bluuebunny/crossref_metadata_2025 huggingface dataset:
Increased Collagen Deposition and Elevated Expression of Connective Tissue Growth Factor in Human Thoracic Aortic Dissection
Authors: Wang Xinwen , LeMaire Scott A. , Chen Li , Shen Ying H. , Gan Yehua , Bartsch Heather , Carter Stacey A. , Utama Budi , Ou Hesheng , Coselli Joseph S. , Wang Xing Li
Published: July 2006

Background—

Thoracic aortic dissection (TAD) is characterized by dysregulated extracellular matrix. Little is known about the alterations of collagen and stimulators of collagen synthesis, eg, connective tissue growth factor (CTGF), in patients with TAD. In this study, we examined their roles in TAD.

Methods and Results—

Surgical specimens of the aortic wall of TAD patients (n=10) and controls (n=10) were tested for collagen types I and III and CTGF expression. When compared with controls, protein levels of type I and III collagen and CTGF were significantly increased by 3.2-, 3.7-, and 5.3-fold, respectively (
P
<0.05 for all). Similar patterns were shown in mRNA levels of type Iα and Iα2 collagen and CTGF. Using immunohistochemistry and trichrome staining, we also observed elevated levels of collagen in the aortic media and adventitia. Treatment with recombinant human CTGF increased collagen synthesis in cultured aortic smooth muscle cells in a dose- and time-dependent fashion, in which expression of collagens increased from 506±108 counts per minute to 2764±240 cpm by 50 ng/mL CTGF, and from 30±43 cpm to 429±102 cpm at 48 hours.

Conclusions—

TAD patients exhibited significantly increased expression of aortic collagen types I and III as well as CTGF, which is likely to be responsible for the compromised aortic distensibility and systemic compliance. Because CTGF can increase collagen expression, CTGF may be a new target molecule in the pathogenesis and progression of TAD.
Three-Dimensional Geometry of the Tricuspid Annulus in Healthy Subjects and in Patients With Functional Tricuspid Regurgitation
Authors: Fukuda Shota , Saracino Giuseppe , Matsumura Yoshiki , Daimon Masao , Tran Hung , Greenberg Neil L. , Hozumi Takeshi , Yoshikawa Junichi , Thomas James D. , Shiota Takahiro
Published: July 2006

Background—

Most rings currently used for tricuspid valve annuloplasty are formed in a single plane, whereas the actual tricuspid annulus (TA) may have a nonplanar or 3-dimensional (3D) structure. The purpose of this study was therefore to investigate the 3D geometry of the TA in healthy subjects and in patients with functional tricuspid regurgitation (TR).

Methods and Results—

This study consisted of 15 healthy subjects and 16 patients with functional TR who had real-time 3D echocardiography. With our customized software, 8 points along the TA were determined with the rotated plane around the axis at 45°intervals. The TA was traced during a cardiac cycle. The distance between diagonals connecting 2 points was measured. The height was defined as the distance from the plane determined by least-squares regression analysis at all 8 points. Both the maximum (7.5±2.1 versus 5.6±1.0 cm
2
/m
2
) and minimum (5.7±1.3 versus 3.9±0.8 cm
2
/m
2
) TA areas in patients with TR were larger than those in healthy subjects (both
P
<0.01). Healthy subjects had a nonplanar-shaped TA with homogeneous contraction. The posteroseptal portion was the lowest toward the apex from the right atrium, and the anteroseptal portion was the highest. In patients with functional TR, the TA was dilated in the septal to lateral direction, resulting in a more circular shape than in healthy subjects. A similar 3D pattern was observed in patients with TR, but it was more planar than that in healthy subjects.

Conclusions—

Real-time 3D echocardiography showed a complicated 3D structure of the TA, which appeared to be different from the “saddle-shaped” mitral annulus, suggesting an annuloplasty for TR different from that for mitral regurgitation.
Mitral Valve Repair Versus Revascularization Alone in the Treatment of Ischemic Mitral Regurgitation
Authors: Kang Duk-Hyun , Kim Mi-Jeong , Kang Soo-Jin , Song Jong-Min , Song Hyun , Hong Myeong-Ki , Choi Kee-Joon , Song Jae-Kwan , Lee Jae-Won
Published: July 2006

Background—

For patients with ischemic mitral regurgitation (MR), it is not clear whether adjunctive mitral valve (MV) repair at the time of coronary artery bypass graft surgery (CABG) is beneficial. We sought to test the hypothesis that MV repair with CABG is superior to CABG alone in improving MR without increasing operative or long-term mortality.

Methods and Results—

A total of 107 consecutive patients with moderate or severe ischemic MR, as determined by preoperative echocardiography, underwent CABG with concomitant MV repair (repair group, n=50) or CABG only (CABG group, n=57). Degree of MR was graded as none, mild, moderate, or severe by the proximal isovelocity surface area method. The groups were similar with respect to age, gender, baseline New York Heart Association class, ejection fraction, and number of bypass grafts. The repair group had a higher percentage of patients with atrial fibrillation or severe MR than the CABG group. The operative mortality was significantly higher for the repair group (12%) than the CABG group (2%), whereas the 5-year actuarial survival rate of the 2 groups was similar (88%±5% versus 87%±6%). On multivariate logistic regression analysis, older age, higher New York Heart Association class, and atrial fibrillation were independent predictors of operative mortality (
P
<0.05). Among patients with severe MR, ischemic MR was improved in all patients of the repair group and in 67% of patients in the CABG group (
P
<0.001), whereas improvement rates in patients with moderate MR were similar in the 2 groups (75% versus 67%, P=NS).

