bluuebunny/crossref_metadata_2025 huggingface dataset:
Cell Transplantation as Future Therapy for Cardiovascular Disease?
Authors: Reinlib Leslie , Field Loren
Published: June 2012

Abstract
—Despite the development of improved therapies and the significant advances in the understanding of the basis of disease pathogenesis, millions of Americans continue to live with life-threatening cardiovascular diseases. Recent breakthroughs suggest exciting directions that are likely to produce more effective therapies for the treatment of cardiovascular disease. One such area, cell transplantation (grafting of healthy cells into the diseased heart), holds enormous potential as an approach to cardiovascular pathophysiology. Once thought to be a scientific long shot, cell transplantation is becoming recognized as a viable strategy to strengthen weak hearts and limit infarct growth. The technology could also be used for the long-term delivery of beneficial recombinant proteins to the heart, which is a strategy to complement molecular biology advances and provide an alternative strategy for gene therapy. On August 24, 1998, the National Heart, Lung, and Blood Institute convened a workshop to discuss the current status of this fast-moving line of research and to explore its promise for treating cardiovascular disease. The participants included basic and clinical researchers, with representatives from academic and commercial research settings. The workshop was designed to establish the state-of-the-art and to equate current research with practical clinical application. The group recommended short- and long-term goals to assist in realizing, in the most expedient manner, the potential utility of cell transplantation for the treatment of cardiovascular disease. A summary of the meeting discussions and recommendations for future areas of research is presented.
Safety of Intracoronary γ-Radiation on Uninjured Reference Segments During the First 6 Months After Treatment of In-Stent Restenosis
Authors: Ahmed Javed M. , Mintz Gary S. , Waksman Ron , Weissman Neil J. , Mehran Roxana , Pichard Augusto D. , Satler Lowell F. , Kent Kenneth M. , Leon Martin B.
Published: June 2012

Background
—The effects of endovascular irradiation on uninjured reference segments during the treatment of in-stent restenosis are unknown.

Methods and Results
—In the Washington Radiation for In-Stent restenosis Trial (WRIST), patients with in-stent restenosis were first treated with conventional catheter-based techniques and then randomized (blinded) to receive either γ-irradiation (
192
Ir) or a placebo (dummy seeds). We identified all patients in whom the active (n=19) or dummy seeds (n=19) extended >10 mm proximal and distal to the in-stent restenosis lesion. Serial (postirradiation and follow-up) external elastic membrane (EEM), lumen, and plaque and media (EEM−lumen) areas were measured (using intravascular ultrasound) every 1 mm over 5-mm-long reference segments that were 6 to 10 mm proximal and distal to the in-stent restenosis lesion. During follow-up, a similar small increase occurred in the plaque and media area in the proximal and distal reference segments in both
192
Ir and placebo patients. However, in the
192
Ir patients, an increase in both proximal and distal EEM area occurred; as a result, no change in lumen area occurred. Conversely, in the placebo patients, the proximal reference EEM area decreased, and no change occurred in the distal reference EEM area; this contributed to a decrease in lumen area.

Conclusions
—There was no evidence of a deleterious effect of γ-irradiation on angiographically normal uninjured reference segments in the first 6 months after the treatment of in-stent restenosis.
Lack of Benefit for Intravenous Thrombolysis in Patients With Myocardial Infarction Who Are Older Than 75 Years
Authors: Thiemann David R. , Coresh Josef , Schulman Steven P. , Gerstenblith Gary , Oetgen William J. , Powe Neil R.
Published: June 2012

Background
—The benefit of intravenous thrombolytic therapy in elderly patients with myocardial infarction is uncertain. There are no randomized trials of thrombolytic efficacy or observational studies of clinical effectiveness that focus specifically on the elderly.

Methods and Results
—To determine whether thrombolytic therapy for elderly patients is associated with a survival advantage in a large observational database, we conducted a retrospective cohort study of 7864 Medicare fee-for-service patients aged 65 to 86 years with the primary discharge diagnosis of acute myocardial infarction who were admitted with clinical and ECG indications for thrombolytic therapy and no absolute contraindications. The study included all US acute care nongovernment hospitals without on-site angioplasty capability. Using proportional-hazards methods, we found that in a comprehensive multivariate model, there was a significant interaction (
P
<0.001) between age and the effect of thrombolytic therapy on 30-day mortality rates. For patients 65 to 75 years old, thrombolytic therapy was associated with a survival benefit, consistent with randomized trials. Among patients aged 76 to 86 years, thrombolytic therapy was associated with a survival disadvantage, with a 30-day mortality hazard ratio of 1.38 (95% CI 1.12 to 1.71,
P
=0.003). For these patients, there was no benefit from thrombolytic therapy in any clinical subgroup.

Conclusions
—In nationwide clinical practice, thrombolytic therapy for patients >75 years old is unlikely to confer survival benefit and may have a significant survival disadvantage. Reperfusion research that is focused on elderly patients is urgently needed.
Smoking Is Associated With Reduced Serum Paraoxonase Activity and Concentration in Patients With Coronary Artery Disease
Authors: James Richard W. , Leviev Ilia , Righetti Alberto
Published: June 2012

Background
—Paraoxonase is an HDL-associated enzyme that protects lipoproteins from oxidative modifications. Smoking is a major cardiovascular risk factor that promotes lipid peroxidation. Cigarette smoke has been shown in vitro to inhibit paraoxonase. The present study examined the hypothesis that smoking is associated with modulated serum activities and concentrations of paraoxonase.

