.G. , van Boven Ad J. , Reiber Johan H.C. , Bal Egbert T. , Zwinderman Aeilko H. , Jansen Hans , Boerma Geert J.M. , van Rappard Feikje M. , Lie Kong I.
Published: June 2012

Background
Intensive lowering of serum cholesterol may retard progression of coronary atherosclerosis in selected groups of patients. However, few data are available on the potential benefit of serum cholesterol reduction in the broad range of patients with coronary atherosclerosis and normal to moderately elevated serum cholesterol levels who undergo various forms of treatment. The Regression Growth Evaluation Statin Study (REGRESS) addresses this group of patients.

Methods and Results
REGRESS is a double-blind, placebo-controlled multicenter study to assess the effects of 2 years of treatment with the 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitor pravastatin on progression and regression of coronary atherosclerosis in 885 male patients with a serum cholesterol level between 4 and 8 mmol/L (155 and 310 mg/dL) by quantitative coronary arteriography. Primary end points were (1) change in average mean segment diameter per patient and (2) change in average minimum obstruction diameter per patient. Clinical events were also analyzed. Of the 885 patients, 778 (88%) had an evaluable final angiogram. Mean segment diameter decreased 0.10 mm in the placebo group versus 0.06 mm in the pravastatin group (
P
=.019): The mean difference between treatment groups was 0.04 mm, with a 95% CI of 0.01 to 0.07 mm. The median minimum obstruction diameter decreased 0.09 mm in the placebo group versus 0.03 mm in the pravastatin group (
P
=.001): The difference of the medians between the treatment groups was 0.06 mm, with a CI of 0.02 to 0.08 mm. At the end of the follow-up period, 89% (CI, 86% to 92%) of the pravastatin patients and 81% (CI, 77% to 85%) of the placebo patients were without new cardiovascular events (
P
=.002).

Conclusions
In symptomatic men with significant coronary atherosclerosis and normal to moderately elevated serum cholesterol, less progression of coronary atherosclerosis and fewer new cardiovascular events were observed in the group of patients treated with pravastatin than in the placebo group.
Effects of Long-term Enalapril Therapy on Cardiac Structure and Function in Patients With Left Ventricular Dysfunction
Authors: Greenberg Barry , Quinones Miguel A. , Koilpillai Chris , Limacher Marian , Shindler Daniel , Benedict Claude , Shelton Brent
Published: June 2012

Background
Studies of Left Ventricular Dysfunction (SOLVD) demonstrated that enalapril therapy significantly improved the clinical course of patients with left ventricular (LV) dysfunction. The goals of this substudy were to evaluate changes in LV structure and function in SOLVD patients and to test the hypothesis that enalapril inhibits remodeling in patients with LV dysfunction.

Methods and Results
Patients entering both the prevention and treatment arms of SOLVD from 5 of the 23 clinical centers were recruited for this substudy. The 301 patients who participated underwent Doppler-echocardiographic evaluation according to standard protocol before randomization to either enalapril or placebo and again after 4 and 12 months of therapy. Recorded data were analyzed in a blinded fashion at a central core laboratory. Analysis of baseline clinical characteristics showed that patients enrolled in the substudy were generally representative of the SOLVD population, although prevention arm patients were slightly overrepresented in the substudy group (69.8% compared with 61.9% of remaining SOLVD patients). The enalapril group demonstrated significant reductions in the mitral annular E-wave–to–A-wave velocity ratio (due predominantly to a reduction in E-wave velocity), and this response was different from that seen in the placebo group (
P
=.030). Changes in the E-to-A ratio in the enalapril group correlated significantly with changes in plasma atrial natriuretic peptide (
r
=.56;
P
≤.01). LV end-diastolic and end-systolic volumes increased in placebo but not enalapril-treated patients, and the differences in response between the treatment groups were significant (
P
=.025 and .019, respectively). LV mass tended to increase in placebo patients and to be reduced in enalapril-treated patients, and the difference in response between the groups was highly significant (
P
≤.001).

