bluuebunny/crossref_metadata_2025 huggingface dataset:
Mitofusin 2 Triggers Vascular Smooth Muscle Cell Apoptosis via Mitochondrial Death Pathway
Authors: Guo Xiaomei , Chen Kuang-Hueih , Guo Yanhong , Liao Hua , Tang Jian , Xiao Rui-Ping
Published: September 2007

Previous studies have shown that mitofusin 2 (
Mfn-2
) (or hyperplasia suppressor gene [
HSG
]) inhibits vascular smooth muscle cell (VSMC) proliferation. Here, we demonstrate that Mfn-2 is a primary determinant of VSMC apoptosis. First, oxidative stress with H
2
O
2
, inhibition of protein kinase C with staurosporine, activation of protein kinase A with forskolin, and serum deprivation concurrently elevate Mfn-2 expression and induce VSMC apoptosis. Second, overexpression of Mfn-2 also triggers apoptosis of VSMCs in culture and in balloon-injured rat carotid arteries, thus contributing to Mfn-2–mediated prevention of neointima formation after angioplasty. Third, Mfn-2 silencing protects VSMCs against H
2
O
2
or Mfn-2 overexpression–induced apoptosis, indicating that upregulation of Mfn-2 is necessary and sufficient for oxidative stress–mediated VSMC apoptosis. The Mfn-2 proapoptotic effect is independent of its role in mitochondrial fusion but mainly mediated by inhibition of Akt signaling and the resultant activation of the mitochondrial apoptotic pathway, as manifested by decreased Akt phosphorylation, increased mitochondrial Bax/Bcl-2 ratio, cytochrome
c
release, and activation of caspases-9 and caspase-3. Furthermore, Mfn-2–induced apoptosis was blocked by overexpression of an active phosphoinositide 3-kinase mutant or Bcl-xL or inhibition of caspase-9 but not caspases-8. Thus, in addition to its antiproliferative effects, Mfn-2 constitutes a primary determinant of VSMC apoptosis.
Visualization of Discrete Microinfarction After Percutaneous Coronary Intervention Associated With Mild Creatine Kinase-MB Elevation
Authors: Ricciardi Mark J. , Wu Edwin , Davidson Charles J. , Choi Kelly M. , Klocke Francis J. , Bonow Robert O. , Judd Robert M. , Kim Raymond J.
Published: September 2007

Background
—Mild elevations in creatine kinase-MB (CK-MB) are common after successful percutaneous coronary interventions and are associated with future adverse cardiac events. The mechanism for CK-MB release remains unclear. A new contrast-enhanced MRI technique allows direct visualization of myonecrosis.

Methods and Results
—Fourteen patients without prior infarction underwent cine and contrast-enhanced MRI after successful coronary stenting; 9 patients had procedure-related CK-MB elevation, and 5 did not (negative controls). The mean age of all patients was 61 years, 36% had diabetes, 43% had multivessel coronary artery disease, and all had a normal ejection fraction. Twelve patients (86%) received an intravenous glycoprotein IIb/IIIa inhibitor; none underwent atherectomy, and all had final TIMI 3 flow. Of the 9 patients with CK-MB elevation, 5 had a minor side branch occlusion during stenting, 2 had transient ECG changes, and none developed Q-waves. The median CK-MB was 21 ng/mL (range, 12 to 93 ng/mL), which is 2.3× the upper limit of normal. Contrast-enhanced MRI demonstrated discrete regions of hyperenhancement within the target vessel perfusion territory in all 9 patients. Only one developed a new wall motion abnormality. The median estimated mass of myonecrosis was 2.0 g (range, 0.7 to 12.2 g), or 1.5% of left ventricular mass (range, 0.4% to 6.0%). Hyperenhancement persisted in 5 of the 6 who underwent a repeat MRI at 3 to 12 months. No control patient had hyperenhancement.

Conclusions
—Contrast-enhanced MRI provides an anatomical correlate to biochemical evidence of procedure-related myocardial injury, despite the lack of ECG changes or wall motion abnormalities. Mild elevation of CK-MB after percutaneous coronary intervention is the result of discrete microinfarction.
Increase in Circulating Endothelial Progenitor Cells by Statin Therapy in Patients With Stable Coronary Artery Disease
Authors: Vasa Mariuca , Fichtlscherer Stephan , Adler Klaudia , Aicher Alexandra , Martin Hans , Zeiher Andreas M. , Dimmeler Stefanie
Published: September 2007

Background
—Therapeutic neovascularization may constitute an important strategy to salvage tissue from critical ischemia. Circulating bone marrow–derived endothelial progenitor cells (EPCs) were shown to augment the neovascularization of ischemic tissue. In addition to lipid-lowering activity, hydroxymethyl glutaryl coenzyme A reductase inhibitors (statins) reportedly promote the neovascularization of ischemic tissue in normocholesterolemic animals.

Methods and Results
—Fifteen patients with angiographically documented stable coronary artery disease (CAD) were prospectively treated with 40 mg of atorvastatin per day for 4 weeks. Before and weekly after the initiation of statin therapy, EPCs were isolated from peripheral blood and counted. In addition, the number of hematopoietic precursor cells positive for CD34, CD133, and CD34/kinase insert domain receptor was analyzed. Statin treatment of patients with stable CAD was associated with an ≈1.5-fold increase in the number of circulating EPCs by 1 week after initiation of treatment; this was followed by sustained increased levels to ≈3-fold throughout the 4-week study period. Moreover, the number of CD34/kinase insert domain receptor–positive hematopoietic progenitor cells was significantly augmented after 4 weeks of therapy. Atorvastatin treatment increased the further functional activity of EPCs, as assessed by their migratory capacity.