Methods and Results
—Coronary artery disease was assessed with the use of coronary arteriography in participants recruited from a hospital cardiology division. Medical and lifestyle data were obtained, and a fasting blood sample was provided. Three smoking categories were established (never, ex-smokers, and current smokers), and serum paraoxonase variables were compared among them. The activities and concentrations of paraoxonase were significantly lower in current than in never smokers. Ex-smokers had values comparable to those of never smokers. Ex-smokers who had recently stopped (<3 months) had activities and concentrations comparable to those of current smokers; values returned to the levels of never smokers within 2 years of cessation of smoking. Smoking status was an independent determinant of paraoxonase activity and concentration in multivariate analysis. Finally, lower paraoxonase was associated with more severe coronary disease and a reduced capacity to protect LDL from oxidation.

Conclusions
—Smoking is independently associated with significant decreases in serum paraoxonase activities and concentrations, which normalize within a relatively short time of cessation. Lower serum paraoxonase is linked to more severe coronary artery disease and a lower antioxidant capacity. The data are consistent with the hypothesis that smoking modifies serum paraoxonase such that there is an increased risk of coronary artery disease due to a diminished capacity to protect lipoproteins from oxidative stress.
Modulation of Sympathetic Coronary Vasoconstriction by Cardiac Renin-Angiotensin System in Human Coronary Heart Disease
Authors: Saino Antonio , Pomidossi Guido , Perondi Rodolfo , Morganti Alberto , Turolo Lucia , Mancia Giuseppe
Published: June 2012

Background
—In humans, angiotensin II enhances the sympathetic coronary vasoconstriction elicited by the cold pressor test (CPT) and diving. Whether this enhancement depends on the circulating angiotensin II or on the locally produced angiotensin II is unknown, however.

Methods and Results
—We addressed this issue in 14 patients with severe coronary artery disease by evaluating the effects of a 2-minute CPT (n=14) and a 30-second dive (n=8) on mean arterial pressure (MAP, arterial catheter), heart rate (ECG), coronary sinus blood flow (CBF, thermodilution technique), and coronary vascular resistance (MAP/CBF ratio). The 2 stimuli were applied at the end of left intracoronary infusion of either saline or benazeprilat diluted at the concentration of 25 μg/mL. The rate of benazeprilat infusion had been preliminarily demonstrated to reduce angiotensin II concentration in the coronary sinus without affecting its arterial concentration. The changes in MAP and heart rate induced by CPT and diving were superimposable during saline and benazeprilat infusions. The decrease in CBF induced by CPT and diving during saline infusion was changed into an increase during benazeprilat infusion with a significant attenuation of the coronary vasoconstrictor response.

Conclusions
—In patients with coronary artery disease, an attenuation of sympathetic coronary vasoconstriction can be obtained by reducing cardiac angiotensin II formation without involving circulating angiotensin II. This suggests a role of the tissue renin-angiotensin system in modulating autonomic cardiac drive in humans.
Relationship of TIMI Myocardial Perfusion Grade to Mortality After Administration of Thrombolytic Drugs
Authors: Gibson C. Michael , Cannon Christopher P. , Murphy Sabina A. , Ryan Kathryn A. , Mesley Rebecca , Marble Susan J. , McCabe Carolyn H. , Van de Werf Frans , Braunwald Eugene
Published: June 2012

Background
—Although improved epicardial blood flow (as assessed with either TIMI flow grades or TIMI frame count) has been related to reduced mortality after administration of thrombolytic drugs, the relationship of myocardial perfusion (as assessed on the coronary arteriogram) to mortality has not been examined.

Methods and Results
—A new, simple angiographic method, the TIMI myocardial perfusion (TMP) grade, was used to assess the filling and clearance of contrast in the myocardium in 762 patients in the TIMI (Thrombolysis In Myocardial Infarction) 10B trial, and its relationship to mortality was examined. TMP grade 0 was defined as no apparent tissue-level perfusion (no ground-glass appearance of blush or opacification of the myocardium) in the distribution of the culprit artery; TMP grade 1 indicates presence of myocardial blush but no clearance from the microvasculature (blush or a stain was present on the next injection); TMP grade 2 blush clears slowly (blush is strongly persistent and diminishes minimally or not at all during 3 cardiac cycles of the washout phase); and TMP grade 3 indicates that blush begins to clear during washout (blush is minimally persistent after 3 cardiac cycles of washout). There was a mortality gradient across the TMP grades, with mortality lowest in those patients with TMP grade 3 (2.0%), intermediate in TMP grade 2 (4.4%), and highest in TMP grades 0 and 1 (6.0%; 3-way
P
=0.05). Even among patients with TIMI grade 3 flow in the epicardial artery, the TMP grades allowed further risk stratification of 30-day mortality: 0.73% for TMP grade 3; 2.9% for TMP grade 2; 5.0% for TMP grade 0 or 1 (
P
=0.03 for TMP grade 3 versus grades 0, 1, and 2; 3-way
P
=0.066). TMP grade 3 flow was a multivariate correlate of 30-day mortality (OR 0.35, 95% CI 0.12 to 1.02,
P
=0.054) in a multivariate model that adjusted for the presence of TIMI 3 flow (
P
=NS), the corrected TIMI frame count (OR 1.02,
P
=0.06), the presence of an anterior myocardial infarction (OR 2.3,
P
=0.03), pulse rate on admission (
P
=NS), female sex (
P
=NS), and age (OR 1.1,
P
<0.001).

Conclusions
—Impaired perfusion of the myocardium on coronary arteriography by use of the TMP grade is related to a higher risk of mortality after administration of thrombolytic drugs that is independent of flow in the epicardial artery. Patients with both normal epicardial flow (TIMI grade 3 flow) and normal tissue level perfusion (TMP grade 3) have an extremely low risk of mortality.
Relation of Left Ventricular Diastolic Properties to Systolic Function in Arterial Hypertension
Authors: de Simone Giovanni , Greco Rosanna , Mureddu GianFrancesco , Romano Carmela , Guida Raffaele , Celentano Aldo , Contaldo Franco
Published: June 2012

Background
—It is unclear whether impairment of left ventricular (LV) diastolic characteristics is independent of systolic dysfunction.