Conclusions—

Although MV repair appears to be more effective at reducing ischemic functional MR, CABG alone may be a preferable treatment option for patients with moderate MR and high operative risk factors such as old age or atrial fibrillation.
Metabolic Syndrome Is Associated With Faster Degeneration of Bioprosthetic Valves
Authors: Briand Martin , Pibarot Philippe , Després Jean-Pierre , Voisine Pierre , Dumesnil Jean G. , Dagenais François , Mathieu Patrick
Published: July 2006

Background—

Several studies have reported similarities between calcification of the native aortic valve and atherosclerosis. Recent studies also suggested that hypercholesterolemia may be a risk factor for calcific degeneration of bioprosthetic valves. The metabolic syndrome (MS) is associated with a higher risk of vascular atherosclerosis. We thus hypothesized that the atherogenic features of MS could accelerate bioprosthetic valve degeneration.

Methods and Results—

We included 217 patients who underwent aortic valve replacement with a bioprosthetic valve in the study. Of these patients, 71 patients (33%) had MS defined according to the modified criteria proposed by the National Cholesterol Education Program Adult Treatment Panel III. The annualized increase in mean transprosthetic gradient and the worsening of transprosthetic regurgitation measured by Doppler echocardiography were used to assess the deterioration of valve hemodynamic function. Patients with MS had higher progression of gradient (+4±5 mm Hg/year versus +2±2 mm Hg/year,
P
<0.001), higher proportion of ≥1/3 degree worsening of regurgitation (25% versus 12%,
P
=0.02), and higher proportion of valve function deterioration defined as regurgitation worsening and/or ≥3 mm Hg/year increase in gradient (41% versus 25%,
P
=0.02) when compared with patients without MS. On multivariate analysis, MS was an independent predictor of gradient progression (
P
=0.01), regurgitation worsening (
P
=0.02), and valve function deterioration (
P
=0.02). The other independent predictors were diabetes, renal insufficiency, and higher mean gradient at baseline.

Conclusions—

This is the first study to report that the MS is independently associated with faster bioprosthetic valve degeneration. This study could pave the way for the development of a new medical therapy able to significantly reduce the structural valve deterioration of bioprostheses.
Therapeutic Delivery of Cyclin A2 Induces Myocardial Regeneration and Enhances Cardiac Function in Ischemic Heart Failure
Authors: Woo Y. Joseph , Panlilio Corinna M. , Cheng Richard K. , Liao George P. , Atluri Pavan , Hsu Vivian M. , Cohen Jeffrey E. , Chaudhry Hina W.
Published: July 2006

Background—

Heart failure is a global health concern. As a novel therapeutic strategy, the induction of endogenous myocardial regeneration was investigated by initiating cardiomyocyte mitosis by expressing the cell cycle regulator cyclin A2.

Methods and Results—

Lewis rats underwent left anterior descending coronary artery ligation followed by peri-infarct intramyocardial delivery of adenoviral vector expressing cyclin A2 (n =32) or empty adeno-null (n =32). Cyclin A2 expression was characterized by Western Blot and immunohistochemistry. Six weeks after surgery, in vivo myocardial function was analyzed using an ascending aortic flow probe and pressure-volume catheter. DNA synthesis was analyzed by proliferating cell nuclear antigen (PCNA), Ki-67, and BrdU. Mitosis was analyzed by phosphohistone-H3 expression. Myofilament density and ventricular geometry were assessed. Cyclin A2 levels peaked at 2 weeks and tapered off by 4 weeks. Borderzone cardiomyocyte cell cycle activation was demonstrated by increased PCNA (40.1±2.6 versus 9.3±1.1;
P
<0.0001), Ki-67 (46.3±7.2 versus 20.4±6.0;
P
<0.0001), BrdU (44.2±13.7 versus 5.2±5.2;
P
<0.05), and phosphohistone-H3 (12.7±1.4 versus 0±0;
P
<0.0001) positive cells/hpf. Cyclin A2 hearts demonstrated increased borderzone myofilament density (39.8±1.1 versus 31.8±1.0 cells/hpf;
P
=0.0011). Borderzone wall thickness was greater in cyclin A2 hearts (1.7±0.4 versus 1.4±0.04 mm;
P
<0.0001). Cyclin A2 animals manifested improved hemodynamics: Pmax (70.6±8.9 versus 60.4±11.8 mm Hg;
P
=0.017), max dP/dt (3000±588 versus 2500±643 mm Hg/sec;
P
<0.05), preload adjusted maximal power (5.75±4.40 versus 2.75±0.98 mWatts/μL
2
;
P
<0.05), and cardiac output (26.8±3.7 versus 22.7±2.6 mL/min;
P
=0.004).

Conclusions—

A therapeutic strategy of cyclin A2 expression via gene transfer induced cardiomyocyte cell cycle activation yielded increased borderzone myofilament density and improved myocardial function. This approach of inducing endogenous myocardial regeneration provides proof-of-concept evidence that cyclin A2 may ultimately serve as an efficient, alternative therapy for heart failure.
Skeletal Myoblast Transplantation in Ischemic Heart Failure
Authors: Hagège Albert A. , Marolleau Jean-Pierre , Vilquin Jean-Thomas , Alhéritière Armelle , Peyrard Séverine , Duboc Denis , Abergel Eric , Messas Emmanuel , Mousseaux Elie , Schwartz Ketty , Desnos Michel , Menasché Philippe
Published: July 2006

Background—

Skeletal myoblast (SM) transplantation (Tx) in a post-myocardial infarction (MI) scar experimentally improves left ventricular (LV) ejection fraction (EF). Short-term follow-up (FU) studies have suggested that a similar benefit could clinically occur despite an increased risk of LV arrhythmias.