Conclusion
—The results of the present study define a novel mechanism of action of statin treatment in patients with stable CAD: the augmentation of circulating EPCs with enhanced functional activity. Given the well-established role of EPCs of participating in repair after ischemic injury, stimulation of EPCs by statins may contribute to the clinical benefit of statin therapy in patients with CAD.
Deficiency of Tissue Factor Pathway Inhibitor Promotes Atherosclerosis and Thrombosis in Mice
Authors: Westrick Randal J. , Bodary Peter F. , Xu ZuoJun , Shen Yue-Chun , Broze George J. , Eitzman Daniel T.
Published: September 2007

Background
—Tissue factor initiates blood coagulation after atherosclerotic plaque disruption. Tissue factor pathway inhibitor (TFPI) inhibits tissue factor activity and may reduce thrombus formation in this setting. We evaluated the effect of heterozygous TFPI deficiency on the development of atherosclerosis and thrombosis in atherosclerosis-prone mice.

Methods and Results
—Mice with a combined heterozygous TFPI deficiency and homozygous apolipoprotein E deficiency (TFPI
+/–
/apoE
–/–
) were generated by crossbreeding, and they were analyzed for atherosclerosis throughout the vascular tree. Compared with mice with a normal TFPI genotype (TFPI
+/+
/apoE
–/–
), mice with a TFPI deficiency exhibited a greater atherosclerotic burden involving the carotid and common iliac arteries. Staining for active tissue factor within the plaque revealed more activity in TFPI
+/–
/apoE
–/–
mice compared with TFPI
+/+
/apoE
–/–
mice. Consistent with increased plaque tissue factor activity, the time to occlusive thrombosis after photochemical carotid plaque injury was significantly decreased in TFPI
+/–
/apoE
–/–
mice.

Conclusions
—These observations indicate that TFPI protects from atherosclerosis and is an important regulator of the thrombosis that occurs in the setting of atherosclerosis.
Accurate Assessment of Patient Effective Radiation Dose and Associated Detriment Risk From Radiofrequency Catheter Ablation Procedures
Authors: Perisinakis Kostas , Damilakis John , Theocharopoulos Nicholas , Manios Emmanouel , Vardas Panayiotis , Gourtsoyiannis Nicholas
Published: September 2007

Background—
Radiofrequency (RF) cardiac catheter ablation procedures may require extended fluoroscopic exposure resulting in elevated radiation risk. The aim of the present study was to accurately establish RF ablation radiation risk levels and to provide means for accurate patient risk estimation from studies performed in any electrophysiology laboratory.

Methods and Results—
Fluoroscopy required during cardiac ablation was classified into 4 types identified by beam orientation and irradiated tissue: (1) posteroanterior exposure during catheter advancing from the groin to the heart, (2) posteroanterior heart exposure, (3) left anterior oblique heart exposure, and (4) right anterior oblique heart exposure. The duration of each exposure was monitored in 24 patients undergoing RF cardiac ablation. Dose per minute of fluoroscopy was measured at 15 organs/tissues for each projection with the use of anthropomorphic phantom and thermoluminescence dosimetry. The effective dose rate was 219, 144, 136, and 112 μGy/min for groin-to-heart posteroanterior, posteroanterior, left anterior oblique, and right anterior oblique exposure, respectively. A typical ablation procedure results in a total effective dose of 8.3 mSv per hour of fluoroscopy. The average excess of fatal cancers was estimated to be 650 and 480 per million patients undergoing RF ablation requiring 1 hour of fluoroscopy for US and UK populations, respectively. The average risk for genetic defects was determined to be 1 per million births.

Conclusions—
Radiation risk from RF cardiac ablation is moderate compared with other complications, but it may highly exceed radiation risk from common radiological procedures. Efforts should be made toward minimization of patient radiation risk from RF ablation procedures.
Cerebral Protection With Filter Devices During Carotid Artery Stenting
Authors: Reimers Bernhard , Corvaja Nicola , Moshiri Sharam , Saccà Salvatore , Albiero Remo , Di Mario Carlo , Pascotto Pietro , Colombo Antonio
Published: September 2007

Background
—Distal embolization of debris during percutaneous carotid artery stenting may result in neurological deficit. Filter devices for cerebral protection potentially reduce the risk of embolization.

Methods and Results
—Elective carotid stent implantation using 3 different types of distal filter protection devices was attempted in 88 consecutive lesions (84 patients) in the internal carotid artery that had >70% diameter stenosis (mean, 78.7±10.7%). Procedures were performed in 3 different centers. The mean age of the patients was 69±8 years, 75% were men, and 35.7% had neurological symptoms. In 86 lesions, a stent was successfully implanted (97.7%). In 83 of these 86 procedures (96.5%), it was possible to position a filter device. In 53% of filters, there was macroscopic evidence of debris. Collected material consisted of lipid-rich macrophages, fibrin material, and cholesterol clefts. Neurological complications during the procedure, in the hospital, and at 30 days of clinical follow-up occurred in only one patient (1.2%). This patient suffered a minor stroke that resolved within 1 week. Two major adverse cardiac events (2.3%) occurred during the 30 days of follow-up.

Conclusions
—Filter protection during carotid artery stenting seems feasible and safe. In the present series, the incidence of neurological complications was low.
Synergistic Effect of Urotensin II With Mildly Oxidized LDL on DNA Synthesis in Vascular Smooth Muscle Cells
Authors: Watanabe Takuya , Pakala Rajbabu , Katagiri Takashi , Benedict Claude R.
Published: September 2007

Background
—The urotensin II (UII) found in coronary atheroma is the most potent vasoconstrictor known to date. Mildly oxidized LDL (moxLDL) contributes to atherogenesis and plaque formation. We assessed the effect of UII and its interaction with moxLDL and the oxidative components of moxLDL on vascular smooth muscle cell (VSMC) proliferation.