Conclusions
These data demonstrate that enalapril attenuates progressive increases in LV dilatation and hypertrophy in patients with LV dysfunction. The results support the possibility that the favorable effects of enalapril reported in the SOLVD trials were related to inhibition of LV remodeling.
Atrial Septal Aneurysm in Adult Patients
Authors: Mügge Andreas , Daniel Werner G. , Angermann Christiane , Spes Christoph , Khandheria Bijoy K. , Kronzon Itzhak , Freedberg Robin S. , Keren Andre , Dennig Karl , Engberding Rolf , Sutherland George R. , Vered Zvi , Erbel Raimund , Visser Cees A. , Lindert Oliver , Hausmann Dirk , Wenzlaff Paul
Published: June 2012

Background
An atrial septal aneurysm (ASA) is a well-recognized abnormality of uncertain clinical relevance. We reevaluated the clinical significance of ASA in a large series of patients. The aims of the study were to define morphological characteristics of ASA by transesophageal echocardiography (TEE), to define the incidence of ASA-associated abnormalities, and to investigate whether certain morphological characteristics of ASA are different in patients with and without previous events compatible with cardiogenic embolism.

Methods and Results
Patients with ASA were enrolled from 11 centers between May 1989 and October 1993. All patients had to undergo transthoracic and transesophageal echocardiography within 24 hours of each other; ASA was defined as a protrusion of the aneurysm >10 mm beyond the plane of the atrial septum as measured by TEE. Patients with mitral stenosis or prosthesis or after cardiothoracic surgery involving the atrial septum were excluded. Based on these criteria, 195 patients 54.6±16.0 years old (mean±SD) were included in this study. Whereas TEE could visualize the region of the atrial septum and therefore diagnose ASA in all patients, ASA defined by TEE was missed by transthoracic echocardiography in 92 patients (47%). As judged from TEE, ASA involved the entire septum in 100 patients (51%) and was limited to the fossa ovalis in 95 (49%). ASA was an isolated structural defect in 62 patients (32%). In 106 patients (54%), ASA was associated with interatrial shunting (atrial septal defect, n=38; patent foramen ovale, n=65; sinus venosus defect, n=3). In only 2 patients (1%), thrombi attached to the region of the ASA were noted. Prior clinical events compatible with cardiogenic embolism were associated with 87 patients (44%) with ASA; in 21 patients (24%) with prior presumed cardiogenic embolism, no other potential cardiac sources of embolism were present. Length of ASA, extent of bulging, and incidence of spontaneous oscillations were similar in patients with and without previous cardiogenic embolism; however, associated abnormalities such as atrial shunts were significantly more frequent in patients with possible embolism.

Conclusions
As shown previously, TEE is superior to the transthoracic approach in the diagnosis of ASA. The most common abnormalities associated with ASA are interatrial shunts, in particular patent foramen ovale. In this retrospective study, patients with ASA (especially with shunts) showed a high frequency of previous clinical events compatible with cardiogenic embolism; in a significant subgroup of patients, ASA appears to be the only source of embolism, as judged by TEE. Our data are consistent with the view that ASA is a risk factor for cardiogenic embolism, but thrombi attached to ASA as detected by TEE are apparently rare.
Prolonged Kinetics of Recovery of Oxygen Consumption After Maximal Graded Exercise in Patients With Chronic Heart Failure
Authors: Cohen-Solal Alain , Laperche Thierry , Morvan Daniel , Geneves Michel , Caviezel Bernard , Gourgon René
Published: June 2012

Background
Patients with chronic heart failure (CHF) often complain of prolonged dyspnea after exercise. The determinants of oxygen consumption after exercise in these patients are unknown. We hypothesized that the kinetics of oxygen consumption recovery after graded exercise was prolonged in parallel with the recovery of muscle energy stores, was not affected by the exercise level, and could be used to assess the circulatory response to exercise.