Methods and Results
—To address this issue, 159 consecutive hypertensive patients (44±11 years, 78 obese, 96 women) and 165 normotensive subjects (32±11 years, 84 obese, 110 women) were studied with the use of Doppler echocardiography. After adjustment for age, body mass index (BMI), and sex, we found that ejection fraction (EF; M-mode,
z
-derived) was higher in hypertensive (66.6±5.2%) than in normotensive (63.9±4.4%,
P
<0.0001) subjects, whereas midwall shortening (MS) was lower (hypertensive patients 16.9±2.0%, normotensive subjects 17.8±2.2%,
P
<0.02), even after correction for end-systolic wall stress (
P
<0.05). Isovolumic relaxation time (IVRT) was greater in hypertensive patients (103±14 ms) than in normotensive subjects (78±19 ms), as was deceleration time of E velocity and peak A velocity (all
P
<0.0001). In multivariate analysis, IVRT was unrelated to EF, but a negative relation was found with MS (
P
<0.001), independent of age, BMI, presence of arterial hypertension, LV geometry, and load (multiple
R
2
=0.58). For comparable age, sex distribution, BMI, and blood pressure values, hypertensive patients with lower afterload-adjusted MS exhibited longer IVRT than patients with normal MS (
P
<0.005). However, IVRT remained higher than in normotensive control subjects after control for LV geometry and load.

Conclusions
—Doppler indices of delayed LV relaxation can be detected in the presence of normal or supranormal EF but are independently related to impaired MS. A less severely abnormal relaxation, however, can be also detected in the presence of normal midwall function, independent of LV geometry and load. Thus, diastolic abnormalities may occur before systolic dysfunction even when it is measured at the midwall.
Endothelium-Derived Nitric Oxide Contributes to the Regulation of Venous Tone in Humans
Authors: Blackman Daniel J. , Morris-Thurgood Jayne A. , Atherton John J. , Ellis Gethin R. , Anderson Richard A. , Cockcroft John R. , Frenneaux Michael P.
Published: June 2012

Background
—Although nitric oxide (NO) is known to play an important part in the regulation of arterial tone, little is known about its role in veins. The aim of this study was to investigate the role of basal and stimulated NO activity in the regulation of tone of the human venous capacitance bed.

Methods and Results
—We measured venous tone using radionuclide forearm venous plethysmography in 24 healthy subjects with no cardiovascular risk factors. In 13 subjects, basal NO activity was assessed by measuring the effects on venous tone of an intra-arterial infusion of the NO synthase inhibitor
N
-monomethyl-
l
-arginine (L-NMMA). In the remaining 11 subjects, stimulated NO activity was evaluated by measuring the effects of an intra-arterial infusion of incremental doses of carbachol, followed in a subgroup by coinfusion with L-NMMA. Infusion of carbachol caused dose-dependent venodilation, with a maximal reduction in forearm venous tone of 40.1±12.5% (
P
<0.0001). Carbachol-induced venodilation was inhibited by L-NMMA (48.9±6.2% reversal of maximal venodilation,
P
<0.01). Infusion of L-NMMA alone caused venoconstriction (9.1±6.4% increase in venous tone,
P
=0.002).

Conclusions
—Human forearm capacitance veins exhibit both stimulated and basal NO activity, which indicates that NO contributes not only to the regulation of venous tone but also to resting venous tone in healthy human subjects.
High-Efficiency, Long-Term Cardiac Expression of Foreign Genes in Living Mouse Embryos and Neonates
Authors: Christensen Geir , Minamisawa Susumu , Gruber Peter J. , Wang Yibin , Chien Kenneth R.
Published: June 2012

Background
—The development of improved strategies for efficient and reproducible in vivo gene transfer into the murine heart will ultimately allow the intersection of somatic and germline gene transfer strategies to study complex features of cardiac biology and diseases.

Methods and Results
—For embryonic gene transfer, an adenovirus vector expressing β-galactosidase was injected in utero into the ventricular cavity of living embryos via microsurgical approaches. The injected embryos were developed to term, and efficient expression of the transgene was detected in all cell types in the heart. For postnatal cardiac gene transfer, adenovirus was injected into the cardiac ventricle of neonatal mice, resulting in efficient expression of the transgene in the outer layer of the myocardium as well as cardiomyocytes in the middle and inner layers of the cardiac wall. Mice examined after 3 weeks displayed a pattern of expression that completely mimicked the pattern seen after 3 days, and gene expression was also found after 6 months. The infected myocytes can be identified by coinfection of an adenovirus expressing green fluorescent protein without affecting their normal physiological function.

Conclusions
—We have developed a new strategy to achieve efficient and long-term foreign gene expression in both embryonic and postnatal mouse myocardium via direct intracardiac injection of recombinant adenovirus. The strategy should allow the functional assessment of the expression of dominantly acting exogenous genes, overexpression of wild-type genes, and Cre recombinase–mediated gene ablations at the single-cell level in the context of the intact adult mouse myocardium.
Significant Frequencies of T Cells With Indirect Anti-Donor Specificity in Heart Graft Recipients With Chronic Rejection
Authors: Hornick Philip I. , Mason Philip D. , Baker Richard J. , Hernandez-Fuentes Maria , Frasca Loredana , Lombardi Giovanna , Taylor Kenneth , Weng Ling , Rose Marlene L. , Yacoub Magdi H. , Batchelor Richard , Lechler Robert I.
Published: June 2012

Background
—The purpose of this study was to determine whether T cells with indirect allospecificity could be detected in heart transplant recipients with chronic rejection.