Methods and Results
—Growth-arrested VSMCs were incubated in serum-free medium with different concentrations of LDL, moxLDL, oxLDL, hydrogen peroxide, lysophosphatidylcholine, or 4-hydroxy-2-nonenal, with or without UII. [
3
H]Thymidine incorporation into DNA was measured as an index of VSMC proliferation. UII stimulated [
3
H]thymidine incorporation in a dose-dependent manner, with a maximal effect at a concentration of 50 nmol/L (161%). Low concentrations of UII potentiated the mitogenic effect of LDL (108% to 242%), oxLDL (129% to 302%), moxLDL (120% to 337%), hydrogen peroxide (177% to 226%), lysophosphatidylcholine (115% to 332%), and 4-hydroxy-2-nonenal (142% to 299%). The synergistic interaction between UII and moxLDL was partially inhibited by anti-Gq/11α antibody, the epidermal growth factor receptor tyrosine kinase inhibitor erbstatin A (10 μmol/L), and the intracellular free radical scavenger N-acetylcysteine (400 μmol/L) and was completely inhibited by the c-Src tyrosine kinase inhibitor radicicol (10 μmol/L), the protein kinase C (PKC) inhibitor Ro31-8220 (0.1 μmol/L), and the mitogen-activated protein kinase (MAPK) kinase inhibitor PD098059 (10 μmol/L).

Conclusions
—Our results suggest that UII acts synergistically with moxLDL in inducing VSMC proliferation via the c-Src/PKC/MAPK pathway, which may explain the relatively rapid progression of atherosclerosis in patients with hypertension and hypercholesterolemia.
Biomechanical Strain Induces Class A Scavenger Receptor Expression in Human Monocyte/Macrophages and THP-1 Cells
Authors: Sakamoto Hironosuke , Aikawa Masanori , Hill Christopher C. , Weiss Daiana , Taylor W. Robert , Libby Peter , Lee Richard T.
Published: September 2007

Background
—Although hypertension is an important risk factor for the development of atherosclerosis, the mechanisms for this interaction are incompletely described. Previous studies have suggested that biomechanical strain regulates macrophage phenotype. We tested the hypothesis that biomechanical strain can induce expression of the class A scavenger receptor (SRA), an important lipoprotein receptor in atherogenesis.

Methods and Results
—Human monocyte/macrophages or THP-1 cells were cultured in a device that imposes uniform biaxial cyclic 1-Hz strains of 0%, 1%, 2%, or 3%, and SRA expression was analyzed. Mechanical strains induced SRA mRNA (3.5±0.6-fold at 3% strain for 48 hours,
P
<0.01) and SRA protein in THP-1 cells in an amplitude-dependent manner. This induction was accompanied by augmented expression of the class B scavenger receptor CD36 (2.8±0.3-fold,
P
<0.001) but not by increased peroxisome proliferator–activated receptor-γ expression. To evaluate this effect in vivo, apolipoprotein E
−/−
mice were randomly assigned to receive standard chow, a high-cholesterol diet, or a high-cholesterol diet with hypertension induced by angiotensin II infusion for 8 weeks. Immunohistochemistry revealed that among macrophages in atherosclerotic lesions of the aorta, the proportion of macrophages with SRA expression was highest in hypertensive animals on a high-cholesterol diet (43.9±0.7%, versus 12.0±2.0% for normotensive animals on a high-cholesterol diet and 4.7±4.7% for animals on standard chow;
P
<0.001).

Conclusions
—Biomechanical strain induces SRA expression by monocyte/macrophages, suggesting a novel mechanism for promotion of atherosclerosis in hypertensive patients.
Investigation of Coronary Venous Anatomy by Retrograde Venography in Patients With Malignant Ventricular Tachycardia
Authors: Meisel Eckhard , Pfeiffer Dietrich , Engelmann Lothar , Tebbenjohanns Jürgen , Schubert Bernd , Hahn Stephen , Fleck Eckart , Butter Christian
Published: September 2007

Background

The coronary venous system is increasingly used for left ventricular or biventricular pacing in patients with severe heart failure. The present study investigated the structure of the coronary veins in patients presenting with structural heart disease and malignant ventricular tachyarrhythmias. The availability of veins for possible lead placement was assessed.

Methods and Results

The number, relative size, and location of coronary veins were evaluated by retrograde venography in 129 patients undergoing cardioverter-defibrillator implantation. Detailed x-ray image analysis was performed in 86 patients, for whom optimal coronary sinus occlusion and vein visualization was achieved. The anterior interventricular vein and the middle cardiac vein were visible in 85 (99%) of 86 patients and in 86 (100%) of 86 patients, respectively. Between these 2 veins, at least 1 additional prominent vein was visible in 85 (99%) of 86 patients. Just 1 vein was present in 44 (51%) of 86 patients. Two veins were observed in 40 (46%) of 86 patients, and >2 veins were visualized in 2 (2%) of 86 patients. Venous anatomy allowed positioning of a 0.014-in guidewire in a coronary vein in 115 (93%) of 124 patients.

Conclusions

The presence, diameter, angulation, and tortuosity of veins as visualized by retrograde venography determine their acceptability for the placement of a lead in a predetermined location. Despite the considerable variability of the coronary venous system among patients, a lateral vessel for lead introduction was available in 82%, and a posterior or lateral vessel was available in 99% of individuals within a patient population that could potentially benefit from a lead on the left ventricle.
Pharmacodynamics and Pharmacokinetics of Higher-Dose, Double-Bolus Eptifibatide in Percutaneous Coronary Intervention
Authors: Gilchrist Ian C. , O’Shea J. Conor , Kosoglou Teddy , Jennings Lisa K. , Lorenz Todd J. , Kitt Michael M. , Kleiman Neal S. , Talley David , Aguirre Frank , Davidson Charles , Runyon John , Tcheng James E.
Published: September 2007

Background

Pharmacodynamics of eptifibatide, a cyclic heptapeptide antagonist of platelet glycoprotein IIb/IIIa, are substantially altered by anticoagulants that chelate calcium, resulting in overestimation ex vivo of the in vivo effects of this agent. We conducted a dose-ranging study to characterize the pharmacodynamics and pharmacokinetics of eptifibatide under physiological conditions.