Methods and Results—

We report the long-term FU of the first worldwide cohort of grafted patients (n =9, 61.8±11.6 years, previous MI, EF ≤35%) operated on (autologous SM Tx and bypass surgery) in 2000 to 2001 and evaluated before Tx, at 1 month (M1) and at a median FU of 52 (18 to 58) months after Tx (37 patient-years). NYHA class improved from 2.5±0.5 to 1.8±0.4 at M1 (
P
=0.004 versus baseline) and 1.7±0.5 at FU (
P
=not significant versus M1;
P
=0.0007 versus baseline). EF increased from 24.3±4% to 31±4.1% at M1 (+28%,
P
=0.001 versus baseline) and remained stable thereafter (28.7±8.1%, +18% versus baseline). There were 5 hospitalizations for heart failure in 3 patients at 28.6±9.9 months, allowing implant in 2 patients with a resynchronization pacemaker. An automatic cardiac defibrillator (ACD) was implanted in 5 patients for nonsustained (n =1) or sustained (n =4) ventricular tachycardia at 12.2±18.6 (1 to 45) months. Despite a beta-blocker/amiodarone combination therapy, there were 14 appropriate shocks for 3 arrhythmic storms in 3 patients at 6, 7, and 18 months after ACD implantation.

Conclusions—

In this cohort of severe heart failure patients both clinical status and EF stably improve over time with a strikingly low incidence of hospitalizations for heart failure (0.13/patient-years) and the arrhythmic risk can be controlled by medical therapy and/or on-request ACD implantation.
Mitral Leaflet Remodeling in Dilated Cardiomyopathy
Authors: Timek Tomasz A. , Lai David T. , Dagum Paul , Liang David , Daughters George T. , Ingels Neil B. , Miller D. Craig
Published: July 2006

Background—

Normal mammalian mitral leaflets have regional heterogeneity of biochemical composition, collagen fiber orientation, and geometric deformation. How leaflet shape and regional geometry are affected in dilated cardiomyopathy is unknown.

Methods and Results—

Nine sheep had 8 radio-opaque markers affixed to the mitral annulus (MA), 4 markers sewn on the central meridian of the anterior mitral leaflet (AML) forming 4 distinct segments S
1
to S
4
and 2 on the posterior leaflet (PML) forming 2 distinct segments S
5
and S
6
. Biplane videofluoroscopy and echocardiography were performed before and after rapid pacing (180 to 230 bpm for 15±6 days) sufficient to develop tachycardia-induced cardiomyopathy (TIC) and functional mitral regurgitation (FMR). Leaflet tethering was defined as change of displacement of AML and PML edge markers from the MA plane from baseline values while leaflet length was obtained by summing the segments between respective leaflet markers. With TIC, total AML and PML length increased significantly (2.11±0.16 versus 2.43±0.23 cm and 1.14±0.27 versus 1.33±0.25 cm before and after pacing for AML and PML, respectively;
P
<0.05 for both), but only segments near the edge of each leaflet (S
4
lengthened by 23±17% and S
5
by 24±18%;
P
<0.05 for both) had significant regional remodeling. AML shape did not change and no leaflet tethering was observed.

Conclusion—

TIC was not associated with leaflet tethering or shape change, but both anterior and posterior leaflets lengthened because of significant remodeling localized near the leaflet edge. Leaflet remodeling accompanies mitral regurgitation in cardiomyopathy and casts doubt on FMR being purely “functional” in etiology.
Cardioprotection Via Activation of Protein Kinase C-δ Depends on Modulation of the Reverse Mode of the Na+/Ca2+Exchanger
Authors: Bouwman R. Arthur , Salic Kanita , Padding F. Gieneke , Eringa Etto C. , van Beek-Harmsen Brechje J. , Matsuda Toshio , Baba Akemichi , Musters René J.P. , Paulus Walter J. , de Lange Jaap J. , Boer Christa
Published: July 2006

Background—Pretreatment with the volatile anesthetic sevoflurane protects cardiomyocytes against subsequent ischemic episodes caused by a protein kinase C (PKC)-δ mediated preconditioning effect. Sevoflurane directly modulates cardiac Ca2+handling, and because Ca2+also serves as a mediator in other cardioprotective signaling pathways, possible involvement of the Na+/Ca2+exchanger (NCX) in relation with PKC-δ in sevoflurane-induced cardioprotection was investigated.

Methods and Results—Isolated right ventricular rat trabeculae were subjected to simulated ischemia and reperfusion (SI/R), consisting of superfusion with hypoxic glucose-free buffer for 40 minutes after rigor development, followed by reperfusion with normoxic glucose containing buffer. Preconditioning with sevoflurane before SI/R improved isometric force development during contractile recovery at 60 minutes after the end of hypoxic superfusion (83±7% [sevo] versus 57±2% [SI/R];n=8;P<0.01). Inhibition of the reverse mode of the NCX by KB-R7943 (10 μmol/L) or SEA0400 (1 μmol/L) during preconditioning attenuated the protective effect of sevoflurane. KB-R7943 and SEA0400 did not have intrinsic effects on the contractile recovery. Furthermore, inhibition of the NCX in trabeculae exposed to sevoflurane reduced sevoflurane-induced PKC-δ translocation toward the sarcolemma, as demonstrated by digital imaging fluorescent microscopy. The degree of PKC-δ phosphorylation at serine643as determined by western blot analysis was not affected by sevoflurane.

Conclusions—Sevoflurane-induced cardioprotection depends on the NCX preceding PKC-δ translocation presumably via increased NCX-mediated Ca2+influx. This may suggest that increased myocardial Ca2+load triggers the cardioprotective signaling cascade elicited by volatile anesthetic agents similar to other modes of preconditioning.
Role and Results of Surgery in Acute Type B Aortic Dissection
Authors: Trimarchi Santi , Nienaber Christoph A. , Rampoldi Vincenzo , Myrmel Truls , Suzuki Toru , Bossone Eduardo , Tolva Valerio , Deeb Michael G. , Upchurch Gilbert R. , Cooper Jeanna V. , Fang Jianming , Isselbacher Eric M. , Sundt Thoralf M. , Eagle Kim A.
Published: July 2006

Background—

The clinical profiles and outcomes of patients treated surgically for acute type B aortic dissection (ABAD) are often reported for those in small series or for those cared for at a single institution over a long time period, during which a continuous evolution in techniques has occurred. Accordingly, we sought to evaluate the clinical features and surgical results of patients enrolled in the International Registry of Acute Aortic Dissection by identifying primary factors that influenced surgical outcome and estimating average surgical mortality for ABAD in the current era.