Methods and Results
—Human T-cell clones were used to determine the most effective way to deliver major histocompatibility complex alloantigens for indirect presentation. Seven allograft recipients with evidence of progressive, chronic rejection were selected. Four heart graft recipients with no evidence of chronic rejection were used as controls. Peripheral blood T cells and antigen-presenting cells from the recipients were cultured with frozen/thawed stored donor cells or major histocompatibility complex class I–derived synthetic peptides in limiting dilution cultures and then compared with controls using tetanus toxoid and frozen/thawed third-party cells with no human leukocyte antigens in common with the donor. In 5 of 7 patients analyzed who had chronic rejection, elevated frequencies of T cells with indirect, anti-donor specificity (iHTLf) were detected. No such elevated iHTLf were detected in recipients without chronic rejection.

Discussion
—iHTLf can be obtained from human transplant recipients, which supports the contention that the indirect pathway is involved in chronic transplant rejection.
Calcineurin Expression, Activation, and Function in Cardiac Pressure-Overload Hypertrophy
Authors: Lim Hae W. , De Windt Leon J. , Steinberg Leonard , Taigen Tyler , Witt Sandra A. , Kimball Thomas R. , Molkentin Jeffery D.
Published: June 2012

Background
—Vascular hypertension resulting in increased cardiac load is associated with left ventricular hypertrophy and is a leading predicator for progressive heart disease. The molecular signaling pathways that respond to increases in cardiac load are poorly understood. One potential regulator of the hypertrophic response is the calcium-sensitive phosphatase calcineurin.

Methods and Results
—We showed that calcineurin enzymatic activity is increased 3.2-fold in the heart in response to pressure-overload hypertrophy induced by abdominal aortic banding in the rat. Western blot analysis further demonstrates that calcineurin A (catalytic subunit) protein content and association with calmodulin are increased in response to pressure-overload hypertrophy. This increase in calcineurin protein content was prevented by administration of the calcineurin inhibitor cyclosporine A (CsA). CsA administration attenuated load-induced cardiac hypertrophy in a dose-dependent manner over a 14-day treatment protocol. CsA administration also partially reversed pressure-overload hypertrophy in aortic-banded rats after 14 days. CsA also attenuated the histological and molecular indexes of pressure-overload hypertrophy.

Conclusions
—These data suggest that calcineurin is an important upstream regulator of load-induced hypertrophy.
Clinical Profile and Outcome of Idiopathic Restrictive Cardiomyopathy
Authors: Ammash Naser M. , Seward James B. , Bailey Kent R. , Edwards William D. , Tajik A. Jamil
Published: June 2012

Background
—Idiopathic restrictive cardiomyopathy is a poorly recognized entity of unknown cause characterized by nondilated, nonhypertrophied ventricles with diastolic dysfunction resulting in dilated atria and variable systolic function.

Methods and Results
—Between 1979 and 1996, 94 patients (61% women) 10 to 90 years old (mean, 64 years) met strict morphological echocardiographic criteria for idiopathic restrictive cardiomyopathy, mainly dilated atria with nonhypertrophied, nondilated ventricles. None had known infiltrative disease, hypertension of >5 years’ duration, or cardiac or systemic conditions associated with restrictive filling. Nineteen percent were in NYHA class I, 53% in class II, and 28% in class III or IV. Atrial fibrillation was noted in 74% of patients and systolic dysfunction in 16%. Follow-up (mean, 68 months) was complete for 93 patients (99%). At follow-up, 47 patients (50%) had died, 32 (68%) of cardiovascular causes. Four had heart transplantation. The death rate compared with actuarial statistics was significantly higher than expected (
P
<0.0001). Kaplan-Meier 5-year survival was 64%, compared with expected survival of 85%. Multivariate analysis using proportional hazards showed that the risk of death approximately doubles with male sex (hazard ratio [HR] =2.1), left atrial dimension >60 mm (HR=2.3), age >70 years (HR=2.0), and each increment of NYHA class (HR=2.0).

Conclusions
—Idiopathic restrictive cardiomyopathy or nondilated, nonhypertrophic ventricles with marked biatrial dilatation, as defined morphologically by echocardiography, affects predominantly elderly patients but can occur in any age group. Patients present with systemic and pulmonary venous congestion and atrial fibrillation and have a poor prognosis, particularly men >70 years old with higher NYHA class and left atrial dimension >60 mm.
In Vivo Magnetic Resonance Evaluation of Atherosclerotic Plaques in the Human Thoracic Aorta
Authors: Fayad Zahi A. , Nahar Tamana , Fallon John T. , Goldman Martin , Aguinaldo J. Gilberto , Badimon Juan J. , Shinnar Meir , Chesebro James H. , Fuster Valentin
Published: June 2012

Background
—The structure and composition of aortic atherosclerotic plaques are associated with the risk of future cardiovascular events. Magnetic resonance (MR) imaging may allow accurate visualization and characterization of aortic plaques.

Methods and Results
—We developed a noninvasive MR method, free of motion and blood flow artifacts, for submillimeter imaging of the thoracic aortic wall. MR imaging was performed on a clinical MR system in 10 patients with aortic plaques identified by transesophageal echocardiography (TEE). Plaque composition, extent, and size were assessed from T1-, proton density–, and T2- weighted images. Comparison of 25 matched MR and TEE cross-sectional aortic plaque images showed a strong correlation for plaque composition (χ
2
=43.5,
P
<0.0001; 80% overall agreement; n=25) and mean maximum plaque thickness (
r
=0.88, n=25; 4.56±0.21 mm by MR and 4.62±0.31 mm by TEE). Overall aortic plaque extent as assessed by TEE and MR was also statistically significant (χ
2
=61.77,
P
<0.0001; 80% overall agreement; n=30 regions).