Methods and Results

Patients (n=39) undergoing elective percutaneous coronary intervention were randomly assigned to an eptifibatide bolus followed by an infusion (180-μg/kg bolus followed by 2 μg/kg per minute or 250-μg/kg bolus followed by 3 μg/kg per minute) for 18 to 24 hours. In a 2:1 ratio, these patients received either a second bolus of eptifibatide (90 μg/kg or 125 μg/kg for the initial 180-μg/kg or 250-μg/kg groups, respectively) or placebo 30 minutes after the initial bolus. Bleeding times, ex vivo platelet aggregation, receptor occupancy, and plasma eptifibatide levels at baseline and at 1, 2, 3, 4, 6, and 8 hours were evaluated. Platelet inhibition was dose dependent and >80% in all groups by steady state. The single-bolus regimens had a transient loss of inhibition at 1 hour, consistent with rapid distribution and drug elimination. Pharmacokinetic modeling suggested that optimal dosing of eptifibatide would be obtained with a 180-μg/kg bolus and a 2-μg/kg per minute infusion followed by a second 180-μg/kg bolus 10 minutes later.

Conclusions

A novel higher-dose, double-bolus regimen of eptifibatide in coronary intervention attains and maintains >90% inhibition of platelet aggregation in >90% of patients, providing the pharmacodynamic construct for the design of the Enhanced Suppression of the Platelet IIb/IIIa Receptor with Integrilin Therapy (ESPRIT) trial of adjunctive eptifibatide in coronary stent implantation.
Novel Drug-Delivery Stent
Authors: Honda Yasuhiro , Grube Eberhard , de la Fuente Luis M. , Yock Paul G. , Stertzer Simon H. , Fitzgerald Peter J.
Published: September 2007

Background

The aim of this study was to use serial intravascular ultrasound (IVUS) to evaluate the long-term effect of stent-based 7-hexanoyltaxol (QP2, a taxane analogue) delivery on neointimal tissue growth within the stent and on vessel dimensions at the adjacent reference segments.

Methods and Results

Serial IVUS analyses (immediately after intervention and at follow-up at 8.3 months) were performed in 15 native coronary lesions treated with the QuaDS-QP2 stent. IVUS measurements were performed at 8 cross-sections in each target segment (4 cross-sections within the stent and 2 cross-sections in each reference segment). At baseline, no significant plaque protrusion or thrombus was detected in the target segment. Mild incomplete stent apposition and edge dissection were observed in one and two cases, respectively. Percent expansion of the stent (minimum stent area/average reference lumen area) was 96.0±21.7%. At follow-up, mean neointimal area within the stent was 1.2±1.3 mm
2
, and mean cross-sectional narrowing (neointimal area/stent area) was 13.6±14.9%. At the vessel segments immediately adjacent to the stent, a significant increase in plaque area (1.9±2.6 mm
2
,
P
=0.001) was observed, but vessel area remained unchanged. However, no patients showed clinically significant in-stent or edge restenosis (diameter stenosis ≥50%) during the follow-up period.

Conclusions

The first human experience with the new drug-delivery stent showed a minimal amount of neointimal proliferation in the stented segment. Late lumen loss at the reference sites adjacent to the stent was acceptable and predominantly due to plaque proliferation.
Amelioration of Angiotensin II–Induced Cardiac Injury by a 3-Hydroxy-3-Methylglutaryl Coenzyme A Reductase Inhibitor
Authors: Dechend Ralf , Fiebeler Anette , Park Joon-Keun , Muller Dominik N. , Theuer Juergen , Mervaala Eero , Bieringer Markus , Gulba Dietrich , Dietz Rainer , Luft Friedrich C. , Haller Hermann
Published: September 2007

Background

3-Hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors (statins) have effects that extend beyond cholesterol reduction. We used an angiotensin (Ang) II–dependent model to test the hypothesis that cerivastatin ameliorates cardiac injury.

Methods and Results

We treated rats transgenic for human renin and angiotensinogen (dTGR) chronically from weeks 4 to 7 with cerivastatin (0.5 mg/kg by gavage). We used immunohistochemistry, electrophoretic mobility shift assays, and reverse transcription–polymerase chain reaction techniques. Compared with control dTGR, dTGR treated with cerivastatin had reduced mortality, blood pressure, cardiac hypertrophy, macrophage infiltration, and collagen I, laminin, and fibronectin deposition. Basic fibroblast growth factor mRNA and protein expression were markedly reduced, as was interleukin-6 expression. The transcription factors NF-κB and AP-1 were substantially less activated, although plasma cholesterol was not decreased.

Conclusions

These results suggest that statins ameliorate Ang II–induced hypertension, cardiac hypertrophy, fibrosis, and remodeling independently of cholesterol reduction. Although the clinical significance remains uncertain, the results suggest that statins interfere with Ang II–induced signaling and transcription factor activation, thereby ameliorating end-organ damage.
Randomized Comparison of Ticlopidine and Clopidogrel After Intracoronary Stent Implantation in a Broad Patient Population
Authors: Taniuchi Megumi , Kurz Howard I. , Lasala John M.
Published: September 2007

Background

Although clopidogrel is used to prevent subacute stent thrombosis, its safety and efficacy have not been compared with ticlopidine in a randomized manner in the United States.