Methods and Results
Seventy-two patients with CHF in Weber’s class A (n=28), B (n=21), and C/D (n=23) and 13 healthy subjects performed maximal upright bicycle exercise with breath-by-breath respiratory gas analysis. Kinetics of recovery of ventilation (V̇
e
), oxygen consumption (V̇
o
2
), and CO
2
production (V̇
co
2
) after exercise were characterized by T
1/2
, the time to reach 50% of the peak value. T
1/2
V̇
o
2
(seconds) increased with the severity of CHF (97±17 for CHF A [
P
<.05 versus CHF B,
P
<.05 versus CHF C/D], 119±22 for CHF B [
P
<.05 versus control subjects,
P
<.05 versus CHF A, and
P
<.05 versus CHF C/D], 155±55 for CHF C/D [
P
<.05 versus control subjects,
P
<.05 versus CHF A, and
P
<.05 versus CHF B] compared with 77±17 for control subjects). T
1/2
V̇
co
2
and T
1/2
V̇
e
also increased similarly with the worsening of CHF. T
1/2
V̇
o
2
was correlated negatively with peak V̇
o
2
(
r
=.65) and was reproducible (
r
=.96). To study the relation between T
1/2
V̇
o
2
and the duration of exercise, 10 healthy subjects and 22 patients underwent a second graded test at 75% and/or 50% of peak workload. T
1/2
V̇
o
2
was minimally shortened, at only 50% of peak workload (
P
=.02). Finally, 19 patients underwent
31
P nuclear magnetic resonance spectroscopy of the anterior compartment of the leg during exercise; the half-time of recovery of the ratio of inorganic phosphate to creatine phosphate (T
1/2
P
i
/PCr), reflecting the level of involvement of oxidative metabolism in the restoration of energetic metabolites after exercise, was linearly correlated with the half-time of V̇
o
2
recovery (
r
=.70,
P
<.01).

Conclusions
Postexercise T
1/2
V̇
o
2
increases when CHF worsens, perhaps in part a result of slower kinetics of recovery of muscle energy stores. The time course of oxygen consumption recovery may represent a simple new criterion for measuring the impairment of the circulatory response to exercise in CHF, even submaximal exercise.
Angiotensin-Converting Enzyme Gene Polymorphism Has No Influence on the Circulating Renin-Angiotensin-Aldosterone System or Blood Pressure in Normotensive Subjects
Authors: Lachurié M.-L. , Azizi M. , Guyene T.-T. , Alhenc-Gelas F. , Ménard J.
Published: June 2012

Background
Angiotensin-converting enzyme (ACE) is involved in the metabolism of two major vasoactive peptides, converting angiotensin (Ang) I into Ang II and inactivating bradykinin. An insertion/deletion (I/D) polymorphism is present in the 16th intron of the ACE gene and is strongly associated with plasma and cellular ACE levels. Contrasting with the lack of relation between ACE gene polymorphism and blood pressure level, a large case-control study has shown that the deletion marker allele of the ACE gene was associated with an increased risk of myocardial infarction. The pathophysiological link between ACE gene polymorphism and cardiovascular events remains hypothetical. One hypothesis is that this polymorphism influences Ang II and bradykinin concentrations in the peripheral and/or local circulations through its effects on ACE levels in plasma and endothelial cells. The aim of this study was to investigate the effect of the ACE gene I/D polymorphism on blood pressure, plasma active renin, and aldosterone regulation in normal subjects.

Methods and Results
Twenty-four normotensive male volunteers homozygous for the ACE I/D polymorphism (12 DD and 12 II) received a renin inhibitor infusion (remikiren 0.1 mg · kg
−1
· h
−1
for 130 minutes) to suppress endogenous Ang I and Ang II production. Forty minutes after initiating the remikiren infusion, an exogenous Ang I infusion was begun and increased gradually every 15 minutes from 1 to 10 ng · kg
−1
· min
−1
. Median (range) plasma ACE levels (mU/mL) were 39 (32 to 57) and 24 (12 to 30) in the DD and II groups, respectively. Remikiren suppressed plasma Ang I and Ang II, increased plasma active renin (from 23±12 to 154±161 pg/mL), decreased plasma aldosterone (from 106±42 to 82±33 pg/mL), and slightly decreased diastolic blood pressure (from −2.4±2.7 mm Hg). The blood pressure and hormonal responses to Ang I infusion after renin inhibition and the slope of the rise in plasma Ang II with increasing Ang I dose were identical in both groups, as was the plasma Ang I/Ang II ratio before (DD, 2.09±1.04; II, 2.59±0.76) and after (DD, 0.15±0.13; II, 0.09±0.03) combined renin inhibitor and Ang I infusion.

