bluuebunny/crossref_metadata_2025 huggingface dataset:
Noninvasive Quantification of the Contractile Reserve of Stunned Myocardium by Ultrasonic Strain Rate and Strain
Authors: Jamal Fadi , Strotmann Jörg , Weidemann Frank , Kukulski Tomasz , D’hooge Jan , Bijnens Bart , Van de Werf Frans , De Scheerder Ivan , Sutherland George R.
Published: September 2007

Background

We sought to investigate ultrasonic strain rate and strain as new indices to quantify the contractile reserve of stunned myocardium during dobutamine infusion.

Methods and Results

Stunning of the left ventricular posterior wall was induced in 9 closed-chest pigs after 30 minutes of severe hypoperfusion followed by 60 minutes of reperfusion of the left circumflex coronary artery territory. A second group of 7 animals had no coronary occlusion and served as normal controls. An incremental dobutamine infusion protocol was used in both groups. Changes in regional radial function were monitored by use of ultrasound-derived maximal systolic radial strain rate (SR) and systolic strain (ε). In the control group, dobutamine induced an increase in both SR and maximal dP/dt, which correlated linearly (
r
=0.85). Conversely, ε values increased at low doses of dobutamine (2.5 to 5 μg · kg
−1
· min
−1
) but decreased during higher infusion rates (10 to 20 μg · kg
−1
· min
−1
). During circumflex hypoperfusion, SR and ε of the posterior wall decreased from 5.0±0.3 s
−1
and 63±6% to 2.9±0.3 s
−1
and 27±4%, respectively (
P
<0.01). After 60 minutes of reperfusion, SR and ε failed to fully resume because of stunning, averaging 3.6±0.2 s
−1
and 35±3%, respectively (
P
=0.12 versus ischemia,
P
<0.05 versus baseline). During dobutamine infusion, SR increased at 5 μg · kg
−1
· min
−1
and exceeded baseline values at 20 μg · kg
−1
· min
−1
(
P
<0.05), whereas ε increased only at high doses and remained below baseline levels (
P
<0.05).

Conclusions

The changes in regional function of stunned myocardium during inotropic stimulation could be characterized by use of ultrasonic deformation parameters. During dobutamine infusion, strain-rate values quantified the contractile reserve better than strain values.
Stent-Based Delivery of Sirolimus Reduces Neointimal Formation in a Porcine Coronary Model
Authors: Suzuki Takeshi , Kopia Greg , Hayashi Shin-ichiro , Bailey Lynn R. , Llanos Gerard , Wilensky Robert , Klugherz Bruce D. , Papandreou George , Narayan Pallassana , Leon Martin B. , Yeung Alan C. , Tio Fermin , Tsao Philip S. , Falotico Robert , Carter Andrew J.
Published: September 2007

Background

—

The purpose of this study was to determine the efficacy of stent-based delivery of sirolimus (SRL) alone or in combination with dexamethasone (DEX) to reduce in-stent neointimal hyperplasia. SRL is a potent immunosuppressive agent that inhibits SMC proliferation by blocking cell cycle progression.

Methods and Results

—

Stents were coated with a nonerodable polymer containing 185 μg SRL, 350 μg DEX, or 185 μg SRL and 350 μg DEX. Polymer biocompatibility studies in the porcine and canine models showed acceptable tissue response at 60 days. Forty-seven stents (metal, n=13; SRL, n=13; DEX, n=13; SRL and DEX, n=8) were implanted in the coronary arteries of 16 pigs. The tissue level of SRL was 97±13 ng/artery, with a stent content of 71±10 μg at 3 days. At 7 days, proliferating cell nuclear antigen and retinoblastoma protein expression were reduced 60% and 50%, respectively, by the SRL stents. After 28 days, the mean neointimal area was 2.47±1.04 mm
2
for the SRL alone and 2.42±1.04 mm
2
for the combination of SRL and DEX compared with the metal (5.06±1.88 mm
2
,
P
<0.0001) or DEX-coated stents (4.31±3.21 mm
2
,
P
<0.001), resulting in a 50% reduction of percent in-stent stenosis.

Conclusions

—

Stent-based delivery of SRL via a nonerodable polymer matrix is feasible and effectively reduces in-stent neointimal hyperplasia by inhibiting cellular proliferation.
Heterogeneous Expression of Gap Junction Channels in the Heart Leads to Conduction Defects and Ventricular Dysfunction
Authors: Gutstein David E. , Morley Gregory E. , Vaidya Dhananjay , Liu Fangyu , Chen Franklin L. , Stuhlmann Heidi , Fishman Glenn I.
Published: September 2007

Background
—

Heterogeneous remodeling of gap junctions is observed in many forms of heart disease. The consequent loss of synchronous ventricular activation has been hypothesized to result in diminished cardiac performance. To directly test this hypothesis, we designed a murine model of heterogeneous gap junction channel expression.

Methods and Results
—

We generated chimeric mice formed from connexin43 (Cx43)-deficient embryonic stem cells and wild-type or genetically marked ROSA26 recipient blastocysts. Chimeric mice developed normally, without histological evidence of myocardial fibrosis or hypertrophy. Heterogeneous Cx43 expression resulted in conduction defects, however, as well as markedly depressed contractile function. Optical mapping of chimeric hearts by use of voltage-sensitive dyes revealed highly irregular epicardial conduction patterns, quantified as significantly greater negative curvature of the activation wave front (−1.86±0.40 mm in chimeric mice versus −0.86±0.098 mm in controls;
P
<0.01; n=6 for each group). Echocardiographic studies demonstrated significantly reduced fractional shortening in chimeric mice (26.6±2.3% versus 36.5±1.6% in age-matched 129/Sv×C57BL/6F1 wild-type controls;
P
<0.05).