Methods and Results

Patients with successful intracoronary stent implantation were randomly assigned to therapy with ticlopidine or clopidogrel. Loading doses were administered immediately after the procedure, and the drugs were prescribed for 2 weeks. One thousand sixteen patients were enrolled: 522 patients were randomly assigned to ticlopidine therapy and 494 to clopidogrel. High-risk characteristics included recent myocardial infarction in 41.4% of the cases, angiographically evident thrombus in 20.9%, and abrupt or threatened closure in 3.64%. An intravenous glycoprotein IIb/IIIa inhibitor was used in 48.2% of the cases, and thrombocytopenia occurred in 1.43% of these patients. Failure to complete 2 weeks of therapy occurred in 3.64% of the patients treated with ticlopidine and in 1.62% of the patients treated with clopidogrel (
P
=0.043). Within 30 days, thrombosis of the stent occurred in 1.92% of the patients in the ticlopidine group and in 2.02% of the clopidogrel group (
P
=0.901). A major adverse cardiac event occurred in 4.60% of patients receiving ticlopidine and in 3.85% of patients receiving clopidogrel (
P
=0.551).

Conclusions

Clopidogrel is better tolerated than ticlopidine during a 2-week regimen after intracoronary stent implantation. Combining either thienopyridine with an intravenous platelet IIb/IIIa inhibitor appears to be safe. When applied to a broad spectrum of patients receiving stent implantation, clopidogrel confers similar protection as ticlopidine against subacute stent thrombosis and major adverse cardiac events.
Clinical Implications for Affected Parents and Siblings of Probands With Long-QT Syndrome
Authors: Kimbrough John , Moss Arthur J. , Zareba Wojciech , Robinson Jennifer L. , Hall W. Jackson , Benhorin Jesaia , Locati Emanuela H. , Medina Aharon , Napolitano Carlo , Priori Silvia , Schwartz Peter J. , Timothy Katherine , Towbin Jeffrey A. , Vincent G. Michael , Zhang Li
Published: September 2007

Background

Whenever a proband is identified with long-QT syndrome (LQTS), his or her parents and siblings should be evaluated regarding the possibility of carrying the disorder. In the majority of cases, one of the proband’s parents and one or more siblings are affected. The aim of this study was (1) to determine whether the clinical severity of LQTS in the proband is useful in identifying first-degree family members at high risk for cardiac events, and (2) to evaluate the clinical course of affected parents and siblings of LQTS probands.

Methods and Results

The clinical and ECG characteristics of 211 LQTS probands and 791 first-degree relatives (422 parents and 369 siblings) were studied to determine if the clinical profile of the proband is useful in determining the clinical severity of LQTS in affected parents and siblings. Affected female parents of an LQTS proband had a greater cumulative risk for a first cardiac event than affected male parents. The probability of a parent or sibling having a first cardiac event was not significantly influenced by the severity of the proband’s clinical symptoms. Female sex and QT
c
duration were risk factors for cardiac events among affected parents, and QT
c
was the only risk factor for cardiac events in affected siblings.

Conclusions

The severity profile of LQTS in a proband was not found to be useful in identifying the clinical severity of LQTS in affected first-degree relatives of the proband.
Recombinant Vascular Endothelial Growth Factor Secreted From Tissue-Engineered Bioartificial Muscles Promotes Localized Angiogenesis
Authors: Lu Yongxin , Shansky Janet , Del Tatto Michael , Ferland Paulette , Wang Xiaoyun , Vandenburgh Herman
Published: September 2007

Background

Therapeutic angiogenesis by the administration of recombinant vascular endothelial growth factor (rVEGF) is a novel strategy for the treatment of ischemic disorders. rVEGF has been delivered as a protein, by plasmid DNA, and by genetically engineered cells with different pharmacokinetic and physiological properties. In the present study, we examined a new method for delivery of rVEGF using implantable bioartificial muscle (BAM) tissues made from genetically modified primary skeletal myoblasts. Our goal was to determine whether the rVEGF delivered by this technique promoted controlled angiogenesis in nonischemic and/or ischemic adult mouse tissue.

Methods and Results

Primary adult mouse myoblasts were retrovirally transduced to secrete human or mouse rVEGF and tissue-engineered into implantable 1×10 to 15-mm BAMs containing parallel arrays of postmitotic myofibers. In vitro, they secreted 290 to 511 ng of bioactive mouse or human VEGF/BAM per day. rVEGF BAMs implanted subcutaneously into syngeneic mice caused a 30-fold increase in the number of CD31-positive capillary cells within the BAM by 1 week compared with control BAMs. Implantation of rVEGF-secreting BAMs into ischemic hindlimbs resulted in a 2- to 3-fold increase in capillary density of neighboring host muscle by 1 week and out to 4 weeks with no evidence of hemangioma formation.

Conclusions

Local delivery of rVEGF from BAMs rapidly increases capillary density both within the BAM itself and in adjacent ischemic muscle tissue. Genetically engineered muscle tissue provides a method for therapeutic protein delivery in a dose-regulated fashion.
Peripheral Chemoreceptor Hypersensitivity
Authors: Ponikowski Piotr , Chua Tuan Peng , Anker Stefan D. , Francis Darrel P. , Doehner Wolfram , Banasiak Waldemar , Poole-Wilson Phillip A. , Piepoli Massimo F. , Coats Andrew J.S.
Published: September 2007

Background

Peripheral chemoreceptor hypersensitivity is a feature of abnormal cardiorespiratory reflex control in chronic heart failure (CHF) and may contribute to sympathetic overactivity, attenuated baroreflex sensitivity (BRS), and excessive ventilation during exercise. We studied whether augmented peripheral chemosensitivity carries independent prognostic significance.