Conclusions
—This study demonstrates that noninvasive MR evaluation of the aorta compares well with TEE imaging for the assessment of atherosclerotic plaque thickness, extent, and composition. This MR method may prove useful for the in vivo study of aortic atherosclerosis.
Human Serum Paraoxonases (PON1) Q and R Selectively Decrease Lipid Peroxides in Human Coronary and Carotid Atherosclerotic Lesions
Authors: Aviram Michael , Hardak Emiliya , Vaya Jacob , Mahmood Saeed , Milo Simcha , Hoffman Aaron , Billicke Scott , Draganov Dragomir , Rosenblat Mira
Published: June 2012

Background
—Human serum paraoxonase (PON1) exists in two polymorphic forms: one that differs in the amino acid at position 192 (glutamine and arginine, Q and R, respectively) and the second one that differs in the amino acid at position 55 (methionine and leucine, M and L, respectively). PON1 protects LDL from oxidation, and during LDL oxidation, PON1 is inactivated.

Methods and Results
—The present study compared PON1 isoforms Q and R for their effect on lipid peroxide content in human coronary and carotid lesions. After 24 hours of incubation with PON1Q or PON1R (10 arylesterase units/mL), lipid peroxides content in both coronary and carotid lesion homogenates (0.1 g/mL) was reduced up to 27% and 16%, respectively. The above incubation was associated with inactivation of PON1Q and PON1R by 15% and 45%, respectively. Lesion cholesteryl linoleate hydroperoxides and cholesteryl linoleate hydroxides were hydrolyzed by PON1 to yield linoleic acid hydroperoxides and linoleic acid hydroxides. Furthermore, lesion and pure linoleic acid hydroperoxides were reduced to yield linoleic acid hydroxides. These results thus indicate that PON1 demonstrates esterase-like and peroxidase-like activities. Recombinant PON1 mutants in which the PON1-free sulfhydryl group at cysteine-284 was replaced with either alanine or serine were no longer able to reduce lipid peroxide content in carotid lesions.

Conclusions
—We conclude that PON1 may be antiatherogenic because it hydrolyzes lipid peroxides in human atherosclerotic lesions.
Prevention of Rat Cerebral Aneurysm Formation by Inhibition of Nitric Oxide Synthase
Authors: Fukuda Shunichi , Hashimoto Nobuo , Naritomi Hiroaki , Nagata Izumi , Nozaki Kazuhiko , Kondo Soichiro , Kurino Michiharu , Kikuchi Haruhiko
Published: June 2012

Background
—Cerebral saccular aneurysm is a major cause of subarachnoid hemorrhage, one of the cerebrovascular diseases with the highest mortality. The mechanisms underlying the development of aneurysms, however, still remain unclear. We have made a series of reports on an animal model of experimentally induced cerebral aneurysms that resemble human cerebral aneurysms in their location and morphology, suggesting that the arterial wall degeneration associated with aneurysm formation develops near the apex of arterial bifurcation as a result of an increase in wall shear stress. Using the animal model and human specimens, we examined the role of nitric oxide (NO) in the degenerative changes and cerebral aneurysm formation.

Methods and Results
—Inducible NO synthase (iNOS) was immunohistochemically located at the orifice of human and rat aneurysms. Nitrotyrosine distribution was also seen in the human aneurysm. Although no iNOS immunostaining was found in normal arteries, iNOS immunoreactivity was observed in parallel with the development of early aneurysmal changes in rats. In contrast, during the early development of aneurysm, endothelial NOS immunostaining in the endothelium was weakened compared with that in the control arteries. An NOS inhibitor, aminoguanidine, attenuated both early aneurysmal changes and the incidence of induced aneurysms. A defibrinogenic agent, batroxobin, which may diminish shear stress by reduction of blood viscosity, prevented iNOS induction as well as early aneurysmal changes.

Conclusions
—The evidence suggests that NO, particularly that derived from iNOS, is a key requirement for the development of cerebral aneurysm. The iNOS induction may be caused by an increase in shear stress near the apex.
High Glucose–Induced Apoptosis in Human Endothelial Cells Is Mediated by Sequential Activations of c-Jun NH
2
-Terminal Kinase and Caspase-3
Authors: Ho Feng M. , Liu Shing H. , Liau Chiau S. , Huang Por J. , Lin-Shiau Shoei Y.
Published: June 2012

Background
—Diabetes mellitus causes multiple cardiovascular complications. High glucose can induce reactive oxygen species and apoptosis in endothelial cells. Little is known about the molecular mechanisms in high glucose–induced endothelial cell apoptosis.

Methods and Results
—We elucidated the signaling pathway of high glucose–induced apoptosis in human umbilical vein endothelial cells (HUVECs). HUVECs were treated with media containing 5.5, 19, or 33 mmol/L of glucose in the presence or absence of an antioxidant, ascorbic acid. The level of intracellular H
2
O
2
was measured by flow cytometry. For detection of apoptosis, the cell death detection ELISA assay and the morphological Hoechst staining were used. High glucose was capable of inducing the activity of c-Jun NH
2
-terminal kinase (JNK) but not extracellular signal–regulated kinase 1/2 or p38 mitogen-activated protein kinase during the treatment periods, as evidenced by immunocomplex kinase assay. Moreover, we found that the interleukin 1β–converting enzyme (ICE)/CED-3 family protease (caspase-3) became activated in high glucose–induced apoptosis. Caspase-3/CPP32–specific inhibitor, Ac-DEVD-CHO, could inhibit high glucose–induced apoptosis. Furthermore, we found that JNK1 specific antisense oligonucleotide could suppress caspase-3 activity but not affect H
2
O
2
generation and could block apoptosis induced by high glucose. Also, H
2
O
2
generation, JNK activity, caspase-3 activity, and the subsequent apoptosis induced by high glucose could be suppressed by ascorbic acid.