Methods and Results—

A comprehensive analysis of 290 clinical variables and their relation to surgical outcomes for 82 patients who required surgery for ABAD (from a population of 1256 patients; mean±SD age, 60.6±15.0 years; 82.9% male) and who were enrolled in the International Registry of Acute Aortic Dissection was performed. The overall in-hospital mortality was 29.3%. Factors associated with increased surgical mortality based on univariate analysis were preoperative coma or altered consciousness, partial thrombosis of the false lumen, evidence of periaortic hematoma on diagnostic imaging, descending aortic diameter >6 cm, right ventricle dysfunction at surgery, and shorter time from the onset of symptoms to surgery. Factors associated with favorable outcomes included radiating pain, normotension at surgery (systolic blood pressure 100 to 149 mm Hg), and reduced hypothermic circulatory arrest time. The 2 independent predictors of surgical mortality were age >70 years (odds ratio, 4.32; 95% confidence interval, 1.30 to 14.34) and preoperative shock/hypotension (odds ratio, 6.05; 95% confidence interval, 1.12 to 32.49).

Conclusions—

The present study provides insights into current-day clinical profiles and surgical outcomes of ABAD. Knowledge about different preoperative clinical conditions may help surgeons in making treatment decisions among these high-risk patients.
Simultaneous Autologous Transplantation of Cocultured Mesenchymal Stem Cells and Skeletal Myoblasts Improves Ventricular Function in a Murine Model of Chagas Disease
Authors: Guarita-Souza L.C. , Carvalho K.A.T. , Woitowicz V. , Rebelatto C. , Senegaglia A. , Hansen P. , Miyague N. , Francisco J.C. , Olandoski M. , Faria-Neto J.R. , Brofman P.
Published: July 2006

Background—

Cellular transplantation is emerging as a promising strategy for the treatment of postinfarction ventricular dysfunction. Whether its beneficial effects can be extended to other cardiomyopathies remains an unexplored question. We evaluated the histological and functional effects of simultaneous autologous transplantation of co-cultured stem cells and skeletal myoblasts in an experimental model of dilated cardiomyopathy caused by Chagas disease, characterized by diffuse fibrosis and impairment of microcirculation.

Methods and Results—

Wistar rats weighing 200 grams were infected intraperitoneally with 15×10
4
trypomastigotes. After 8 months, 2-dimensional echocardiographic study was performed for baseline assessment of left ventricle (LV) ejection fraction (EF) (%), left ventricle end-diastolic volume (LVEDV) (mL), and left ventricle end-systolic volume (LVESV) (mL). Animals with LV dysfunction (EF <37%) were selected for the study. Autologous skeletal myoblasts were isolated from muscle biopsy and mesenchymal stem cells from bone marrow aspirates were co-cultured in vitro for 14 days, yielding a cell viability of >90%. Eleven animals received autologous transplant of 5.4×10
6
±8.0×10
6
cells (300 μL) into the LV wall. The control group (n=10) received culture medium (300 μL). Cell types were identified with vimentin and fast myosin. After 4 weeks, ventricular function was reassessed by echo. For histological analysis, heart tissue was stained with hematoxylin and eosin and immunostained for fast myosin. After 4 weeks, cell transplantation significantly improved EF and reduced LVEDV and LVESV. No change was observed in the control group.

Conclusion—

The co-transplant of stem cells and skeletal myoblasts is functionally effective in the Chagas disease ventricular dysfunction.
Outcome of Patients With Low Ejection Fraction Undergoing Coronary Artery Bypass Grafting
Authors: Hillis Graham S. , Zehr Kenton J. , Williams Amy W. , Schaff Hartzell V. , Orzulak Thomas A. , Daly Richard C. , Mullany Charles J. , Rodeheffer Richard J. , Oh Jae K.
Published: July 2006

Background—There are few data regarding medium-term outcome of coronary artery bypass grafting (CABG) in patients with severe left ventricular (LV) systolic dysfunction, particularly in the modern era, and even less assessing preoperative factors that might identify patients at highest risk.

Methods and Results—Three hundred seventy-nine consecutive patients with LV ejection fraction ≤35%, who underwent isolated first CABG between 1995 and 1999 were studied. Potential preoperative and perioperative predictors of outcome were recorded and patients followed-up for a median of 3.8 years. The primary study end-point was all-cause mortality. The 30-day, 1-year, and 3-year survival rates were 94.5%, 88%, and 81%, respectively. The independent predictors of mortality were preoperative estimated glomerular filtration rate (hazard ratio [HR], 0.98; 95% confidence interval [CI], 0.97 to 0.99 per mL/min/1.73m2;P<0.001) and age (HR, 1.03; 95% CI, 1.01 to 1.06 per year;P=0.005).

Conclusions—Patients with significant LV systolic dysfunction undergoing isolated CABG using contemporary techniques have a good medium-term survival. Renal dysfunction is the strongest independent predictor of mortality.
Coronary Revascularization (Surgical or Percutaneous) Decreases Mortality After the First Year in Diabetic Subjects but not in Nondiabetic Subjects With Multivessel Disease
Authors: Soares Paulo R. , Hueb Whady A. , Lemos Pedro A. , Lopes Neuza , Martinez Eulógio E. , Cesar Luis A.M. , Oliveira Sergio A. , Ramires Jose A.F.
Published: July 2006

Background—

It is currently unknown whether revascularization procedures are associated with an improvement in mortality among diabetic subjects, as compared with a more conservative medical treatment.