Conclusions
Despite its association with a major difference in plasma ACE levels, the ACE I/D polymorphism did not influence the Ang II and plasma aldosterone production, plasma active renin decrease, or diastolic blood pressure increase induced by exogenous Ang I infusion, suggesting that ACE has no limiting influence on systemic Ang II generation and effects under these experimental conditions.
Assessment of Left-to-Right Intracardiac Shunting by Velocity-Encoded, Phase-Difference Magnetic Resonance Imaging
Authors: Hundley W. Gregory , Li Hong F. , Lange Richard A. , Pfeifer Dennis P. , Meshack Benjamin M. , Willard John E. , Landau Charles , Willett Duwayne , Hillis L. David , Peshock Ronald M.
Published: June 2012

Background
Velocity-encoded, phase-difference magnetic resonance imaging (MRI) has been shown to provide an accurate assessment of shunt magnitude in patients with large atrial septal defects, but its ability to determine shunt magnitude in patients with intracardiac left-to-right shunts of various locations and sizes has not been evaluated in a prospective and blinded manner. The objective of the present study was to determine whether velocity-encoded, phase-difference MRI can assess the magnitude of intracardiac left-to-right shunting in humans.

Methods and Results
Twenty-one subjects (15 women and 6 men; age range, 15 to 72 years) underwent velocity-encoded, phase-difference MRI measurements of flow in the proximal aorta and pulmonary artery, followed immediately by cardiac catheterization. The presence of left-to-right intracardiac shunting was assessed with hydrogen inhalation, after which shunt magnitude was measured by the oximetric and indocyanine green techniques. Of the 21 patients, 12 had left-to-right intracardiac shunting detected by hydrogen inhalation. There was a good correlation (
r
=.94) between the invasive and MRI assessments of shunt magnitude. In comparison to oximetry and indocyanine green, MRI correctly identified the 12 patients with a ratio of pulmonary to systemic flow (Qp/Qs) of <1.5 (9 without intracardiac shunting and 3 with small shunts) and the 9 patients with a Qp/Qs of ≥1.5 (6 with atrial septal defect, 1 with ventricular septal defect, 1 with patent ductus arteriosus, and 1 with both atrial septal defect and patent ductus arteriosus).

Conclusions
Compared with measurements obtained during cardiac catheterization, velocity-encoded, phase-difference MRI measurements of flow in the proximal great vessels can reliably assess the magnitude of intracardiac left-to-right shunting.
Erythromycin Blocks the Rapid Component of the Delayed Rectifier Potassium Current and Lengthens Repolarization of Guinea Pig Ventricular Myocytes
Authors: Daleau Pascal , Lessard Etienne , Groleau Marie-France , Turgeon Jacques
Published: June 2012

Background
Administration of erythromycin to humans has been associated with lengthening of cardiac repolarization and even proarrhythmia. The objectives of our study were to describe effects of erythromycin on repolarization of isolated hearts and to determine effects of the drug on major K
+
currents involved in cardiac repolarization.

Methods and Results
A first set of experiments was conducted in isolated, buffer-perfused guinea pig hearts electrically stimulated at a basic cycle length of 250 ms. In this model, erythromycin 10
−4
mol/L increased monophasic action potential duration measured at 90% repolarization (MAPD
90
) by 40±7 ms. Increase in MAPD
90
was reproducibly observed in seven hearts studied. To study the mechanism of these effects on cardiac repolarization, a second set of experiments was performed in isolated guinea pig ventricular myocytes using the whole cell configuration of the patch-clamp technique. In these cells, erythromycin 10
−4
mol/L decreased by about 40% (
P
<.05 versus baseline) the time-dependent outward K
+
current elicited by short depolarizations (250 ms) to low depolarizing voltages (−20 to 0 mV). In contrast, the drug was without significant effects on the time-dependent K
+
current elicited by long pulses (5000 ms) to high depolarizing voltages (+10 to +50 mV), on the time-independent background current (mostly I
K1
), and on the slow inward calcium current.