Conclusions
—The present study indicates that reactive oxygen species induced by high glucose may be involved in JNK activation, which in turn triggers the caspase-3 that facilitates the apoptosis in HUVECs.
Tissue Factor Overexpression in Rat Arterial Neointima Models Thrombosis and Progression of Advanced Atherosclerosis
Authors: Hasenstab David , Lea Holly , Hart Charles E. , Lok Si , Clowes Alexander W.
Published: June 2012

Background
—Tissue factor located in the atherosclerotic plaque might cause the clinically significant thrombotic events associated with end-stage disease. It might also affect intimal area by increasing matrix accumulation and stimulating smooth muscle cell (SMC) migration and proliferation. To test this hypothesis, we overexpressed tissue factor in a rat model of the human fibrous plaque.

Methods and Results
—A neointima was generated by seeding tissue factor–overexpressing rat SMCs onto the luminal surface of a balloon-injured syngeneic rat carotid artery. The cells attached and expressed tissue factor over the long term. Mural thrombus accumulation was present at 4 and 7 days and increased neointimal SMC numbers and area by 2-fold at 2 and 4 weeks. Tissue factor overexpression accelerated reendothelialization compared with controls at 2 weeks and 1 month. Tissue factor–overexpressing SMCs exhibited increased migration both in vitro and in vivo. The increased migration by tissue factor–overexpressing SMCs in vitro was not dependent on activation of the coagulation cascade and could be blocked by an inhibitor of tissue factor.

Conclusions
—These results suggest that tissue factor plays a direct role in neointimal development by coagulation-dependent and -independent pathways.
Sympathetically Mediated Hypertension in Autonomic Failure
Authors: Shannon John R. , Jordan Jens , Diedrich Andre , Pohar Bojan , Black Bonnie K. , Robertson David , Biaggioni Italo
Published: June 2012

Background
—Approximately 50% of patients with primary autonomic failure have supine hypertension. We investigated whether this supine hypertension could be driven by residual sympathetic activity.

Methods and Results
—In patients with multiple system atrophy (MSA) or pure autonomic failure (PAF), we studied the effect of oral yohimbine on seated systolic blood pressure (SBP), the effect of ganglionic blockade (with trimethaphan) on supine SBP and plasma catecholamine levels, and the effect of α
1
-adrenoreceptor blockade (phentolamine) on supine SBP. The SBP response to yohimbine was greater in patients with MSA than in those with PAF (area under the curve, 2248±543 versus 467±209 mm Hg · min;
P
=0.022). MSA patients with a higher supine SBP had a greater response than those with a lower supine SBP (3874±809 versus 785±189 mm Hg · min;
P
=0.0017); this relationship was not seen in PAF patients. MSA patients had a marked depressor response to low infusion rates of trimethaphan; the response in PAF patients was more variable. Plasma norepinephrine decreased in both groups, but heart rate did not change in either group. At 1 mg/min, trimethaphan decreased supine SBP by 67±8 and 12±6 mm Hg in MSA and PAF patients, respectively (
P
<0.0001). Cardiac index and total peripheral resistance decreased in MSA patients by 33.4±5.8% and 40.7±9.5%, respectively (
P
=0.0015). Patients having a depressor response to trimethaphan also had a depressor response to phentolamine. In MSA patients, the pressor response to yohimbine and the decrease in SBP with 1 mg/min trimethaphan were correlated (
r
=0.98;
P
=0.001).

Conclusions
—Residual sympathetic activity drives supine hypertension in MSA. It contributes to, but does not completely explain, supine hypertension in PAF.
Sotalol in the Treatment of Fetal Dysrhythmias
Authors: Oudijk Martijn A. , Michon Maaike M. , Kleinman Charles S. , Kapusta Livia , Stoutenbeek Philip , Visser Gerard H. A. , Meijboom Erik J.
Published: June 2012

Background
—Fetal tachycardia may cause hydrops fetalis and lead to fetal death. No unanimity of opinion exists regarding the optimum treatment. This study evaluates our experience with transplacental sotalol therapy to treat fetal tachycardias in terms of safety and efficacy.

Methods and Results
—The charts of 21 patients who were treated with sotalol for fetal tachycardia were reviewed. Ten fetuses had atrial flutter (AF), 10 had supraventricular tachycardia (SVT), and 1 had VT. Hydrops fetalis was present in 9 fetuses. Drug treatment was successful in establishing sinus rhythm in 8 of 10 fetuses with AF and in 6 of 10 fetuses with SVT. The mortality rate in this study was 19% (4 of 21 fetuses; 3 had SVT and 1 had AF); 3 deaths occurred just days after the initiation of sotalol therapy, and 1 occurred after a dosage increase. At birth, tachycardia was present in 6 infants. Two patients who converted to sinus rhythm in utero suffered from neurologic pathology postnatally.

Conclusions
—Fetal tachycardia is a serious condition in which treatment should be initiated, especially in the presence of hydrops fetalis. The high success rate in fetuses with AF suggests that sotalol should be considered a drug of first choice to treat fetal AF. The low conversion rate and the fact that 3 of the 4 deaths in this study occurred in fetuses with SVT indicate that the risks of sotalol therapy outweigh the benefits in this group and that sotalol should, therefore, be limited in the treatment of fetal SVT.
Sympathetic Reinnervation of the Sinus Node and Exercise Hemodynamics After Cardiac Transplantation
Authors: Wilson Robert F. , Johnson Thomas H. , Haidet George C. , Kubo Spencer H. , Mianuelli Marcus
Published: June 2012

Background
—Sympathetic cardiac reinnervation occurs variably after cardiac transplantation (CT) in humans. We hypothesized that sinus node reinnervation would partially restore normal chronotropic response to exercise.