Methods and Results—

In MASS II, a total of 611 patients with stable multivessel coronary disease were randomly assigned to medical treatment, surgery, or angioplasty. From these, 190 patients had diabetes (medical, 75 patients; angioplasty, 56 patients; surgery, 59 patients) and comprised the present study population. Mortality rates were analyzed for the entire 5 years of follow-up. Separate analyzes were also performed for mortality at 2 time intervals: during the first year and after the first year of follow-up. We calculated the probability of death conditional on surviving to the start of the interval analyzed. The cumulative 5-year mortality as well as the mortality during the first year of follow-up was not significantly different among treatment groups, both for diabetic and for nondiabetic subjects. Also, during years 2 to 5, the mortality of the 3 treatment groups was not different for nondiabetic subjects. Among diabetic subjects, however, patients randomized to angioplasty or surgery had a significantly lower mortality between years 2 and 5 than those allocated to medical treatment (
P
=0.039).

Conclusion—

Surgery, angioplasty, and medical treatment appear to be associated with similar mortality rates for non-diabetic subjects. For diabetic subjects, however, coronary revascularization (percutaneous or surgical) significantly decreased the risk of death after the first year and up to 5 years, compared with medical treatment alone.
Cell–Matrix Contact Prevents Recognition and Damage of Endothelial Cells in States of Heightened Immunity
Authors: Methe Heiko , Edelman Elazer R.
Published: July 2006

Background—

Autoimmunity may exacerbate vascular disease, particularly in the form of anti-endothelial cell (EC) antibodies. The increased morbidity of cardiovascular diseases in concert with diabetes mellitus, hypertension, and other systemic illnesses may reflect the increase presence and potency of these antibodies. Matrix-embedded ECs act as powerful regulators of vascular repair accompanied by significant reduction in expected systemic and local inflammation. We compared the immune response against free and matrix-embedded ECs in naïve mice and mice with heightened EC immune reactivity.

Methods and Results—

Mice were presensitized to EC with repeated (days 0, 21, 35) subcutaneous injections of saline-suspended porcine EC (PAE) (5×10
5
cells). Controls received saline injections. On day 42, mice received 5×10
5
matrix-embedded or free PAEs. Circulating PAE-specific antibodies and effector T-cells were analyzed via flow cytometry, and xenoreactive lymphocytes via ELISPOT, 90 days after implantation. PAE-specific antibody-titers, frequency of CD4
+
-effector cells, and xenoreactive splenocytes were 2- to 4-fold lower (
P
<0.0001) when naïve mice were injected with matrix-embedded instead of saline-suspended PAEs. Though basal levels of circulating antibodies were significantly elevated after serial PAE injections (2210±341 mean fluorescence intensity, day 42) and almost doubled again 90 days after injection of a fourth set of free PAEs, antibody levels declined by half in recipients of matrix-embedded PAEs at day 42 (
P
<0.0001). Levels of CD4
+
-effector cells and xenoreactive splenocytes showed similar results.

Conclusions—

Implantation of free PAE elicits a significant immune response in naïve mice and even more pronounced in mice with predeveloped anti-endothelial immunity. Matrix-embedding protects xenogeneic ECs against immune reaction in naïve mice and to a similar extent in mice with heightened immune reactivity. Matrix-embedded EC might offer a promising approach for treatment of advanced cardiovascular disease.
Expression of Matrix Metalloproteinases and Endogenous Inhibitors Within Ascending Aortic Aneurysms of Patients With Marfan Syndrome
Authors: Ikonomidis John S. , Jones Jeffery A. , Barbour John R. , Stroud Robert E. , Clark Leslie L. , Kaplan Brooke S. , Zeeshan Ahmed , Bavaria Joseph E. , Gorman Joseph H. , Spinale Francis G. , Gorman Robert C.
Published: July 2006

Background—

Marfan syndrome (MFS) is known to cause ascending thoracic aortic aneurysms (ATAAs). Transforming growth factor beta (TGF-β) has recently been implicated in this process. Imbalances between the matrix metalloproteinases (MMPs) and their endogenous inhibitors (TIMPs) have also been shown to contribute to aneurysm formation. Whether and to what degree MMP, TIMP, and TGF-β signaling profiles are altered in ATAAs in MFS compared with non-MFS patients remains unknown.

Methods and Results—

ATAA samples taken during aortic replacement from age-matched MFS (n=9) and non-MFS (n=18) patients were assessed for representative subtypes of all MMP classes, all 4 known TIMPs, and type 2 TGF-β receptors (TGFBR2). Results were expressed as a percentage (mean±SEM) of reference control samples (100%; n=18) obtained from patients without ATAA. In MFS, decreased MMP-2 (76±7;
P
<0.05 versus control), increased MMP-12 (161±27% versus control;
P
<0.05), and increased MT1-MMP (248±64% versus 91±21 non-MFS and control;
P
<0.05) were observed. TIMP-3 (74±23%) was reduced compared with control values (
P
<0.05) and TIMP-2 was elevated (128±31%) compared with non-MFS (73±19%;
P
<0.05). In non-MFS samples, MMP-1 (70±16%), MMP-3 (77±18%), MMP-8 (75±11%), MMP-9 (69±14%), and MMP-12 (85±15%) were decreased compared with control (
P
<0.05). TIMPs 1 to 3 were reduced in non-MFS compared with control values (
P
<0.05). TGFBR2 were increased in MFS (193±32%) compared with non-MFS (95±16%) and controls (
P
<0.05).

Conclusions—

A unique MMP and TIMP portfolio was observed in ATAAs from MFS compared with non-MFS patients. In addition, MFS samples showed evidence of increased TGF-β signaling. These differences suggest disparate mechanisms of extracellular matrix remodeling between these 2 groups of patients.
Pacing-Induced Dys-Synchrony Preconditions Rabbit Myocardium Against Ischemia/Reperfusion Injury
Authors: Vanagt Ward Y. , Cornelussen Richard N. , Poulina Quincy P. , Blaauw Erik , Vernooy Kevin , Cleutjens Jack P. , van Bilsen Marc , Delhaas Tammo , Prinzen Frits W.
Published: July 2006

Background—

Because increased mechanical load induces preconditioning (PC) and dys-synchrony increases loading in late-activated regions, we investigated whether dys-synchrony induced by ventricular pacing (VP) at normal heart rate leads to cardioprotection.