Conclusions
The outward time-dependent K
+
current blocked by erythromycin in isolated guinea pig ventricular myocytes had characteristics similar to those described for I
Kr
. Selective block of this component of I
K
gives an explanation for the effects of erythromycin on cardiac repolarization. These effects were observed at clinically relevant concentrations reached after intravenous administration of the drug and warn for potential interactions with other action potential–lengthening drugs.
Increase and Redistribution of Cardiac Mast Cells in Auricular Thrombosis
Authors: Bankl Hans C. , Radaszkiewicz Thaddäus , Klappacher Günter W. , Glogar Dietmar , Sperr Wolfgang R. , Großschmidt Karl , Bankl Hans , Lechner Klaus , Valent Peter
Published: June 2012

Background
The atrial appendage is a predilection site for thrombus formation. Mast cells (MC) are a rich source of mediators that may be involved in the regulation of thrombus formation. We examined number, distribution, and phenotype of MC in thrombosed versus unaffected auricles to elucidate their possible role in auricular thrombosis (AUTHR).

Methods and Results
Sections of atrial appendages (AUTHR, n=14; controls (CO), n=13) were analyzed for MC by Giemsa, toluidine blue, and berberine sulfate stains and by immunohistochemistry. Cardiac MC expressed CD antigens corresponding to the classic MC phenotype as well as tryptase, chymase, and heparin. Thrombosis was associated with a twofold increase in the number of MC in the total appendage (CO, 3.1±1.0 versus AUTHR, 6.4±1.1 MC/mm
2
,
P
<.01). Moreover, in AUTHR, a redistribution of MC to the upper endocardium was observed (AUTHR, 5.3±1.4 versus CO, 0.07±0.15 MC/mm
2
,
P
<.01). Mast cell growth factor (MGF) was expressed in the endothelium and subendothelial space of thrombosed appendages but not in the normal endocardium. Overexpression of MGF was accompanied by a weak or absent expression of the MGF receptor
c
-kit on redistributed MC in AUTHR. Patients with unilateral atrial appendage thrombosis did not exhibit a MC increase or redistribution in the unaffected contralateral appendage. No augmentation of other inflammatory cells was observed. Stimulation of isolated cardiac MC with MGF resulted in mediator release.

Conclusions
This study provides evidence that AUTHR is associated with MC increase and redistribution and MGF overexpression. The role of redistributed MC and their mediators in the pathophysiology of atrial thrombosis requires further investigation.
Digital Subtraction High-Frame-Rate Echocardiography in Detecting Delayed Onset of Regional Left Ventricular Relaxation in Ischemic Heart Disease
Authors: Kondo Hiroya , Masuyama Tohru , Ishihara Ken , Mano Toshiaki , Yamamoto Kazuhiro , Naito Johji , Nagano Reiko , Kishimoto Shinji , Tanouchi Jun , Hori Masatsugu , Takeda Hiroshi , Inoue Michitoshi , Kamada Takenobu
Published: June 2012

Background
Because left ventricular (LV) diastolic function is impaired before systolic function in patients with ischemic heart disease and because ischemic heart disease is constituted of regional rather than global abnormalities of the left ventricle, measures of LV regional diastolic dysfunction, if possible, should provide the most sensitive assessment of the coronary involved region. The objectives of this study are to clarify whether high-frame-rate two-dimensional echocardiography, combined with digital subtraction image processing, may be used to visualize regional LV relaxation abnormalities in patients with ischemic heart disease and to clarify whether this technique provides a measure for the noninvasive assessment of the coronary involved region.