Methods and Results

We assessed peripheral chemosensitivity (ventilatory response to hypoxia using transient inhalation of pure nitrogen) and BRS (phenylephrine and spectral methods) in 80 consecutive CHF patients (age 58±9 years; left ventricular ejection fraction [LVEF] 24±12%; peak oxygen consumption [peak V̇
o
2
] 18±7 mL
−1
· min
−1
). CHF patients demonstrated augmented peripheral chemosensitivity and decreased BRS (all
P
<0.01 versus reference values). During follow-up (median 41 months, >3 years in all survivors), 37 patients died. High peripheral chemosensitivity (>0.72 L · min
−1
· %Sa
o
2
−1
) predicted impaired survival (hazard ratio 3.2, 95% CI 1.6 to 6.0,
P
=0.0006). In the 27 patients (34%) with high peripheral chemosensitivity, 3-year survival was 41% (95% CI 22% to 60%) compared with 77% (66% to 89%) in 53 patients with normal chemosensitivity (
P
=0.0002). In multivariate analyses, augmented chemosensitivity independently predicted death (hazard ratio 2.8, 95% CI 1.5 to 5.5, adjusted for age, peak V̇
o
2
, and V̇
e
/V̇
co
2
[
P
=0.002]; hazard ratio 2.6, 95% CI 1.3 to 5.1, adjusted for age, LVEF, and peak V̇
o
2
[
P
=0.008]). Depressed BRS was related to unfavorable prognosis in univariate analysis (
P
=0.05) but not in multivariate analyses.

Conclusions

Hypersensitivity of the peripheral chemoreceptors independently predicts adverse prognosis in ambulatory patients with CHF. This hyperactive excitatory reflex, through its inhibitory effect on the baroreflex, may be the reason for the previously observed prognostic association of the latter.
Randomized Comparison of Enoxaparin, a Low-Molecular-Weight Heparin, With Unfractionated Heparin Adjunctive to Recombinant Tissue Plasminogen Activator Thrombolysis and Aspirin
Authors: Ross Allan M. , Molhoek Peter , Lundergan Conor , Knudtson Merrill , Draoui Yasmine , Regalado Lorna , Le Louer Veronique , Bigonzi Frederique , Schwartz Whitney , de Jong Egbert , Coyne Karin
Published: September 2007

Background

—

Adjunctive unfractionated heparin (UFH) during thrombolytic therapy for acute myocardial infarction (AMI) promotes the speed and magnitude of coronary artery recanalization and reduces reocclusion. Low-molecular-weight heparins offer practical and potential pharmacological advantages over UFH in multiple applications but have not been systematically studied as adjuncts to fibrinolysis in AMI.

Methods and Results

—

Four hundred patients undergoing reperfusion therapy with an accelerated recombinant tissue plasminogen activator regimen and aspirin for AMI were randomly assigned to receive adjunctive therapy for at least 3 days with either enoxaparin or UFH. The study was designed to show noninferiority of enoxaparin versus UFH with regard to infarct-related artery patency. Ninety minutes after starting therapy, patency rates (thrombolysis in myocardial infarction [TIMI] flow grade 2 or 3) were 80.1% and 75.1% in the enoxaparin and UFH groups, respectively. Reocclusion at 5 to 7 days from TIMI grade 2 or 3 to TIMI 0 or 1 flow and TIMI grade 3 to TIMI 0 or 1 flow, respectively, occurred in 5.9% and 3.1% of the enoxaparin group versus 9.8% and 9.1% in the UFH group. Adverse events occurred with similar frequency in both treatment groups.

Conclusions

—

Enoxaparin was at least as effective as UFH as an adjunct to thrombolysis, with a trend toward higher recanalization rates and less reocclusion at 5 to 7 days.
Heart Failure After Myocardial Infarction
Authors: Gómez A.M. , Guatimosim S. , Dilly K.W. , Vassort G. , Lederer W.J.
Published: September 2007

Background
—

Heart failure (HF) frequently follows the occurrence of myocardial infarction (MI). Questions about how HF develops and what cellular defects contribute to this dysfunction led to this study.

Methods and Results
—

MI was induced in rats by coronary artery ligation. Clinical examination of the post-MI (PMI) surviving animals indicated that they were in overt HF by all measures. Cellular examination of the cardiomyocytes by patch-clamp and confocal [Ca
2+
]
i
imaging methods indicated that cellular function was significantly compromised. At the single-cell level, [Ca
2+
]
i
transient amplitudes were reduced and contractions were decreased and slowed, although Ca
2+
current (
I
Ca
) remained unchanged. The excitation-contraction coupling (ECC) gain function measured as Δ[Ca
2+
]
i
/
I
Ca
was significantly decreased. Ouabain, a cardiotonic steroid that blocks the Na
+
,K
+
-ATPase and activates Ca
2+
entry via cardiac Na
+
channels, largely alleviated this defect.

Conclusions
—

After MI,
I
Ca
becomes less able to trigger release of Ca
2+
from the sarcoplasmic reticulum. This failure of ECC is a major factor contributing to the development of contractile dysfunction and HF in PMI animals. The improved ECC gain, enhanced Ca
2+
entry, and augmented Ca
2+
signaling due to cardiotonic steroids contribute to the beneficial effects of these agents.
Chronic Atrial Fibrillation in Patients With Rheumatic Heart Disease
Authors: Nair Mohan , Shah Prasad , Batra Ravinder , Kumar Manoj , Mohan Jagdish , Kaul Upkar , Arora Ramesh
Published: September 2007

Background

There is little information concerning mapping and radiofrequency ablation (RFA) of arrhythmias seen during reinduction of atrial fibrillation (AF) after pharmacological and/or electrical cardioversion in patients with chronic AF and rheumatic heart disease.

Methods and Results

Seventeen patients with rheumatic heart disease and symptomatic chronic AF underwent multisite atrial mapping during reinduction of AF after cardioversion. An organized atrial arrhythmia of varying duration was seen to precede the AF in all patients. The earliest atrial activity during this organized rhythm was near the coronary sinus ostium (CS OS) in 14 patients and along the left side of the interatrial septum (IAS) in 3 patients. RFA was performed in 16 patients (14 near the CS OS and 2 along the IAS). Postablation AF was inducible in 1 patient in whom RFA was preformed near the CS OS and in both patients when it was performed along the IAS. At a follow-up of 6 to 56 weeks (mean, 32 weeks), 10 of the 13 patients who had successful ablation were in sinus rhythm. All patients in whom AF was reinducible immediately after RFA continue to be in AF.