Methods and Results—

Isolated working rabbit hearts were subjected to 35 minutes of global ischemia and 2 hours of reperfusion. Seven hearts underwent VP PC (3 periods of 5 minutes VP at the posterior left ventricular [LV] wall), 7 hearts underwent ischemic preconditioning (IPC) (3 periods of 5 minutes of global ischemia), and 9 hearts served as control (C). LV pressure and sonomicrometry were used to assess global hemodynamics and segment work (SW) and end-diastolic segment length (EDSL) in anterior and posterior LV myocardium. Myocardial release of lactate and expression of proBNP mRNA were determined to gain insight in molecular processes involved in VP PC (*
P
<0.05). Infarct size (triphenyl tetrazolium chloride staining) was 18.3±13.0% in group C, and was uniformly reduced in the VP PC and IPC groups (1.8±0.8%*, and 3.5±3.1%*, respectively; and not significant between VP PC and IPC). LV posterior wall pacing (VP PC group) increased EDSL (by 6.3±5.8%*) and SW (to 335±207%*) in the LV anterior wall, whereas posterior wall SW decreased to negative values (−23±63%*). LV pacing did not significantly change lactate release and coronary flow but significantly increased proBNP mRNA expression in both anterior and posterior myocardium as compared with controls.

Conclusions—

Intermittent dys-synchrony is equally cardioprotective as “classical” IPC. Stretch-mediated signaling is a more likely trigger for VP PC than ischemia. VP PC is potentially applicable in cardiac surgery.
Overexpression of Transforming Growth Factor-β Is Associated With Increased Hyaluronan Content and Impairment of Repair in Marfan Syndrome Aortic Aneurysm
Authors: Nataatmadja Maria , West Jennifer , West Malcolm
Published: July 2006

Background—

Marfan syndrome (MFS), a condition caused by fibrillin-1 gene mutation is associated with aortic aneurysm that shows elastic lamellae disruption, accumulation of glycosaminoglycans, and vascular smooth muscle cell (VSMC) apoptosis with minimal inflammatory response. We examined aneurysm tissue and cultured cells for expression of transforming growth factor-beta1 to -beta3 (TGFβ1 to 3), hyaluronan content, apoptosis, markers of cell migration, and infiltration of vascular progenitor cells (CD34).

Methods and Results—

MFS aortic aneurysm (6 males, 5 females; age 8 to 78 years) and normal aorta (5 males, 3 females; age 22 to 56 years) were used. Immunohistochemistry showed increased expression of TGFβ1 to 3, hyaluronan, and CD34-positive microcapillaries in MFS aneurysm compared with control. There was increased expression of TGFβ1 to 3 and hyaluronan in MFS cultured VSMCs, adventitial fibroblasts (AF), and skin fibroblasts (SF). Apoptosis was increased in MFS (VSMC: mean cell loss in MFS 29%, n of subjects=5, versus control 8%, n=3,
P
<0.05; AF: 28%, n=5 versus 7%, n=5,
P
<0.05; SF: 29%, n=3 versus 4%, n=3, not significant). In MFS, there was a 2-fold increase in adventitial microcapillaries containing CD34-positive cells compared with control tissue. Scratch wound assay showed absence of CD44, MT1-MMP, and β-3 integrin at the leading edge of migration in MFS indicating altered directional migration. Western blot showed increased expression of TGFβ1 to 3 in MFS but no change in expression of CD44, MT1-MMP, or β-3 integrin compared with controls.

Conclusions—

There was overexpression of TGF-β in MFS associated with altered hyaluronan synthesis, increased apoptosis, impaired progenitor cell recruitment, and abnormal directional migration. These factors limit tissue repair and are likely to contribute to aneurysm development.
Living Autologous Heart Valves Engineered From Human Prenatally Harvested Progenitors
Authors: Schmidt Dörthe , Mol Anita , Breymann Christian , Achermann Josef , Odermatt Bernhard , Gössi Matthias , Neuenschwander Stefan , Prêtre René , Genoni Michele , Zund Gregor , Hoerstrup Simon P.
Published: July 2006

Background—

Heart valve tissue engineering is a promising strategy to overcome the lack of autologous growing replacements, particularly for the repair of congenital malformations. Here, we present a novel concept using human prenatal progenitor cells as new and exclusive cell source to generate autologous implants ready for use at birth.

Methods and Results—

Human fetal mesenchymal progenitors were isolated from routinely sampled prenatal chorionic villus specimens and expanded in vitro. A portion was cryopreserved. After phenotyping and genotyping, cells were seeded onto synthetic biodegradable leaflet scaffolds (n=12) and conditioned in a bioreactor. After 21 days, leaflets were endothelialized with umbilical cord blood-derived endothelial progenitor cells and conditioned for additional 7 days. Resulting tissues were analyzed by histology, immunohistochemistry, biochemistry (amounts of extracellular matrix, DNA), mechanical testing, and scanning electron microscopy (SEM) and were compared with native neonatal heart valve leaflets. Fresh and cryopreserved cells showed comparable myofibroblast-like phenotypes. Genotyping confirmed their fetal origin. Neo-tissues exhibited organization, cell phenotypes, extracellular matrix production, and DNA content comparable to their native counterparts. Leaflet surfaces were covered with functional endothelia. SEM showed cellular distribution throughout the polymer and smooth surfaces. Mechanical profiles approximated those of native heart valves.