Methods and Results
—Thirteen recent CT recipients, 28 late CT recipients (≥1 year after CT), and 20 control subjects were studied. Sinus node sympathetic reinnervation was determined by heart rate (HR) change after tyramine injection into the artery that perfused the sinus node. HR changes of <5 and ≥15 bpm were defined, respectively, as denervation and marked reinnervation. During treadmill exercise, HR, blood pressure, and expired O
2
and CO
2
were measured. All early transplant recipients exhibited features typical of denervation (basal HR, 88±2 bpm; peak HR, 132±4 bpm, peaking 1.8±0.3 minutes after exercise cessation and slowly declining after exercise). A similar pattern was found in the 12 late transplant recipients with persistent sinus node denervation. However, in patients with marked reinnervation, exercise HR rose more (peak HR, 142±4 and 141±2 bpm), peaked earlier after cessation of exercise (0.7±0.4 and 0.3±0.1 minute), and fell more rapidly. Exercise duration and maximal oxygen consumption were not related significantly to reinnervation status, but a trend existed for longer exercise time in markedly reinnervated patients.

Conclusions
—The present studies suggest that sympathetic reinnervation of the sinus node is accompanied by partial restoration of normal HR response to exercise. Both maximal oxygen consumption and exercise duration were markedly shorter in CT patients than in control subjects, and most of the difference was not related to innervation status.
Na
+
/H
+
Exchange Inhibition With HOE642 Improves Postischemic Recovery due to Attenuation of Ca
2+
Overload and Prolonged Acidosis on Reperfusion
Authors: Strömer Hinrik , de Groot Mark C. H. , Horn Michael , Faul Christian , Leupold Andrea , Morgan James P. , Scholz Wolfgang , Neubauer Stefan
Published: June 2012

Background
—Na
+
/H
+
exchange inhibition with HOE642 (cariporide) improves postischemic recovery of cardiac function, but the mechanisms of action remain speculative. Because Na
+
/H
+
exchange is activated on reperfusion, it was hypothesized that its inhibition delays realkalinization and decreases intracellular Na
+
and, via Na
+
/Ca
2+
exchange, Ca
2+
overload. Attenuated Ca
2+
overload and prolonged acidosis are known to be cardioprotective.

Methods and Results
—Left ventricular developed and end-diastolic pressures were measured in isolated buffer-perfused rat hearts subjected to 30 minutes of no-flow ischemia and 30 minutes of reperfusion (37°C) with or without 1 μmol/L HOE642 added to the perfusate 15 minutes before ischemia. Intracellular Ca
2+
concentration ([Ca
2+
]
i
) and pH
i
were measured with aequorin (n=10 per group) and
31
P NMR spectroscopy (n=6 per group), respectively. HOE642 did not affect preischemic mechanical function, [Ca
2+
]
i
, or pH
i
. Mechanical recovery after 30 minutes of reperfusion was substantially improved with HOE642: left ventricular developed pressure (in percent of preischemic values) was 92±3 versus 49±7 and left ventricular end-diastolic pressure was 16±3 versus 46±5 mm Hg (
P
<0.05 for HOE642-treated versus untreated hearts). End-ischemic [Ca
2+
]
i
was significantly lower in HOE642-treated than in untreated hearts (1.04±0.06 versus 1.84±0.02 μmol/L,
P
<0.05). Maximal intracellular Ca
2+
overload during the first 60 seconds of reperfusion was attenuated with HOE642 compared with untreated hearts: 2.0±0.3 versus 3.2±0.3 μmol/L (
P
<0.05). pH
i
was not different at end ischemia (≈5.9±0.05). Realkalinization was similar in the first 90 seconds of reperfusion and significantly delayed in the next 3 minutes (eg, 6.8±0.07 in HOE642-treated hearts compared with 7.2±0.07 in untreated hearts;
P
<0.05).

Conclusions
—HOE642 improves postischemic recovery by reducing Ca
2+
overload during ischemia and early reperfusion and by prolonging postischemic acidosis.
Hemodynamic Stresses Induce Endothelial Dysfunction and Remodeling of Pulmonary Artery in Experimental Compensated Heart Failure
Authors: Driss Ahmed Ben , Devaux Corinne , Henrion Daniel , Duriez Micheline , Thuillez Christian , Levy Bernard I. , Michel Jean-Baptiste
Published: June 2012

Background
—We hypothesized that, in compensated heart failure (HF), hemodynamic perturbations and their consequences exist in pulmonary artery (PA) despite the absence of any perturbation in thoracic aorta (TA).

Methods and Results
—The left coronary artery was ligated in 20 male Wistar rats with compensated HF. Four months after ligation, these rats were compared with 20 sham-operated control rats. Blood pressure, velocity, viscosity, luminal diameter, and wall tensile and shear stresses were determined in PA and TA. Arterial rings were mounted in a myograph for ex vivo study. Endothelial nitric oxide synthase (eNOS) mRNA expression was determined in lung and aorta. Sections of PA and TA were used for histomorphometric study. In PA from rats with compensated HF, (1) blood pressure and wall tensile stress increased, whereas blood velocity and wall shear stress decreased; (2) contractions to KCl were not altered, but maximal contraction to phenylephrine and EC
50
decreased; (3) endothelium-dependent relaxation to acetylcholine and basal NO activity were blunted, whereas endothelium-independent relaxation was preserved; (4) eNOS mRNA levels and eNOS transcription in lung nuclei decreased; and (5) medial cross-sectional area, thickness, smooth muscle cell number, elastin, and collagen contents increased. Conversely, no such changes were found in TA from rats with compensated HF.

