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Biomedical subjects

J A Magovern

Publications and source records attributed to J A Magovern.

At least 19 recordsLinked to original sources
PubMed2007

Cardiac fibroblasts influence cardiomyocyte phenotype in vitro.

Cardiac fibroblasts impact myocardial development and remodeling through intercellular contact with cardiomyocytes, but less is known about noncontact, profibrotic signals whereby fibroblasts alter cardiomyocyte behavior. Fibroblasts and cardiomyocytes were harvested from newborn rat ventricles and separated by serial digestion and gradient centrifugation. Cardiomyocytes were cultured in 1) standard medium, 2) standard medium diluted 1:1 with PBS, or 3) standard medium diluted 1:1 with medium conditioned > or =72 h by cardiac fibroblasts. Serum concentrations were held constant under all media conditions, and complete medium exchanges were performed daily. Cardiomyocytes began contracting within 24 h at clonal or mass densities with <5% of cells expressing vimentin. Immunocytochemical analysis revealed progressive expression of alpha-smooth muscle actin in cardiomyocytes after 24 h in all conditions. Only cardiomyocytes in fibroblast-conditioned medium stopped contracting by 72 h. There was a significant, sustained increase in vimentin expression specific to these cultures (means +/- SD: conditioned 46.3 +/- 6.0 vs. control 5.3 +/- 2.9%, P < 0.00025) typically with cardiac myosin heavy chain coexpression. Proteomics assays revealed 10 cytokines (VEGF, GRO/KC, monocyte chemoattractant protein-1, leptin, macrophage inflammatory protein-1alpha, IL-6, IL-10, IL-12p70, IL-17, and tumor necrosis factor-alpha) at or below detection levels in unconditioned medium that were significantly elevated in fibroblast-conditioned medium. Latent transforming growth factor-beta and RANTES were present in unconditioned medium but rose to higher levels in conditioned medium. Only granulocyte-macrophage colony-stimulating factor was present above threshold levels in standard medium but decreased with fibroblast conditioning. These data indicated that under the influence of fibroblast-conditioned medium, cardiomyocytes exhibited marked hypertrophy, diminished contractile capacity, and phenotype plasticity distinct from the dedifferentiation program present under standard culture conditions.

Actins↗
PubMed2004

Molecular dynamics of the compensatory response to myocardial infarct.

Myocardial infarct via occlusion of the left anterior descending coronary in rats caused overriding depression in transcription, signal transduction, inflammation and extracellular matrix pathways in the infarct zone within 24 h. In contrast, remote zone gene expression was reciprocally activated during the immediate post-infarct period. Infarct zone signal transduction occurred primarily through TGFbeta1 induction while the remote zone exhibited elevated WNT, NOTCH, GPCR and transmembrane signaling. A minimal day 1 acute phase, inflammatory response was detected in the infarct zone while interleukins (IL1alpha, IL1beta, IL6, IL12alpha, IL18) and the TNFalpha superfamily were activated in the remote zone. Different cytochrome subsets were activated in each left ventricular region on day 1 while anti-oxidant genes were elevated only in the remote zone. The infarct zone exhibited mixed early transcription factor activation across all binding domains with a balance favoring constitutive gene activation and differentiation pathways as opposed to cell proliferation. In contrast, the remote zone exhibited activation of extensive developmental transcription factors involved in specification of cell phenotype, tissue-specific interactions and position-specific cell proliferation on day 1. The day 28 infarct zone response mirrored the day 1 remote zone response including activation of genes associated with matrix remodeling (metallothionein and metalloproteinase 9, 12, 23), as well as genes associated with cell proliferation and phenotype specification (MYC, EGR2, ATF3, HOXA1) recapitulating developmental histogenesis programs.

Animals↗
PubMed2003

Effect of muscle origin and phenotype on satellite cell muscle-specific gene expression.

Satellite cells from adult mouse tongue, diaphragm, vastus lateralis, rectus femoris, tibialis anterior, soleus, and extensor digitorum longus muscles were isolated, expanded, and differentiated under identical culture conditions. Proliferating myoblasts and differentiated myofiber cultures were analyzed via SDS-PAGE, immunochemical, and PCR methods for expression of myosin heavy chains (MyHC) and muscle creatine kinase (MCK) as indices of muscle fiber type. Contralateral muscles were harvested for simultaneous, parallel analysis utilizing these assays. The MyHC profile of differentiated primary satellite cells was equivalent across all cultures with MyHC(2A) and MyHC(1/slow) co-expressed in all myotube and myofiber structures. Trace amounts of MyHC(2B) and MyHC(neo) were detected in a few myofibers. MCK was expressed at a uniform, similar level among these cultures. In contrast, contralateral muscles expressed each muscle-specific indicator at levels correlated with the fiber-type distribution within each muscle. MM14 and C2C12 cells, mouse satellite cell lines, were expanded and compared to primary cell cultures. MM14 cells had a high differentiation index (>95%) and co-expressed MyHC(2A) and MyHC(1/slow) along with trace amounts of MyHC(neo) throughout myotube cultures. Myofibers obtained from C2C12 cells exhibited less differentiation (~75%) with MyHC(2A) as the dominant isoform. These data indicate that primary satellite cells from adult muscle form a uniform differentiated cell type regardless of the fiber-type, anatomic location, and embryonic origin of the donor muscles. MM14 cells expressed an adult MyHC isoform profile similar to primary satellite cells. The results suggest that satellite cells provide a uniform cell source for use in autologous transplantation studies and do not acquire a heritable fiber-type-specific phenotype from their host muscle.