Conclusions—

Prenatal fetal progenitors obtained from routine chorionic villus sampling were successfully used as an exclusive, new cell source for the engineering of living heart valve leaflets. This concept may enable autologous replacements with growth potential ready for use at birth. Combined with the use of cell banking technology, this approach may be applied also for postnatal applications.
Differential Effect of Intracoronary Infusion of Mobilized Peripheral Blood Stem Cells by Granulocyte Colony–Stimulating Factor on Left Ventricular Function and Remodeling in Patients With Acute Myocardial Infarction Versus Old Myocardial Infarction
Authors: Kang Hyun-Jae , Lee Hae-Young , Na Sang-Hoon , Chang Sung-A , Park Kyung-Woo , Kim Hyung-Kwan , Kim Song-Yi , Chang Ho-Joon , Lee Whal , Kang Won Jun , Koo Bon-Kwon , Kim Yong-Jin , Lee Dong Soo , Sohn Dae-Won , Han Kyou-Sup , Oh Byung-Hee , Park Young-Bae , Kim Hyo-Soo
Published: July 2006

Background—

The efficacy of intracoronary infusion of granulocyte colony-stimulating factor (G-CSF) mobilized peripheral blood stem cells (PBSCs) has not been compared between patients with acute (AMI) versus old myocardial infarction (OMI). In addition, the potential risk of restenosis associated with G-CSF–based stem cell therapy has not been evaluated in the setting of drug eluting stent (DES) implantation.

Methods and Results—

We randomly allocated 96 patients with myocardial infarction who underwent coronary revascularization with DES for the culprit lesion into 4 groups. Eighty-two patients completed 6-month follow-up; AMI cell infusion (n=25), AMI control (n=25), OMI cell infusion (n=16), and OMI control group (n=16). In cell infusion groups, PBSCs were mobilized by G-CSF for 3 days and delivered to infarcted myocardium via intracoronary infusion. The AMI cell infusion group showed a significant additive improvement in left ventricular ejection fraction (LVEF) and remodeling compared with controls (change of LVEF: +5.1±9.1% versus −0.2±8.6%,
P
<0.05; change of end-systolic volume: −5.4±17.0 mL versus 6.5±21.9 mL,
P
<0.05). In OMI patients, however, there was no significant change of LVEF and ventricular remodeling in spite of significant improvement of coronary flow reserve after cell infusion. G-CSF–based cell therapy did not aggravate neointimal growth with DES implantation.

Conclusions—

Intracoronary infusion of mobilized PBSCs with G-CSF improves LVEF and remodeling in patients with AMI but is less definite in patients with OMI. G-CSF–based stem cell therapy with DES implantation is both feasible and safe, eliminating any potential for restenosis.
Autologous Human Tissue-Engineered Heart Valves
Authors: Mol Anita , Rutten Marcel C.M. , Driessen Niels J.B. , Bouten Carlijn V.C. , Zünd Gregor , Baaijens Frank P.T. , Hoerstrup Simon P.
Published: July 2006

Background—

Tissue engineering represents a promising approach for the development of living heart valve replacements. In vivo animal studies of tissue-engineered autologous heart valves have focused on pulmonary valve replacements, leaving the challenge to tissue engineer heart valves suitable for systemic application using human cells.

Methods and Results—

Tissue-engineered human heart valves were analyzed up to 4 weeks and conditioning using bioreactors was compared with static culturing. Tissue formation and mechanical properties increased with time and when using conditioning. Organization of the tissue, in terms of anisotropic properties, increased when conditioning was dynamic in nature. Exposure of the valves to physiological aortic valve flow demonstrated proper opening motion. Closure dynamics were suboptimal, most likely caused by the lower degree of anisotropy when compared with native aortic valve leaflets.

Conclusions—

This study presents autologous tissue-engineered heart valves based on human saphenous vein cells and a rapid degrading synthetic scaffold. Tissue properties and mechanical behavior might allow for use as living aortic valve replacements.
Functional Growth in Tissue-Engineered Living, Vascular Grafts
Authors: Hoerstrup Simon P. , Cummings MRCS Ian , Lachat Mario , Schoen Frederick J. , Jenni Rolf , Leschka Sebastian , Neuenschwander Stefan , Schmidt Dörthe , Mol Anita , Günter Christina , Gössi Mathias , Genoni Michele , Zund Gregor
Published: July 2006

Background—

Living autologous vascular grafts with the capacity for regeneration and growth may overcome the limitations of contemporary artificial prostheses. Particularly in congenital cardiovascular surgery, there is an unmet medical need for growing replacement materials. Here we investigate growth capacity of tissue-engineered living pulmonary arteries in a growing lamb model.

Methods and Results—

Vascular grafts fabricated from biodegradable scaffolds (ID 18±l mm) were sequentially seeded with vascular cells. The seeded constructs were grown in vitro for 21days using biomimetic conditions. Thereafter, these tissue-engineered vascular grafts (TEVGs) were surgically implanted as main pulmonary artery replacements in 14 lambs using cardiopulmonary bypass and followed up for ≤100 weeks. The animals more than doubled their body weight during the 2-year period. The TEVG showed good functional performance demonstrated by regular echocardiography at 20, 50, 80, and 100 weeks and computed tomography-angiography. In particular, there was no evidence of thrombus, calcification, stenosis, suture dehiscence, or aneurysm. There was a significant increase in diameter by 30% and length by 45%. Histology showed tissue formation reminiscent of native artery. Biochemical analysis revealed cellularity and proteoglycans and increased collagen contents in all of the groups, analogous to those of native vessels. The mechanical profiles of the TEVG showed stronger but less elastic tissue properties than native pulmonary arteries.

Conclusions—

This study provides evidence of growth in living, functional pulmonary arteries engineered from vascular cells in a full growth animal model.
Impact of Moderate Functional Mitral Insufficiency in Patients Undergoing Surgical Revascularization
Authors: Grossi Eugene A. , Crooke Gregory A. , DiGiorgi Paul L. , Schwartz Charles F. , Jorde Ulrich , Applebaum Robert M. , Ribakove Greg H. , Galloway Aubrey C. , Grau Juan B. , Colvin Stephen B.
Published: July 2006

Background—

Mild and moderate functional ischemic mitral insufficiency present at the time of surgical revascularization present clinical uncertainty. It is unclear whether the relatively poor outcomes in this cohort are dependent on valvular function or related to left ventricular dysfunction. The purpose of this study was to examine the early and late outcomes in patients with less-than-severe functional ischemic mitral insufficiency at the time of isolated coronary artery bypass grafting (CABG).