Conclusions
—

These data suggest that heterogeneous Cx43 expression, by perturbing the normal pattern of coordinated myocardial excitation, may directly depress cardiac performance.
Increased Bleeding Tendency and Decreased Susceptibility to Thromboembolism in Mice Lacking the Prostaglandin E Receptor Subtype EP
3
Authors: Ma Hong , Hara Akiyoshi , Xiao Chun- Yang , Okada Yuji , Takahata Osamu , Nakaya Kazuhiro , Sugimoto Yukihiko , Ichikawa Atsushi , Narumiya Shuh , Ushikubi Fumitaka
Published: September 2007

Background
—

Among the prostanoids, thromboxane (TX) A
2
is a potent stimulator of platelets, whereas prostaglandin (PG) I
2
inhibits their activation. The roles of PGE
2
in the regulation of platelet function have not been established, however, and the contribution of PGE
2
in hemostasis and thromboembolism is poorly understood. The present study was intended to clarify these roles of PGE
2
by using mice lacking the PGE
2
receptor subtype 3 (EP
3
−/−
mice).

Methods and Results
—

Expression of mRNAs for EP
3
in murine platelets was confirmed by quantitative reverse transcription-polymerase chain reaction. PGE
2
and AE-248, a selective EP
3
agonist, showed concentration-dependent potentiation of platelet aggregation induced by U46619, a TXA
2
receptor agonist, although PGE
2
alone could not induce aggregation. PGE
2
and AE-248 increased cytosolic calcium ion concentration ([Ca
2+
]
i
), and AE-248 inhibited the forskolin-induced increase in cytosolic cAMP concentration ([cAMP]
i
), suggesting G
i
coupling of EP
3
. The potentiating effects of PGE
2
and AE-248 on platelet aggregation along with their effects on [Ca
2+
]
i
and [cAMP]
i
were absent in EP
3
−/−
mice. In vivo, the bleeding time was significantly prolonged in EP
3
−/−
mice. Moreover, when mice were challenged intravenously with arachidonic acid, mortality and thrombus formation in the lung were significantly reduced in EP
3
−/−
mice.

Conclusions
—

PGE
2
potentiated platelet aggregation induced by U46619 via EP
3
by increasing [Ca
2+
]
i
, decreasing [cAMP]
i
, or both. This potentiating action of PGE
2
via EP
3
is essential in mediating both physiological and pathological effects of PGE
2
in vivo.
Improvement in Survival and Cardiac Metabolism After Gene Transfer of Sarcoplasmic Reticulum Ca
2+
-ATPase in a Rat Model of Heart Failure
Authors: del Monte Federica , Williams Eric , Lebeche Djemal , Schmidt Ulrich , Rosenzweig Anthony , Gwathmey Judith K. , Lewandowski E. Douglas , Hajjar Roger J.
Published: September 2007

Background
—

In heart failure, sarcoplasmic reticulum (SR) Ca
2+
-ATPase (SERCA2a) activity is decreased, resulting in abnormal calcium handling and contractile dysfunction. We have previously shown that increasing SERCA2a expression by gene transfer improves ventricular function in a rat model of heart failure created by ascending aortic constriction.

Methods and Results
—

In this study, we tested the effects of gene transfer of SERCA2a on survival, left ventricular (LV) volumes, and metabolism. By 26 to 27 weeks after aortic banding, all animals developed heart failure (as documented by >25% decrease in fractional shortening) and were randomized to receive either an adenovirus carrying the SERCA2a gene (Ad.SERCA2a) or control virus (Ad.βgal-GFP) by use of a catheter-based technique. Sham-operated rats, uninfected or infected with either Ad.βgal-GFP or Ad.SERCA2a, served as controls. Four weeks after gene transfer, survival in rats with heart failure treated with Ad.βgal-GFP was 9%, compared with 63% in rats receiving Ad.SERCA2a. LV volumes were significantly increased in heart failure (0.64±0.05 versus 0.35±0.03 mL,
P
<0.02). Overexpression of SERCA2a normalized LV volumes (0.46±0.07 mL) in the failing hearts.
31
P NMR analysis showed a reduced ratio of phosphocreatine to ATP content in failing+Ad.βgal-GFP compared with sham+Ad.βgal-GFP (0.82±0.13 versus 1.38±0.14,
P
<0.01). Overexpression of SERCA2a in failing hearts improved the phosphocreatine/ATP ratio (1.23±0.28).

Conclusions
—

In this study, we show that unlike inotropic agents that improve contractile function at the expense of increased mortality and worsening metabolism, gene transfer of SERCA2a improves survival and the energy potential in failing hearts.
Early Reinfarction After Fibrinolysis
Authors: Hudson Michael P. , Granger Christopher B. , Topol Eric J. , Pieper Karen S. , Armstrong Paul W. , Barbash Gabriel I. , Guerci Alan D. , Vahanian Alec , Califf Robert M. , Ohman E. Magnus
Published: September 2007

Background

Trials report a 2% to 6% incidence of reinfarction after fibrinolysis for acute myocardial infarction (MI). We combined the Global Utilization of Streptokinase and Tissue plasminogen activator (alteplase) for Occluded coronary arteries (GUSTO I) and Global Use of Strategies To Open occluded coronary arteries (GUSTO III) populations to better define frequency, timing, and clinical predictors of in-hospital reinfarction.

Methods and Results

In 55 911 patients with ST-segment elevation myocardial infarction (MI) who were receiving fibrinolysis, we compared baseline characteristics and mortality rate by reinfarction incidence and developed multivariable logistic regression models to predict in-hospital reinfarction and composite of death or reinfarction. Reinfarction occurred in 2258 patients (4.3%) a median of 3.8 days after fibrinolysis; rates did not differ between GUSTO I (4.0%) and GUSTO III (4.2%) or by fibrinolytic assignment (streptokinase, 4.1%; alteplase, 4.3%; reteplase, 4.5%; combined streptokinase and alteplase, 4.4%;
P
=0.55). Advanced age, shorter time to fibrinolysis, non-US enrollment, nonsmoking status, prior MI or angina, female sex, anterior MI, and lower systolic blood pressure were associated significantly with reinfarction. Patients with reinfarction had higher mortality at 30 days (11.3% versus 3.5% without reinfarction; odds ratio, 3.5;
P
<0.001) and from 30 days to 1 year (4.7% versus 3.2%; hazard ratio, 1.5;
P
<0.001). Significant multivariate predictors of in-hospital death or reinfarction included age, Killip class, systolic and diastolic blood pressures, heart rate, anterior MI, smoking status, prior MI, sex, and country of enrollment (all
P
<0.001).