Conclusions
—In compensated HF induced by small myocardial infarction, hemodynamics, vascular wall function, and structure are altered in PA but preserved in TA. These results indicate that the pulmonary vascular bed is an early target of regional circulatory alterations in HF.
PhysioBank, PhysioToolkit, and PhysioNet
Authors: Goldberger Ary L. , Amaral Luis A. N. , Glass Leon , Hausdorff Jeffrey M. , Ivanov Plamen Ch. , Mark Roger G. , Mietus Joseph E. , Moody George B. , Peng Chung-Kang , Stanley H. Eugene
Published: June 2012

Abstract
—The newly inaugurated Research Resource for Complex Physiologic Signals, which was created under the auspices of the National Center for Research Resources of the National Institutes of Health, is intended to stimulate current research and new investigations in the study of cardiovascular and other complex biomedical signals. The resource has 3 interdependent components. PhysioBank is a large and growing archive of well-characterized digital recordings of physiological signals and related data for use by the biomedical research community. It currently includes databases of multiparameter cardiopulmonary, neural, and other biomedical signals from healthy subjects and from patients with a variety of conditions with major public health implications, including life-threatening arrhythmias, congestive heart failure, sleep apnea, neurological disorders, and aging. PhysioToolkit is a library of open-source software for physiological signal processing and analysis, the detection of physiologically significant events using both classic techniques and novel methods based on statistical physics and nonlinear dynamics, the interactive display and characterization of signals, the creation of new databases, the simulation of physiological and other signals, the quantitative evaluation and comparison of analysis methods, and the analysis of nonstationary processes. PhysioNet is an on-line forum for the dissemination and exchange of recorded biomedical signals and open-source software for analyzing them. It provides facilities for the cooperative analysis of data and the evaluation of proposed new algorithms. In addition to providing free electronic access to PhysioBank data and PhysioToolkit software via the World Wide Web (http://www.physionet.org), PhysioNet offers services and training via on-line tutorials to assist users with varying levels of expertise.
Short-Term Clinical Outcome of Patients With Acute Pulmonary Embolism, Normal Blood Pressure, and Echocardiographic Right Ventricular Dysfunction
Authors: Grifoni Stefano , Olivotto Iacopo , Cecchini Paolo , Pieralli Filippo , Camaiti Alberto , Santoro Gennaro , Conti Alberto , Agnelli Giancarlo , Berni Giancarlo
Published: June 2012

Background
—The role of echocardiographic right ventricular (RV) dysfunction in predicting clinical outcome in clinically stable patients with pulmonary embolism (PE) is undefined. In this study, we assessed the prevalence and clinical outcome of normotensive patients with RV dysfunction among a broad spectrum of PE patients.

Methods and Results
—This prospective clinical outcome study included cohort of 209 consecutive patients (age, 65±15 years) with documented PE. Acute RV dysfunction was diagnosed in the presence of ≥1 of the following: RV dilatation (without hypertrophy), paradox septal systolic motion, and Doppler evidence of pulmonary hypertension. Four groups were identified: 28 patients presenting with shock or cardiac arrest (13%), 19 hypotensive patients without shock (9%), 65 normotensive patients with echocardiographic RV dysfunction (31%), and 97 normotensive patients without RV dysfunction (47%). Among normotensive patients with RV dysfunction, 6 (10%) developed PE-related shock after admission: 3 of these patients died, and 3 were successfully treated with thrombolytic agents. In comparison, none of the 97 normotensive patients without RV dysfunction developed shock or died as a result of PE.

Conclusions
—A significant proportion (31%) of normotensive patients with acute PE presents with RV dysfunction; these patients with latent hemodynamic impairment have a 10% rate of PE-related shock and 5% in-hospital mortality and may require aggressive therapeutic strategies. Conversely, normotensive patients without echocardiographic RV dysfunction have a benign short-term prognosis. Thus, early detection of echocardiographic RV dysfunction is of major importance in the risk stratification of normotensive patients with acute PE.
Left Ventricular Hypertrophy in Ascending Aortic Stenosis Mice
Authors: Ding Bo , Price Robert L. , Goldsmith Edie C. , Borg Thomas K. , Yan Xinhua , Douglas Pamela S. , Weinberg Ellen O. , Bartunek Jozef , Thielen Thomas , Didenko Vladimir V. , Lorell Beverly H.
Published: June 2012

Background
—To determine potential mechanisms of the transition from hypertrophy to very early failure, we examined apoptosis in a model of ascending aortic stenosis (AS) in male FVB/n mice.

Methods and Results
—Compared with age-matched controls, 4-week and 7-week AS animals (n=12 to 16 per group) had increased ratios of left ventricular weight to body weight (4.7±0.7 versus 3.1±0.2 and 5.7±0.4 versus 2.7±0.1 mg/g, respectively,
P
<0.05) with similar body weights. Myocyte width was also increased in 4-week and 7-week AS mice compared with controls (19.0±0.8 and 25.2±1.8 versus 14.1±0.5 μm, respectively,
P
<0.01). By 7 weeks, AS myocytes displayed branching with distinct differences in intercalated disk size and staining for β
1
-integrin on both cell surface and adjacent extracellular matrix. In vivo left ventricular systolic developed pressure per gram as well as endocardial fractional shortening were similar in 4-week AS and controls but depressed in 7-week AS mice. Myocyte apoptosis estimated by in situ nick end-labeling (TUNEL) was extremely rare in 4-week AS and control mice; however, a low prevalence of TUNEL-positive myocytes and DNA laddering were detected in 7-week AS mice. The specificity of TUNEL labeling was confirmed by in situ ligation of hairpin oligonucleotides.

Conclusions
—Our findings indicate that myocyte apoptosis develops during the transition from hypertrophy to early failure in mice with chronic biomechanical stress and support the hypothesis that the disruption of normal myocyte anchorage to adjacent extracellular matrix and cells, a process called anoikis, may signal apoptosis.