Method and Results
In 30 normal subjects and 59 patients with ischemic heart disease, two-dimensional echocardiograms obtained at a rate of 60 frames per second were provided on line for digital subtraction analysis, with which digitized images were continuously subtracted on a frame-by-frame basis. The subtracted images were analyzed to determine the onset of the segmental outward motion of the LV wall in early diastole in each of 16 segments per subject. Regional relaxation index, defined as the interval from the second heart sound to the onset of outward wall motion, was significantly prolonged in the coronary involved segments compared with the normal segments (36.3±18.0 versus 101.2±34.0 ms,
P
<.01). The prolongation in the regional relaxation index was observed even in the coronary involved segments without reduction in systolic wall motion. When a cutoff level of 50.0 ms was used, coronary involved segments could be distinguished from normal or border segments with a sensitivity of 92% and a specificity of 81%.

Conclusions
Digital subtraction high-frame-rate echocardiography may be used to visualize regional LV relaxation abnormalities in patients with ischemic heart disease. The time interval from the second heart sound to the onset of the segmental outward motion of the LV wall (regional relaxation index) obtained with this technique provides a noninvasive and accurate measure for assessing coronary involved regions.
Extended Inhibition of Platelet Aggregation With the Orally Active Platelet Inhibitor SC-54684A
Authors: Szalony James A. , Haas Neal F. , Salyers Anita K. , Taite Beatrice B. , Nicholson Nancy S. , Mehrotra Devan V. , Feigen Larry P.
Published: June 2012

Background
Platelet aggregation is important in thrombotic events, and platelets play a major role in the etiology of several cardiovascular diseases. Platelet aggregation requires the binding of fibrinogen (fgn) to activated platelets. Synthetic peptides modeled after the RGD binding sequence on the fgn α-chain block the platelet glycoprotein (GP) IIb/IIIa receptor for fgn and effectively inhibit aggregation. SC-54684A (SCp, orally active prodrug of the active moiety SC-54701, SCa) is a mimetic of the RGD-containing peptide sequence that is recognized by the platelet GPIIb/IIIa receptor. SCa blocks the binding of fgn to the platelet and therefore prevents platelet aggregation in response to all agonists.

Methods and Results
SCp was administered orally at 1.25, 2.5, 5.0, and 7.5 mg/kg in a single-dose, dose-ranging study. Blood samples were taken periodically for 24 hours, and platelet-rich plasma was prepared and tested for inhibition of ex vivo collagen-induced platelet aggregation. The plasma concentration of active moiety was determined by bioassay. The time, inhibition, and concentration data were used to predict two doses that would result in minimum daily inhibition levels of 30% and 70% when administered twice daily (0.6 and 2.4 mg/kg, respectively). SCp was administered orally to conscious dogs twice daily for 14 days (after dose adjustment). Blood samples were obtained at daily peak and trough plasma levels (predicted from dose-ranging study). Inhibition of ex vivo collagen-induced platelet aggregation and concentration of active moiety in the plasma were determined. Average inhibition of platelet aggregation and plasma concentration of active moiety amounted to approximately 21% and 14 ng/mL at 1.5 mg/kg BID and 75% and 24 ng/mL at 2.4 mg/kg BID at daily minimum plasma levels (trough) in steady state. Platelet counts in the 2.4-mg/kg group declined from 3.2×10
5
/μL to 2.5×10
5
/μL in the first 9 days of dosing, with no further decline despite continued administration of compound. No changes were observed in the animals receiving 1.5 mg/kg.

Conclusions
The results of the dose-ranging study show that oral administration of SCp results in dose-dependent inhibition of platelet aggregation. As shown in the 14-day administration, this dose-dependent inhibition can be maintained for an extended period while exhibiting no adverse effects. SCp is a leading candidate for development and is currently in clinical trials.
Effect of Left Ventricular Hypertrophy and Its Regression on Ventricular Electrophysiology and Vulnerability to Inducible Arrhythmia in the Feline Heart
Authors: Rials Seth J. , Wu Ying , Ford Nancy , Pauletto Ferrel J. , Abramson Sandra V. , Rubin Andrew M. , Marinchak Roger A. , Kowey Peter R.
Published: June 2012

Background
Left ventricular hypertrophy (LVH) is associated with an increased risk of death, susceptibility to ventricular arrhythmia, and multiple electrophysiological abnormalities. The purpose of the present study was to determine whether the susceptibility to arrhythmia and electrical abnormalities persists after regression of hypertrophy in an animal model of LVH.