Conclusion

Reinfarction occurs infrequently after fibrinolysis but confers increased risk of 30-day and 1-year mortality. Some predictors of reinfarction differ from known predictors of death after MI. Improved treatment and prevention strategies for reinfarction deserve study.
Effect of Inhaled Iloprost Plus Oral Sildenafil in Patients With Primary Pulmonary Hypertension
Authors: Wilkens Heinrike , Guth Angelika , König Jochem , Forestier Nicole , Cremers Bodo , Hennen Benno , Böhm Michael , Sybrecht Gerhard W.
Published: September 2007

Background

The application of iloprost, a stable prostacyclin analogue, by inhalation has been shown to improve hemodynamic variables in patients with primary pulmonary hypertension. However, repetitive inhalations are required due to its short-term effects. One potential approach to prolong and increase the vasorelaxant effects of aerosolized iloprost might be to combine use with phosphodiesterase inhibitors.

Methods and Results

The short-term effects of 8.4 to 10.5 μg of aerosolized iloprost, the phosphodiesterase type 5 inhibitor sildenafil, and the combination thereof were compared in 5 patients with primary pulmonary hypertension. Aerosolized iloprost resulted in a more pronounced decrease in mean pulmonary arterial pressure (PAP) than sildenafil alone (9.4±1.3 versus 6.4±1.1 mm Hg;
P
<0.05). The reduction in mean PAP after sildenafil was maximal after the first dose (25 mg). The combination of sildenafil plus iloprost lowered mean PAP significantly more than iloprost alone (13.8±1.4 versus 9.4±1.3 mm Hg;
P
<0.009). No significant changes in heart rate or systemic arterial pressure were observed during any treatment. The treatments were well tolerated, without major adverse effects.

Conclusions

Sildenafil caused a long-lasting reduction in mean PAP and pulmonary vascular resistance, with a further additional improvement after iloprost inhalation. These data suggest that small doses of a phosphodiesterase type 5 inhibitor may be a useful adjunct to inhaled iloprost in the management of pulmonary hypertension.
Circulating Monocyte-Platelet Aggregates Are a More Sensitive Marker of In Vivo Platelet Activation Than Platelet Surface P-Selectin
Authors: Michelson Alan D. , Barnard Marc R. , Krueger Lori A. , Valeri C. Robert , Furman Mark I.
Published: September 2007

Background

Platelet surface P-selectin is considered the “gold standard” marker of platelet activation. Degranulated, P-selectin–positive platelets, however, aggregate with leukocytes in vitro and rapidly lose surface P-selectin in vivo.

Methods and Results

Flow cytometric tracking of autologous, biotinylated platelets in baboons enabled us to directly demonstrate for the first time in vivo that (1) infused degranulated platelets very rapidly form circulating aggregates with monocytes and neutrophils, and (2) 30 minutes after infusion of the degranulated platelets, the percentage of circulating monocytes aggregated with infused platelets persist at high levels, whereas the percentage of circulating neutrophils aggregated with infused platelets and the platelet surface P-selectin of nonaggregated infused platelets return to baseline. We therefore performed 2 clinical studies in patients with acute coronary syndromes. First, after percutaneous coronary intervention (n=10), there was an increased number of circulating monocyte-platelet (and to a lesser extent, neutrophil-platelet) aggregates but not P-selectin–positive platelets. Second, of 93 patients presenting to an Emergency Department with chest pain, patients with acute myocardial infarction (AMI) (n=9) had more circulating monocyte-platelet aggregates (34.2±10.3% [mean±SEM]) than patients with no AMI (n=84, 19.3±1.4%,
P
<0.05) and normal control subjects (n=10, 11.5±0.8%,
P
<0.001). Circulating P-selectin–positive platelets, however, were not increased in chest pain patients with or without AMI.

Conclusions

As demonstrated by 3 independent means (in vivo tracking of activated platelets in baboons, human coronary intervention, and human AMI), circulating monocyte-platelet aggregates are a more sensitive marker of in vivo platelet activation than platelet surface P-selectin.
Adenovirus-Mediated Heme Oxygenase-1 Gene Transfer Inhibits the Development of Atherosclerosis in Apolipoprotein E–Deficient Mice
Authors: Juan Shu-Hui , Lee Tzong-Shyuan , Tseng Kuang-Wen , Liou Jun-Yang , Shyue Song-Kun , Wu Kenneth K. , Chau Lee-Young
Published: September 2007

Background

Increasing evidence supports the role of heme oxygenase-1 (HO-1) in cytoprotective response and iron homeostasis. The object of this study was to investigate whether adenovirus-mediated gene transfer of HO-1 in arteries reduces iron overload and inhibits lesion formation in apolipoprotein E (apoE)–deficient mice.

Methods and Results

Infection of rat aortic smooth muscle cells with adenovirus carrying the human HO-1 gene (Adv-HO-1) resulted in a high-level expression of HO-1 protein, which effectively reduced the hemin-induced iron overload in these cells. Adenovirus-mediated gene transfer in arteries in vivo was achieved by direct injection of Adv-HO-1 into the left ventricles of anesthetized animals. Transgene was expressed in the endothelium and aortic lesion of apoE-deficient mice after they had received recombinant adenovirus for 1 week and gradually decayed during the next 5 weeks. When young apoE-deficient mice (14 weeks old) received Adv-HO-1 (2.5×10
9
pfu) for 6 weeks, lesions that developed in the aortic root or aortic arch were significantly smaller than those in control littermates receiving empty viral vector. Furthermore, the iron deposition as well as tissue iron content was much less in aortic tissue of Adv-HO-1–treated mice. The inhibitory effect of HO-1 gene transfer on the progression of advanced lesions was also observed in older apoE-deficient mice (20 weeks old) receiving Adv-HO-1 intraventricularly.