Methods and Results—

From 1996 through 2004, 2242 consecutive patients undergoing isolated CABG were identified as having none to moderate mitral regurgitation (MR) and no valve leaflet pathology. All of the patients at this single institution routinely had an intraoperative transesophageal echocardiography, prospectively quantified MR, and ejection fraction (EF). The New York State Cardiac Surgery Reporting System infrastructure was used to prospectively collect in-hospital patient variables and outcomes. Social Security Death Benefit Index was used to determine long-term survival. Odds ratio and significance (
P
value) are presented for each determined risk factor. There were 841 patients (37.5%) with no MR, 1137 (50.7%) with mild MR, and 264 (11.8%) with moderate MR. The patients with moderate MR were more likely to be older, female, and have more renal disease, previous MI, congestive heart failure, previous cardiac surgery, and lower EFs. Hospital mortality was independently and significantly associated with renal disease, decreasing EF, increasing age, previous cardiac operation, and cerebral vascular disease. Multivariable analysis revealed decreased survival with increasing age, previous operation, congestive heart failure, diabetes, nonelective operation, decreasing EF, and the presence of moderate MR (expβ = 1.49;
P
=0.007) and mild MR (expβ = 1.34;
P
=0.033).

Conclusions—

Independent of ventricular function, mild and moderate functional mitral insufficiency are associated with significantly decreased survival in patients undergoing CABG. Whether correction of moderate functional MR at the time of CABG improves outcome still needs to be determined.
Tricuspid Valve Repair With an Annuloplasty Ring Results in Improved Long-Term Outcomes
Authors: Tang Gilbert H. L. , David Tirone E. , Singh Steve K. , Maganti Manjula D. , Armstrong Susan , Borger Michael A.
Published: July 2006

Background—

The purpose of this study was to compare the long-term results of tricuspid valve (TV) repair with or without an annuloplasty ring.

Methods and Results—

702 patients underwent TV repair at our institution (1978 to 2003), of which 493 had, predominantly, a De Vega procedure (no ring) and 209 had an annuloplasty ring (ring). TV pathology was functional (secondary) in 74% of patients. Concomitant procedures consisted of mitral valve surgery in 80% of patients, aortic valve surgery in 33%, and coronary bypass in 14%. Clinical and echocardiographic follow-up data were obtained. Follow-up was 99% complete and was 5.9±4.9 (mean±SD) years long. Ring patients were younger (55±14 versus 59±14 years;
P
=0.001) and less likely to have coronary artery disease (10% versus 17%;
P
=0.02), more likely to be female (75% versus 65%;
P
=0.01) and having had previous cardiac surgery (56% versus 42%;
P
=0.001). Operative times were similar between the 2 groups. Long-term survival, event-free survival and freedom from recurrent TR were significantly better in the ring group, and there was a trend toward fewer TV reoperations. Multivariable analysis demonstrated that the use of an annuloplasty ring was an independent predictor of long-term survival (hazard ratio [HR], 0.7; 95% confidence interval [CI], 0.5 to 1.0;
P
=0.03) and event-free survival (HR, 0.8; CI, 0.6 to 1.0;
P
=0.04).

Conclusions—

Placement of an annuloplasty ring in patients undergoing tricuspid valve repair is associated with improved survival and event-free survival.
Collagen Matrices Enhance Survival of Transplanted Cardiomyoblasts and Contribute to Functional Improvement of Ischemic Rat Hearts
Authors: Kutschka Ingo , Chen Ian Y. , Kofidis Theo , Arai Takayasu , von Degenfeld Georges , Sheikh Ahmad Y. , Hendry Stephen L. , Pearl Jeremy , Hoyt Grant , Sista Ramachadra , Yang Phillip C. , Blau Helen M. , Gambhir Sanjiv S. , Robbins Robert C.
Published: July 2006

Background—

Cardiac cell transplantation is limited by poor graft viability. We aimed to enhance the survival of transplanted cardiomyoblasts using growth factor-supplemented collagen matrices.

Methods and Results—

H9c2 cardiomyoblasts were lentivirally transduced to express firefly luciferase and green fluorescent protein (GFP). Lewis rats underwent ligation of the left anterior descending artery (LAD) ligation to induce an anterior wall myocardial infarction. Hearts (n=9/group) were harvested and restored ex vivo with 1×10
6
genetically labeled H9c2 cells either in (1) saline-suspension, or seeded onto (2) collagen-matrix (Gelfoam [GF];), (3) GF/Matrigel (GF/MG), (4) GF/MG/VEGF (10 μg/mL), or (5) GF/MG/FGF (10 μg/mL). Hearts were then abdominally transplanted into syngeneic recipients (working heart model). Controls (n=6/group) underwent infarction followed by GF implantation or saline injection. Cell survival was evaluated using optical bioluminescence on days 1, 5, 8, 14, and 28 postoperatively. At 4 weeks, fractional shortening and ejection fraction were determined using echocardiography and magnetic resonance imaging, respectively. Graft characteristics were assessed by immunohistology. Bioluminescence signals on days 5, 8, and 14 were higher for GF-based grafts compared with plain H9c2 injections (
P
<0.03). Signals were higher for GF/MG grafts compared with GF alone (
P
<0.02). GFP-positive, spindle-shaped H9c2 cells were found integrated in the infarct border zones at day 28. Left ventricular (LV) function of hearts implanted with collagen-based grafts was better compared with controls (
P
<0.05). Vascular endothelial growth factor or fibroblast growth factor did not further improve graft survival or heart function.

Conclusions—

Collagen matrices enhance early survival of H9c2 cardiomyoblasts after transplantation into ischemic hearts and lead to improved LV function. Further optimization of the graft design should make restoration of large myocardial infarctions by tissue engineering approaches effective.