Methods and Results
We placed constricting bands on the ascending aorta of cats (n=9) or performed sham operations (n=9). Serial cardiac echocardiography was performed to measure left ventricular wall thickness. After LVH had developed in the banded animals, the constricting bands were removed and serial echocardiograms were used to monitor for regression of hypertrophy. Electrophysiological studies were performed in cats that showed regression of LVH (Regress, n=5), those that showed no change in LV wall thickness (No Regress, n=4), and in the sham-operated animals (Sham). Cats with persistent LVH had a higher incidence of inducible polymorphic ventricular tachycardia (4 of 4) compared with Regress (1 of 5) or Sham (1 of 9) cats (
P
<.05) and had lower ventricular fibrillation thresholds (9±2 mA) than Regress (17±4 mA) or Sham (16±3 mA) cats (
P
<.05). Persistent LVH in the No Regress group was associated with prolongation of epicardial monophasic action potential duration (MAPD) in the left but not the right ventricle. Dispersion of refractoriness was greater in the No Regress group (
P
<.05 versus Regress or Sham). Regress cats were identical to Sham cats in having a low incidence of inducible polymorphic ventricular arrhythmia, high fibrillation threshold, and MAPD measurements (
P
=NS versus Sham).

Conclusions
LVH produces multiple electrophysiological abnormalities and increased vulnerability to inducible polymorphic ventricular arrhythmia in this model of LVH. Cats that show regression of hypertrophy have normal ventricular electrophysiology and have the same low vulnerability to inducible ventricular arrhythmia as Sham animals.
Toward a Molecular Understanding of Congenital Heart Disease
Authors: Payne R. Mark , Johnson Mark C. , Grant James W. , Strauss Arnold W.
Published: June 2012

Background
This review discusses the incidence and importance of congenital heart disease (CHD), the reasons that investigation of causative mechanisms for human CHD has been slow, and the limitations of the multifactorial theory for the etiology of CHD.

Methods and Results
The molecular defects underlying three vasculopathies—Marfan’s syndrome (fibrillin), supravalvar aortic stenosis, and Williams’ syndrome (elastin)—and hereditary telangiectasia are presented to emphasize the role of microfibrils and extracellular matrix in the pathophysiology of these vascular defects. Animal models of CHD, including situs inversus, canine conotruncal malformations, and chick neural crest ablation, are examined to emphasize how such studies relate to human CHD, especially by pointing to single-gene defects for conotruncal malformations, candidate loci for situs inversus, and phenotypic variability caused by neural crest lesions. The crucial role of cardiac transcription factors in heart morphogenesis is emphasized by review of gene knockout studies of these factors, which cause fetal death secondary to heart maldevelopment. Several lines of evidence demonstrating genetic etiologies of human CHD are also presented, including the mapping of familial atrial septal defects, to prove that one anatomic type of CHD may be due to single-gene defects at different loci. Review of atrioventricular canal, both secondary to trisomy 21 and as an autosomal-dominant familial defect, reiterates this conclusion. The evidence that monosomy on chromosome 22 causes multiple types of CHD, including aortic arch and conotruncal defects as part of the CATCH-22 syndrome, is presented, with results supporting the idea that deletions at this site alone may cause 5% of surgically treated CHD.

Conclusions
We conclude that (1) human CHD is frequently due to single-gene defects and that even sporadic defects may arise from a single-gene abnormality; (2) a common genetic defect may cause several apparently different forms of CHD; (3) elucidation of the genetic basis of CHD provides clues to normal cardiovascular developmental biology; (4) the same cardiac malformation can be caused by mutant genes at different loci; and (5) interactions of clinical investigators (cardiologists and cardiothoracic surgeons) with basic scientists should allow more rapid progress in defining the genetic basis of CHD.