Conclusions

Overexpression of HO-1 in vascular cells facilitates iron metabolism and attenuates development of atherosclerosis in apoE-deficient mice.
Left Ventricular Muscle Mass and Elevated Heart Rate Are Associated With Coronary Plaque Disruption
Authors: Heidland Ulrich E. , Strauer Bodo E.
Published: September 2007

Background

Plaque disruption is the central pathophysiological mechanism underlying acute coronary syndromes and the progression of coronary atherosclerosis. There exists only scant information about the factors that are associated with its development. The aim of the current study was to analyze the contribution of hemodynamic forces in the pathogenesis of plaque disruption. Plaque disruption was diagnosed by coronary angiography of stenosed but not completely occluded coronary arteries.

Methods and Results

This study retrospectively analyzed 106 patients who underwent 2 coronary angiography procedures within 6 months. We investigated 53 patients with initially smooth stenoses who developed plaque disruption by the time of the second coronary angiogram and compared these patients with 53 age- and sex-matched individuals with smooth stenoses without angiographic signs of plaque disruption. The 2 groups were compared by analyzing central hemodynamics, echocardiographic measurements, and cardiovascular medication use. Logistic regression analysis identified positive associations between plaque disruption, left ventricular muscle mass >270 g, and a mean heart rate >80 bpm and a negative association with the use of β-blockers.

Conclusions

The associations documented by our investigation indicate that hemodynamic forces may play a crucial role in the pathogenesis of plaque disruption. These findings may help to identify patients who are at an increased risk of plaque disruption and who might gain benefit from pharmacological interventions aimed at reducing heart rate, for example, by the use of β-blockers, or a reduction of left ventricular hypertrophy.
Severely Impaired Cardiac Autonomic Nervous Activity After the Fontan Operation
Authors: Ohuchi Hideo , Hasegawa Satoshi , Yasuda Kenji , Yamada Osamu , Ono Yasuo , Echigo Shigeyuki
Published: September 2007

Background

Elevated neurohumoral activity and an abnormal cardiopulmonary response to exercise are well-established characteristics in patients after the Fontan operation. However, there have been few studies addressing cardiac autonomic nervous activity (CANA) in these patients.

Methods and Results

We evaluated CANA in 63 post-Fontan patients and 44 controls. Cardiac parasympathetic nervous activity (PSNA) was estimated by heart rate (HR) changes after cholinergic blockade, HR variability, and arterial baroreflex sensitivity. Cardiac sympathetic nervous activity was estimated by the heart to mediastinum [
123
I]metaiodobenzylguanidine activity ratio (H/M) and the HR increase (ΔHR) after isoproterenol infusion (β). ΔHR and peak oxygen uptake (V̇
o
2
) were measured by exercise test. There was no difference in β between the Fontan group and controls. PSNA and H/M were markedly lower than in controls (
P
<0.001). PSNA and β were related to ΔHR (
P
<0.05); however, peak V̇
o
2
was not correlated with ΔHR. Neither PSNA nor H/M was associated with clinical features, including hemodynamics, type of repair, number of surgical procedures, age at Fontan operation, or follow-up period, and administration of an angiotensin-converting enzyme inhibitor did not improve the impaired CANA in these patients.

Conclusions

After the Fontan procedure, postsynaptic β-sensitivity is maintained and is important in ΔHR during exercise as is PSNA, although ΔHR does not determine exercise capacity. The lack of a relationship between CANA and clinical features implies that, in addition to surgical damage, the Fontan circulation per se may impair CANA. Angiotensin-converting enzyme inhibitor administration does not change this abnormality.
Prior Coronary Artery Bypass Surgery and Risk of Death Among Patients With Ischemic Left Ventricular Dysfunction
Authors: Veenhuyzen George D. , Singh Steven N. , McAreavey Dorothea , Shelton Brent J. , Exner Derek V.
Published: September 2007

Background

Patients with ischemic LV dysfunction are at high risk of sudden death. However, no benefit from prophylactic defibrillator therapy was observed in a group of patients with LV dysfunction undergoing CABG (CABG Patch trial). Thus, the effect of CABG on future risk of sudden death in patients with LV dysfunction is of considerable interest.

Methods and Results

Mortality and modes of death in 5410 patients with ischemic LV dysfunction who were enrolled in the Studies of Left Ventricular Dysfunction (SOLVD) trials were evaluated. Outcomes of patients with (n=1870, 35%) versus without (n=3540) history of prior CABG were compared, and stratification by baseline ejection fraction (EF) values (<0.25, 0.25 to 0.30, and >0.30) was performed. Prior CABG was associated with a 25% (95% CI, 15% to 36%) reduction in risk of death and a 46% (95% CI, 30% to 58%) reduction in risk of sudden death independent of EF and severity of heart failure symptoms. As baseline EF declined, absolute reduction in risk of sudden death with prior CABG increased (
P
<0.01). No alteration in risk of death from progressive heart failure was observed with prior CABG. When these results were applied to a group of patients with LV dysfunction who had not undergone prior surgery (Coronary Artery Surgery Study Registry) predicted annual rates of death (8.2%) and sudden death (2.4%) were similar to those observed in the CABG Patch trial (7.9% and 2.3%, respectively).

Conclusions

In patients with ischemic LV dysfunction, prior CABG is associated with a significant independent reduction in mortality. These results appear to account for the lack of benefit from defibrillator therapy in the CABG Patch trial.
Electrical Remodeling in Pressure-Overload Cardiac Hypertrophy
Authors: Wang Zhengyi , Kutschke William , Richardson Kenneth E. , Karimi Mohsen , Hill Joseph A.
Published: September 2007

Background

Myocyte hypertrophy accompanies many forms of heart disease, but its contribution to electrical remodeling is unknown.