Conclusions

Induced AF in patients with rheumatic heart disease begins as a rapid organized arrhythmia with earliest atrial activity near the CS OS in most patients. RFA targeting the region of the CS OS is successful in suppressing the arrhythmia immediately in most of the patients and in most on follow-up.
Efficacy of Pacing Therapies for Treating Atrial Tachyarrhythmias in Patients With Ventricular Arrhythmias Receiving a Dual-Chamber Implantable Cardioverter Defibrillator
Authors: Adler Stuart W. , Wolpert Christian , Warman Eduardo N. , Musley Shailesh K. , Koehler Jodi L. , Euler David E. ,   for the Worldwide Jewel AF Investigators
Published: September 2007

Background

—

Although overdrive pacing for treating atrial flutter is well established, the efficacy of device-based atrial pacing for treating spontaneous atrial tachyarrhythmias in patients with implantable cardioverter defibrillators (ICD) is unknown. This study evaluated the efficacy of novel pacing therapies for treating atrial tachyarrhythmias in patients receiving a dual-chamber ICD to treat ventricular tachyarrhythmias.

Methods and Results

—

A Jewel AF ICD was implanted in 537 patients with ventricular arrhythmia who were followed for 11.4±8.2 months (74% had a documented history of atrial tachyarrhythmias). The device discriminated atrial tachycardia (AT) from atrial fibrillation (AF) on the basis of cycle length and regularity, and it used 3 different methods of overdrive atrial pacing (Ramp, Burst+, and 50-Hz burst) to treat AT episodes and one method (50-Hz burst) to treat AF episodes. Pacing successfully terminated 59% of 1500 spontaneous AT episodes in 127 patients and 30% of 880 AF episodes in 101 patients (
P
<0.001). With AT and AF episodes combined, pacing efficacy was 48%. Pacing efficacy was significantly reduced at AT cycle lengths ≤220 ms and AF cycle lengths ≤160 ms (
P
<0.01) The median time from pacing to AT/AF termination was 1.1 minute for the pacing successes and 96 minutes for the failures (
P
<0.001).

Conclusions

—

Atrial pacing terminated 48% of AT/AF episodes in patients with a history of ventricular arrhythmias. Pacing efficacy was greater for device-classified AT than AF. Pacing efficacy was significantly influenced by tachycardia cycle length. Successful pacing significantly reduces the time required for AT/AF termination.
Cerebral Autoregulatory Responses to Head-Up Tilt in Normal Subjects and Patients With Recurrent Vasovagal Syncope
Authors: Carey Brian J. , Manktelow Bradley N. , Panerai Ronney B. , Potter John F.
Published: September 2007

Background

—

The effect of orthostatic stress on dynamic cerebral autoregulation (CA) in normal subjects and patients with recurrent vasovagal syncope (VVS) is unclear. This study assessed the dynamic CA responses of both groups to head-up tilt.

Methods and Results

—

Seventeen patients with recurrent VVS and 17 pair-matched control subjects underwent 70° head-up tilt for up to 30 minutes. Bilateral middle cerebral artery blood flow velocities (CBFV) were measured with transcranial Doppler ultrasound along with noninvasive beat-to-beat blood pressure (BP), heart rate, and transcutaneous and end-tidal CO
2
concentrations. Indices of dynamic CA were derived for periods before, during, and after tilt. Eight normal subjects who developed VVS in an identical protocol but who had no previous clinical history of syncope were also studied. CBFV and transcutaneous and end-tidal CO
2
levels declined significantly during head-up tilt in all groups (
P
<0.0001). Dynamic CA indices were unchanged throughout tilt in nonsyncopal control subjects and were initially unchanged in patients but deteriorated significantly in patients and syncopal control subjects in the minutes before (
P
=0.027 and
P
=0.012, respectively) and after (
P
=0.002 and
P
=0.007, respectively) syncope.

Conclusions

—

Dynamic CA is preserved in patients and control subjects initially after head-up tilt. Autoregulatory function remains intact in nonsyncopal control subjects during prolonged orthostasis but deteriorates in patients and syncopal control subjects immediately before and after VVS.
Predisposition to Vasovagal Syncope in Subjects With Blood/Injury Phobia
Authors: Accurso Valentina , Winnicki Mikolaj , Shamsuzzaman Abu S.M. , Wenzel Amy , Johnson Alan Kim , Somers Virend K.
Published: September 2007

Background
—

Most subjects with blood/injury phobia experience syncope or presyncope as part of the phobic response. We tested the hypothesis that these subjects have a constitutional autonomic dysregulation that predisposes them to vasovagal syncope during head-up tilt.

Methods and Results
—

We studied 11 subjects (9 females, 2 males) who had a history of syncope or presyncope only in response to a blood or injury stimulus and 11 healthy matched controls (10 females, 1 male) without a history of syncope. Blood pressure (BP) and heart rate (HR) were measured during a 15-minute baseline period with subjects in the supine position and then during 45 minutes of head-up tilt to 70°. Measurements at rest did not differ between the blood phobic and control subjects. During tilt, 9 (82%) of the 11 blood phobic subjects experienced presyncope or syncope, leading to termination of the study after 22±17 minutes of tilt. Only 1 (9%) of the 11 control subjects experienced presyncope (χ
2
=11.7,
P
=0.001). Hemodynamic responses to tilt were consistent with a vasovagal mechanism in the blood phobic subjects, with simultaneous decreases in BP and HR during tilt. During tilt, systolic BP fell by 21±15 mm Hg (
P
=0.001), and HR fell by 22±25 bpm (
P
=0.01). By contrast, BP and HR were very stable in the control group.