Methods and Results

We studied mouse hearts subjected to pressure overload by surgical thoracic aortic banding. In unbanded control hearts, action potential duration (APD) was significantly longer in subendocardial myocytes compared with subepicardial myocytes. Hypertrophy-associated APD prolongation was significantly greater in subendocardial myocytes compared with subepicardial myocytes, indicating stress-induced amplification of repolarization dispersion. To investigate the underlying basis, we performed voltage-clamp recordings on dissociated myocytes. Under control unoperated conditions, subendocardial myocytes exhibited significantly less transient outward current (I
to
) than did subepicardial cells. Hypertrophy was not associated with significant changes in I
to
, sustained current, or inward rectifier current densities, but peak L-type Ca
2+
current density (I
Ca,L
) increased 26% (
P
<0.05). Recovery from I
Ca,L
inactivation was accelerated in hypertrophied myocytes. Inhibition of calcineurin with cyclosporin A prevented increases in heart mass and myocyte size but was associated with an intermediate APD. The hypertrophy-associated increase in I
Ca,L
and the accelerated recovery from inactivation were blocked by cyclosporin A.

Conclusions

These data reveal regional variation in the electrophysiological response within the left ventricle by way of a mechanism involving upregulated Ca
2+
current and calcineurin. Furthermore, these results reveal partial uncoupling of electrophysiological and structural remodeling in hypertrophy.
Developing a Vasopressor Combination in a Pig Model of Adult Asphyxial Cardiac Arrest
Authors: Mayr Viktoria D. , Wenzel Volker , Voelckel Wolfgang G. , Krismer Anette C. , Mueller Tilko , Lurie Keith G. , Lindner Karl H.
Published: September 2007

Background

The purpose of this study was to investigate the effects of vasopressin versus epinephrine, and both drugs combined, in a porcine model of simulated adult asphyxial cardiac arrest.

Methods and Results

At ≈7 minutes after the endotracheal tube had been clamped, cardiac arrest was present in 24 pigs and remained untreated for another 8 minutes. After 4 minutes of basic life support cardiopulmonary resuscitation, pigs were randomly assigned to receive, every 5 minutes, either epinephrine (45, 200, or 200 μg/kg; n=6); vasopressin (0.4, 0.8, or 0.8 U/kg; n=6); or epinephrine combined with vasopressin (high-dose epinephrine/vasopressin combination, μg/kg and U/kg: 45/0.4, 200/0.8, or 200/0.8; n=6; optimal-dose epinephrine/vasopressin combination, 45/0.4, 45/0.8, or 45/0.8; n=6). Mean±SEM coronary perfusion pressure was significantly (
P
<0.05) higher 90 seconds after high- or optimal-dose epinephrine/vasopressin combinations versus vasopressin alone and versus epinephrine alone (37±10 versus 25±7 versus 19±8 versus 6±3 mm Hg; 42±6 versus 40±5 versus 21±5 versus 14±6 mm Hg; and 39±6 versus 37±4 versus 9±3 versus 12±4 mm Hg, respectively). Six of 6 high-dose, 6 of 6 optimal-dose vasopressin/epinephrine combination, 0 of 6 vasopressin, and 1 of 6 epinephrine pigs had return of spontaneous circulation (
P
<0.05).

Conclusions

Epinephrine combined with vasopressin, but not epinephrine or vasopressin alone, maintained elevated coronary perfusion pressure during cardiopulmonary resuscitation and resulted in significantly higher survival rates in this adult porcine asphyxial model.
Chronic Phosphocreatine Depletion by the Creatine Analogue β-Guanidinopropionate Is Associated With Increased Mortality and Loss of ATP in Rats After Myocardial Infarction
Authors: Horn Michael , Remkes Helga , Strömer Hinrik , Dienesch Charlotte , Neubauer Stefan
Published: September 2007

Background

The failing myocardium is characterized by reductions of phosphocreatine (PCr) and free creatine content and by decreases of energy reserve via creatine kinase (CK), ie, CK reaction velocity (Flux
CK
). It has remained unclear whether these changes contribute directly to contractile dysfunction. In the present study, myocardial PCr stores in a heart failure model were further depleted by feeding of the PCr analogue β-guanidinopropionate (GP). Functional and metabolic consequences were studied.

Methods and Results

Rats were subjected to sham operation or left coronary artery ligation (MI). Surviving rats were assigned to 4 groups and fed with 0% (n=7, Sham; n=5, MI) or 1% (n=7 Sham+GP, n=8 MI+GP) GP. Two additional groups were fed GP for 2 or 4 weeks before MI. After 8 weeks, hearts were isolated and perfused, and left ventricular pressure-volume curves were obtained. High-energy phosphate metabolism was determined with
31
P NMR spectroscopy. After GP feeding or MI, left ventricular pressure-volume curves were depressed by 33% and 32%, respectively, but GP feeding in MI hearts did not further impair mechanical function. Both MI and GP feeding reduced PCr content and Flux
CK
, but here, effects were additive. In MI+GP rats, PCr levels and Flux
CK
were reduced by 87% and 94%, respectively. Although ATP levels were maintained in the GP and MI groups, ATP content was reduced by 18% in MI+GP hearts. Furthermore, 24-hour mortality in GP-prefed rats was 100%.

Conclusions

Rats with an 87% predepletion of myocardial PCr content cannot survive an acute MI. Chronically infarcted hearts subjected to additional PCr depletion cannot maintain ATP homeostasis.
Central Arterial Compliance Is Associated With Age- and Habitual Exercise–Related Differences in Cardiovagal Baroreflex Sensitivity
Authors: Monahan Kevin D. , Tanaka Hirofumi , Dinenno Frank A. , Seals Douglas R.
Published: September 2007

Background

Cardiovagal baroreflex sensitivity (BRS) declines with age but is favorably modulated by habitual aerobic exercise. We tested the hypothesis that compliance (transducing capacity) of an elastic artery in which baroreceptors are located is associated with these age-exercise interactions.

Methods and Results

Nine young (28±1 years old) and 9 older (65±1) sedentary and 10 young (27±1) and 9 older (63±2) endurance-trained healthy men were studied. Cardiovagal BRS was assessed conventionally (R-R interval–systolic blood pressure [SBP] relation) by the Oxford technique. Because of age-associated increases in central arterial stiffness, cardiovagal BRS was expressed with both peripheral (Finapres) and central (applanation tonometry) SBP values. The change in carotid artery end-systolic lumen diameter (ultrasonography) per unit increase in SBP and the slope of the R-R interval–carotid artery diameter relation also were determined. Cardiovagal BRS declined with age in both sedentary (≈65%) and endurance-trained (≈40%) men but was higher in endurance-trained than sedentary older men regardless of the SBP values used (all
P
<0.05). Changes in carotid artery lumen diameter per unit increase in SBP mirrored these differences in cardiovagal BRS (all
P
<0.05). Thus, R-R interval prolongation per unit increase in carotid artery diameter was not different among the groups (
P
>0.70).

Conclusions

These results demonstrate that age- and habitual exercise–related differences in cardiovagal BRS are associated with corresponding differences in carotid artery compliance among healthy men.
Magnetic Resonance Imaging Permits In Vivo Monitoring of Catheter-Based Vascular Gene Delivery
Authors: Yang Xiaoming , Atalar Ergin , Li Dechun , Serfaty Jean-Michel , Wang Danming , Kumar Ananda , Cheng Linzhao
Published: September 2007

Background

Gene therapy is an exciting frontier in modern medicine. To date, most investigations about the imaging of gene therapy have primarily focused on noncardiovascular systems, and no in vivo imaging modalities are currently available for monitoring vascular gene therapy. The purpose of this study was to develop an in vivo imaging tool to monitor a catheter-based vascular gene delivery procedure.

Methods and Results

We produced gadolinium/blue dye and gadolinium/gene-vector media by mixing Magnevist with a trypan-blue or a lentiviral vector carrying a green fluorescent protein (GFP) gene. The gadolinium was used as an imaging marker for magnetic resonance (MR) imaging to visualize vessel wall enhancement, and the blue dye/GFP was used as a tissue stain marker for histology/immunohistochemistry to confirm the success of the transfer. Using Remedy gene delivery catheters, we transferred the gadolinium/blue dye (n=8) or gadolinium/GFP lentivirus (n=4) into the arteries of 12 pigs, that were monitored under high-resolution MR imaging. The results showed, in all 12 pigs, the gadolinium enhancement of the target vessel walls on MR imaging and the blue/GFP staining of the target vessel tissues with histology/immunohistochemistry. This study shows the potential of using MR imaging to dynamically visualize (1) where the gadolinium/genes are delivered; (2) how the target portion is marked; and (3) whether the gene transfer procedure causes complications.

Conclusions

We present a technical development that uses high-resolution MR imaging as an in vivo imaging tool to monitor catheter-based vascular gene delivery.
Hypothermia After Cardiac Arrest
Authors: Felberg R.A. , Krieger D.W. , Chuang R. , Persse D.E. , Burgin W.S. , Hickenbottom S.L. , Morgenstern L.B. , Rosales O. , Grotta J.C.
Published: September 2007

Background

No proven neuroprotective treatment exists for ischemic brain injury after cardiac arrest. Mild-to-moderate induced hypothermia (MIH) is effective in animal models.

Methods and Results

A safety and feasibility trial was designed to evaluate mild-to-moderate induced hypothermia by use of external cooling blankets after cardiac arrest. Inclusion criteria were return of spontaneous circulation within 60 minutes of advanced cardiac life support, hypothermia initiated within 90 minutes, persistent coma, and lack of acute myocardial infarction or unstable dysrhythmia. Hypothermia to 33°C was maintained for 24 hours followed by passive rewarming. Nine patients were prospectively enrolled. Mean time from advanced cardiac life support to return of spontaneous circulation was 11 minutes (range 3 to 30); advanced cardiac life support to initiation of hypothermia was 78 minutes (range 40 to 109); achieving 33°C took 301 minutes (range 90 to 690). Three patients completely recovered, and 1 had partial neurological recovery. One patient developed unstable cardiac dysrhythmia. No other unexpected complications occurred.

Conclusions

Mild-to-moderate induced hypothermia after cardiac arrest is feasible and safe. However, external cooling is slow and imprecise. Efforts to speed the start of cooling and to improve the cooling process are needed.
Mildly Oxidized LDL Induces Activation of Platelet-Derived Growth Factor β-Receptor Pathway
Authors: Escargueil-Blanc Isabelle , Salvayre Robert , Vacaresse Nathalie , Jürgens Günther , Darblade Benoit , Arnal Jean-François , Parthasarathy Sampath , Nègre-Salvayre Anne
Published: September 2007

Background

Mildly oxidized LDL (moxLDL) is thought to play a role in atherogenesis. MoxLDL induces derivatization of cell proteins and triggers a variety of intracellular signaling. We aimed to investigate whether moxLDL-induced protein derivatization may influence the activity of platelet-derived growth factor receptor β (PDGFRβ), a tyrosine kinase receptor of major importance in vascular biology and atherogenesis.

Methods and Results

In cultured rabbit arterial smooth muscle cells, moxLDL induces activation of the PDGFRβ signaling pathway, as shown by PDGFRβ tyrosine phosphorylation on Western blot and coimmunoprecipitation of SH2-containing proteins. The cellular events involved in the moxLDL-induced PDGFRβ activation can be summarized as follows. Oxidized lipids from moxLDL trigger two phases of PDGFRβ activation involving two separate mechanisms, as shown by experiments on cultured cells (in situ) and on immunopurified PDGFRβ (in vitro): (1) the first phase may be mediated by 4-hydroxynonenal, which induces PDGFRβ adduct formation and subsequent PDGFRβ activation (antioxidant-insensitive step); (2) the second phase involves ceramide-mediated generation of H
2
O
2
(these steps being inhibited by tosylphenylalanylchloromethylketone, an inhibitor of ceramide formation, and by antioxidant BHT, exogenous catalase, or overexpressed human catalase). Because 4-hydroxynonenal–PDGFRβ adducts are also detected in atherosclerotic aortas, it is suggested that this novel mechanism of moxLDL-induced PDGFRβ activation may occur during atherogenesis.