Conclusions
—

Subjects with syncope related to blood/injury phobia have an underlying autonomic dysregulation predisposing them to neurally mediated syncope, even in the absence of any blood or injury stimulus. Fainting related to these stimuli may in large part be due to dysfunction in neural circulatory control, which may secondarily lead to the phobia because of repeated syncopal events.
Mechanical Unloading Restores β-Adrenergic Responsiveness and Reverses Receptor Downregulation in the Failing Human Heart
Authors: Ogletree-Hughes Monique L. , Stull Linda B. , Sweet Wendy E. , Smedira Nicholas G. , McCarthy Patrick M. , Moravec Christine Schomisch
Published: September 2007

Background

—

Mechanical unloading of the failing human heart with a left ventricular assist device (LVAD) results in clinically documented reversal of chamber dilation and improvement of cardiac function. We tested the hypothesis that LVAD support normalizes the ability of cardiac muscle to respond to sympathetic nervous system stimulation by reversing the downregulation of β-adrenergic receptors.

Methods and Results

—

Human LV tissue was obtained from nonfailing hearts of unmatched organ donors and failing hearts at the time of transplantation, with or without LVAD. Baseline contractile parameters and inotropic response to a β-adrenergic agonist were measured in isolated trabecular muscles. β-Adrenergic receptor density was quantified by radioligand binding. Results showed a significant increase in the response to β-adrenergic stimulation after LVAD (developed tension increased by 0.76±0.09 g/mm
2
in nonfailing, 0.38±0.07 in failing, and 0.68±0.10 in failing+LVAD;
P
<0.01), accompanied by an increased density of β-adrenergic receptors (58.7±9.6 fmol/mg protein in nonfailing, 26.2±3.8 in failing, and 63.0±8.3 in failing+LVAD;
P
<0.05). These changes were unrelated to the duration of support.

Conclusions

—

Data demonstrate that mechanically supporting the failing human heart with an LVAD can reverse the downregulation of β-adrenergic receptors and restore the ability of cardiac muscle to respond to inotropic stimulation by the sympathetic nervous system. This indicates that functional impairment of cardiac muscle in human heart failure is reversible.
Cardioprotective Effects of Ramipril and Losartan in Right Ventricular Pressure Overload in the Rabbit
Authors: Rouleau Jean L. , Kapuku Gaston , Pelletier Stéphane , Gosselin Hugues , Adam Albert , Gagnon Caroline , Lambert Chantal , Meloche Sylvain
Published: September 2007

Background

—

The role of kinins in the cardioprotective effects of ACE inhibitors remains controversial.

Methods and Results

—

Right ventricular pressure overload in rabbits was produced by pulmonary artery banding for 21 days. Rabbits were untreated, or they received the ACE inhibitor ramipril with or without bradykinin B
1
and B
2
receptor blockers or the angiotensin (Ang) II type I (AT
1
) receptor blocker losartan. Pulmonary artery banding caused right ventricular hypertrophy, depressed papillary muscle contractility, and loss of Ang II contractile effects because of a signaling defect downstream of AT
1
receptors. Paradoxically, AT
1
receptor density and G protein α subunits αq and αi1/2 increased. Inotropic responsiveness to the α-receptor agonist phenylephrine was normal. Ramipril preserved cardiac contractility, but this effect was attenuated by simultaneous use of kinin receptor blockers. Ramipril also maintained responsiveness to Ang II and prevented AT
1
receptor and G protein upregulation. The simultaneous use of a kinin receptor blocker attenuated but did not prevent upregulation in the AT
1
receptor and G protein. Losartan had no effect on baseline contractility, but it maintained cardiac inotropic responsiveness to Ang II, prevented upregulation of AT
1
receptors, but did not modify G protein upregulation.

Conclusions

—

Pressure overload of the right ventricle decreases contractility, uncouples AT
1
receptors to downstream signaling pathways, and changes the expression of components of the AT
1
receptor signaling pathway. Ramipril attenuates these effects via kinins. Interventions that prevent local increases in Ang II or block AT
1
receptors also prevent decreased responsiveness of the AT
1
receptor in this model.
Angiotensin-Converting Enzyme Inhibitor Preserves p21 and Endothelial Nitric Oxide Synthase Expression in Monocrotaline-Induced Pulmonary Arterial Hypertension in Rats
Authors: Kanno Shinichi , Wu Yi-Jen L. , Lee Paul C. , Billiar Timothy R. , Ho Chien
Published: September 2007

Background

—

Pulmonary arterial hypertension (PAH) is associated with structural changes in the pulmonary vasculature characterized by the proliferation of cellular components of the vessels. ACE inhibitor (ACEI) may have beneficial effects in treating PAH, but its precise mechanism of action in the remodeling process is unclear. p21 is a cyclin-dependent kinase inhibitor that may have a protective role in this process by inhibiting cellular proliferation. Endothelial nitric oxide synthase (eNOS) has also been shown to be protective by its vasodilatory effect. Therefore, we investigated whether expression of p21 and eNOS was modulated by ACEI treatment in a rat model.

Methods and Results

—

Monocrotaline (MCT) was administered to 2 groups of Sprague-Dawley rats fed a high-cholesterol diet, ie, one group received MCT concomitantly with enalapril treatment (MCT
+
/ACEI
+
rats), and the other group did not receive enalapril (MCT
+
/ACEI
−
rats). After 5 weeks, MRI showed right ventricular hypertrophy in MCT
+
/ACEI
−
rats. MCT
+
/ACEI
+
rats showed a preserved right ventricular morphology. Isolated pulmonary perfusion studies showed that ACEI significantly upregulated NO production, as measured by nitrite levels. Addition of
N
-methyl–
d
-glucamine dithiocarbamate–Fe solution, an NO-trapping agent, reversed the basal vasodilatory effect of ACEI in the pulmonary vasculature. Immunoblot analysis showed decreased p21 and eNOS expression in the lung in MCT
+
/ACEI
−
rats, whereas their expression was preserved with enalapril treatment.

Conclusions

—

ACEI suppresses the development of MCT-induced PAH in rats. The mechanism of action might involve the preservation of p21 and eNOS expression. Both p21 and endothelium-derived NO appear to have protective roles in the development of PAH.