Conclusions

MoxLDL acts as a local autoparacrine mediator in the vascular wall, and PDGFRβ acts as a sensor for both oxidized lipids and oxidative stress. This constitutes a novel mechanism of PDGFRβ activation in atherosclerotic areas.
Increased Adenosine Monophosphate–Activated Protein Kinase Activity in Rat Hearts With Pressure-Overload Hypertrophy
Authors: Tian Rong , Musi Nicolas , D’Agostino Jessica , Hirshman Michael F. , Goodyear Laurie J.
Published: September 2007

Background

Recent reports suggest that activation of adenosine monophosphate (AMP)–activated protein kinase (AMPK), in response to acute changes in cellular energy status in cardiac and skeletal muscles, results in altered substrate utilization. We hypothesized that chronic alterations in myocardial energetics in hypertrophied hearts (left ventricular hypertrophy, LVH) will lead to elevated AMPK activity, which in turn regulates substrate utilization.

Methods and Results

Using
31
P NMR spectroscopy and biochemical assays, we found that in LVH hearts, adenosine triphosphate (ATP) concentration decreased by 10%, phosphocreatine concentration decreased by 30%, and total creatine concentration was unchanged. Thus, the ratio of phosphocreatine/creatine decreased to one third of controls, and the ratio of AMP/ATP increased to 5 times above controls. These changes were associated with increased α
1
and α
2
AMPK activity (3.5- and 4.8-fold above controls, respectively). The increase in AMPK α
1
activity was accompanied by a 2-fold increase in α
1
expression, whereas α
2
expression was decreased by 30% in LVH. The basal rate of 2-deoxyglucose uptake increased by 3-fold in LVH, which was associated with an increased amount of glucose transporters present on the plasma membrane.

Conclusions

These results demonstrate for the first time that chronic changes in myocardial energetics in hypertrophied hearts are accompanied by significant elevations in AMPK activity and isoform-specific alterations in AMPK expression. It also raises the possibility that AMPK signaling plays an important role in regulating substrate utilization in hypertrophied hearts.
Long-Term Effects of Nonselective Endothelin A and B Receptor Antagonism in Postinfarction Rat
Authors: Nguyen Quang Trinh , Cernacek Peter , Sirois Martin G. , Calderone Angelino , Lapointe Nathalie , Stewart Duncan J. , Rouleau Jean L.
Published: September 2007

Background

Some controversy exists as to the effects of endothelin (ET) receptor antagonism on long-term post–myocardial infarction (MI) evolution, particularly as it relates to the timing of the intervention after MI (<24 hours versus 10 days).

Methods and Results

Sham rats and rats surviving an acute MI for >20 hours (n=301) were assigned to treatment with saline or the nonselective ET
A
and ET
B
receptor antagonist LU 420627 (LU) started <24 hours (early) or 10 days (late) after MI and continued for 100 days. Long-term LU treatment led to increased mortality of rats with large MI, regardless of the timing of initiation of therapy. Early initiation of LU reduced survival from 61% to 16% (
P
<0.001 versus untreated), and later initiation reduced survival to 36% (
P
=0.012 versus untreated and
P
<0.001 versus early initiation). Early initiation of LU led to scar thinning, further left ventricular (LV) dilatation, LV dysfunction, and an excessive rise in right ventricular systolic pressure. Later initiation of LU did not modify scar formation but resulted in LV dilatation and dysfunction compared with the untreated group. Cardiac fibrosis tended to increase in the LU-treated MI groups. LU in the sham group reduced cardiac endothelial constitutive nitric oxide synthase but did not modify the changes that occurred with a large MI.

Conclusions

The use of the nonselective ET
A
and ET
B
receptor antagonist LU results in reduced survival, ventricular dilatation, and dysfunction whether started early or late after MI. Early initiation of LU resulted in scar expansion and a particularly unfavorable outcome.
Ventricular Dysfunction After Cardioplegic Arrest Is Improved After Myocardial Gene Transfer of a β-Adrenergic Receptor Kinase Inhibitor
Authors: Tevaearai Hendrik T. , Eckhart Andrea D. , Shotwell Kyle F. , Wilson Katrina , Koch Walter J.
Published: September 2007

Background

Acute cardiac contractile dysfunction is common after cardiopulmonary bypass (CPB). A potential molecular mechanism is enhanced β-adrenergic receptor kinase (βARK1) activity, because β-adrenergic receptor (βAR) signaling is altered in cardiomyocytes after cardioplegia. Therefore, we examined whether adenovirus-mediated intracoronary delivery of a βARK1 inhibitor (Adv-βARKct) could prevent post-CPB dysfunction.

Methods and Results

Rabbits were randomized to receive 5×10
11
total viral particles of Adv-βARKct or PBS. After 5 days, hearts were arrested with University of Wisconsin solution, excised, and stored at 4°C for 15 minutes or 4 hours before reperfusion on a Langendorff apparatus. Left ventricular (LV) function measured by end-diastolic pressure response to preload augmentation, contractility (LV dP/dt
max
), and relaxation (LV dP/dt
min
) was assessed by use of increasing doses of isoproterenol and compared with a control group of nonarrested hearts acutely perfused on the Langendorff apparatus. In the PBS-treated hearts, LV function decreased in a temporal manner and was significantly impaired compared with control hearts after 4 hours of cardioplegic arrest. LV function in Adv-βARKct-treated hearts, however, was significantly enhanced compared with PBS treatment and was similar to control nonarrested hearts even after 4 hours of cardioplegia. Biochemically, several aspects of βAR signaling were dysfunctional in PBS-treated hearts, whereas they were normalized in βARKct-overexpressing hearts.

Conclusions

Myocardial gene transfer of Adv-βARKct stabilizes βAR signaling and prevents LV dysfunction induced by prolonged cardioplegic arrest. Thus, βARK1 inhibition may represent a novel target in limiting depressed ventricular function after CPB.
Promotion of Collateral Growth by Granulocyte-Macrophage Colony-Stimulating Factor in Patients With Coronary Artery Disease
Authors: Seiler Christian , Pohl Tilmann , Wustmann Kerstin , Hutter Damian , Nicolet Pierre-Alain , Windecker Stephan , Eberli Franz R. , Meier Bernhard
Published: September 2007

Background

Experimentally, activated macrophages have been documented to induce vascular proliferation.

Methods and Results

In 21 patients (age 74±9 years) with extensive coronary artery disease not eligible for coronary artery bypass surgery, the effect of granulocyte-macrophage colony-stimulating factor (GM-CSF, Molgramostim) on quantitatively assessed collateral flow was tested in a randomized, double-blind, placebo-controlled fashion. The study protocol consisted of an invasive collateral flow index (CFI) measurement immediately before intracoronary injection of 40 μg of GM-CSF (n=10) or placebo (n=11) and after a 2-week period with subcutaneous GM-CSF (10 μg/kg) or placebo, respectively. CFI was determined by simultaneous measurement of mean aortic pressure (P
ao
, mm Hg), distal coronary occlusive pressure (P
occl
, mm Hg; using intracoronary sensor guidewires), and central venous pressure (CVP, mm Hg): CFI=(P
occl
−CVP)/(P
ao
−CVP). CFI, expressing collateral flow during coronary occlusion relative to normal antegrade flow during vessel patency, changed from 0.21±0.14 to 0.31±0.23 in the GM-CSF group (
P
<0.05) and from 0.30±0.16 to 0.23±0.11 in the placebo group (
P
=NS). The treatment-induced difference in CFI was +0.11±0.12 in the GM-CSF group and -0.07±0.12 in the placebo group (
P
=0.01). ECG signs of myocardial ischemia during coronary balloon occlusion occurred in 9 of 10 patients before and 5 of 10 patients after GM-CSF treatment (
P
=0.04), whereas they were observed in 5 of 11 patients before and 8 of 11 patients after placebo (
P
=NS).

Conclusions

This first clinical study investigating the potential of GM-CSF to improve collateral flow in patients with coronary artery disease documents its efficacy in a short-term administration protocol.
“Edge Effect” of
32
P Radioactive Stents Is Caused by the Combination of Chronic Stent Injury and Radioactive Dose Falloff
Authors: van der Giessen Willem J. , Regar Evelyn , Harteveld Miranda S. , Coen Veronique L.M.A. , Bhagwandien Rohit , Au Arthur , Levendag Peter C. , Ligthart Jurgen , Serruys Patrick W. , den Boer Ad , Verdouw Pieter D. , Boersma Eric , Hu Ty , van Beusekom Heleen M.M.
Published: September 2007

Background

Radioactive stents have been reported to reduce in-stent neointimal thickening. An unexpected increase in neointimal response was observed, however, at the stent-to-artery transitions, the so-called “edge effect.” To investigate the factors involved in this edge effect, we studied stents with 1 radioactive half and 1 regular nonradioactive half, thereby creating a midstent radioactive dose-falloff zone next to a nonradioactive stent-artery transition at one side and a radioactive stent-artery transition at the other side.

Methods and Results

Half-radioactive stents (n=20) and nonradioactive control stents (n=10) were implanted in the coronary arteries of Yucatan micropigs. Animals received aspirin and clopidogrel as antithrombotics. After 4 weeks, a significant midstent stenosis was observed by angiography in the half-radioactive stents. Two animals died suddenly because of coronary occlusion at this mid zone at 8 and 10 weeks. At 12-week follow-up angiography, intravascular ultrasound and histomorphometry showed a significant neointimal thickening at the midstent dose-falloff zone of the half-radioactive stents, but not at the stent-to-artery transitions at both extremities. Such a midstent response (mean angiographic late loss 1.0 mm) was not observed in the nonradioactive stents (mean loss 0.4 to 0.6 mm;
P
< 0.01).

Conclusions

The edge effect of high-dose radioactive stents in porcine coronary arteries is associated with the combination of stent injury and radioactive dose falloff.
Nonselective Versus Selective β-Adrenergic Receptor Blockade in Congestive Heart Failure
Authors: Azevedo Eduardo R. , Kubo Toshihiko , Mak Susanna , Al-Hesayen Abdul , Schofield Anne , Allan Rebecca , Kelly Susan , Newton Gary E. , Floras John S. , Parker John D.
Published: September 2007

Background

Activation of the sympathetic nervous system has important prognostic implications in chronic heart failure. Nonselective versus selective β-adrenergic receptor antagonists may have differential effects on norepinephrine release from nerve terminals mediated by prejunctional β
2
-adrenergic receptors.

Methods and Results

—

Thirty-six patients with chronic heart failure were randomized to the nonselective β-blocker carvedilol or the selective β-blocker metoprolol (double-blind). Measurements of hemodynamics and cardiac and systemic norepinephrine spillover as well as microneurographic recordings of muscle sympathetic nerve traffic were made before and after 4 months of therapy. In the carvedilol group (n=17), there were significant reductions in both total body (−1.7±0.5 nmol/min,
P
<0.01) and cardiac norepinephrine spillover (−87±29 pmol/min,
P
<0.01). By contrast, in the metoprolol group (n=14), there were no significant changes in total body or cardiac norepinephrine spillover. Responses in the carvedilol group were significantly different from those observed in the metoprolol group (
P
<0.05). Both agents caused a reduction in heart rate and increases in pulse pressure, although mean arterial pressure did not change. Importantly, microneurographic measures of sympathetic nerve traffic to skeletal muscle did not change in either group.

Conclusions

Therapy with carvedilol caused significant decreases in systemic and cardiac norepinephrine spillover, an indirect measure of norepinephrine release. Such changes were not observed in patients treated with metoprolol. There was no effect of either agent on sympathetic efferent neuronal discharge to skeletal muscle. These findings suggest that carvedilol, a nonselective β-blocker, caused its sympathoinhibitory effect by blocking peripheral, prejunctional β-adrenergic receptors.