Animals↗
PubMed2001

Clinical results with left axillary to left anterior descending coronary artery bypass.

BACKGROUND: The minimally invasive direct coronary artery bypass procedure is not feasible if the left internal mammary artery has been used or has inadequate flow. We have applied a modified minimally invasive direct coronary artery bypass procedure, which uses a graft from the left axillary artery to the left anterior descending coronary artery in such situations. METHODS: The graft is anastomosed to the left axillary artery adjacent to the clavicle and tunneled underneath the vein, where it enters the thorax through the first interspace and courses to the left anterior descending coronary artery along the mediastinum. RESULTS: Since 1997 we have used this operation in 22 patients with a mean age of 70 years (range, 52 to 83 years). All patients were high-risk candidates because of advanced age (70 +/- 7 years), depressed left ventricular function (mean left ventricular ejection fraction, 38% +/- 6%), or previous heart operation (20 of 22, 91%). Conduits for the graft were saphenous vein (n = 18) or radial artery (n = 4). Ten patients were extubated in the operating room, and the mean duration of mechanical ventilation was 5.8 +/- 6 hours. There was one operative death (1 of 22, 4.5%). The mean length of intensive care unit and hospital stay was 1.5 days (range, 1 to 6 days) and 6 days (range, 2 to 15 days), respectively. At a mean follow-up of 6 months, all discharged patients are alive and functionally improved. None have required surgical or catheter-based revascularization of the left anterior descending coronary artery. CONCLUSIONS: The left axillary artery to left anterior descending coronary artery graft should be considered for high-risk patients in whom a minimally invasive direct coronary artery bypass procedure is not possible.

Aged↗
PubMed2001

Clinical results with the AB-180 left ventricular assist device.

BACKGROUND: This report reviews the initial clinical experience with the AB-180 ventricular assist device. METHODS: Between Dec 1997 and July 2000, the AB-180 was implanted in 17 patients at five institutions. The mean age was 52 years (range 21 to 68 years) and 14 of 17 were male. The indications for implantation were postcardiotomy shock (12 of 17, 70%), decompensated cardiomyopathy (2 of 17, 12%), viral myocarditis (2 of 17, 12%), and acute myocardial infarction (1 of 17, 6%). RESULTS: The mean duration of support was 8.5 days (range 1 to 28 days). In the group of 17 patients, 8 were weaned from the device and 2 underwent transplantation. Four of the weaned patients (4 of 8, 50%) and 1 of the transplant patients (1 of 2, 50%) survived. The overall weaning and survival rates were 58% (10 of 17) and 29% (5 of 17). There were no major device-related complications and no major device malfunctions. CONCLUSIONS: The AB-180 provides reliable circulatory support for reversible forms of heart failure.

Adult↗
PubMed2001

Pressure overload induces heterologous expression of the atrial natriuretic factor (ANF) gene.

Several investigations have demonstrated the regional heterogeneity of myocardial phenotype, and hypertrophy may also induce regionally disparate changes. We have utilized the direct DNA injection technique to study regional variations in overload-induced ANF expression. Pressure overload was induced by stenosis of the ascending aorta in canines. ANF promoter reporters were injected into the left ventricle; in different regions including the base, the midwall region, and the apex. Injections were made at different depths to include the epicardial and endocardial layers. The animals were sacrificed 7 days following surgery and the left ventricle harvested for tissue analysis. Under normotensive conditions, ANF reporter expression was similar throughout the heart. PO increased ANF expression and the increases were greater in the endocardium than in the epicardium. PO also significantly increased expression in the midwall and base regions, but not in the apex. It is unknown from these experiments, whether the greater increases in midwall expression are a function of greater wall stress, metabolic demand, or phenotypic differences in the midwall myocytes. These findings do indicate that regional differences in overload-induced changes in gene expression are evident and may be functionally important in determining myocardial response to increased functional demand.

Animals↗
PubMed2001

Method for measuring long-term function of muscle-powered implants via radiotelemetry.

Long-term remote monitoring of muscle-powered implants has been made possible with development of an adjustable workload that can be remotely monitored to assess device function. This technique obviates the need for percutaneous access lines and allows test animals to remain untethered, eliminating deleterious effects caused by infection, sedation, or animal stress. Hardware components include a latex bladder fixed within a hermetically sealed canister, multichannel implantable telemetry unit, and subcutaneous access port (for pressure charge adjustment). To validate this method, in vitro tests were performed by using a third-generation muscle energy converter designed to function as an implantable hydraulic pump. Two channels of telemetered pressure data were collected and used to calculate six indexes of device function. Calculated parameters were then compared with measured values to determine accuracy. Correlation between measured and calculated parameters was high in all instances, with most estimates yielding errors of <3%. These results demonstrate the utility of this approach and support its use as a means to monitor muscle-powered devices during long-term animal trials.

Animals↗
PubMed2000

Evaluation of graft patency during minimally invasive coronary artery bypass grafting with Doppler flow analysis.

BACKGROUND: An objective method for determining intraoperative graft patency is an essential part of minimally invasive direct coronary artery bypass. This study compares angiography and Doppler methods for graft analysis during minimally invasive direct coronary artery bypass and presents long-term outcome in a cohort of patients. METHODS: Between March and October 1997, 35 patients had elective minimally invasive direct coronary artery bypass procedures in which the left internal mammary artery was anastomosed to the left anterior descending coronary artery. Immediate graft patency was determined with intraoperative angiography using selective injection of the left internal mammary artery from a femoral approach and with Doppler flow analysis using a 1-mm, 20-MHz Doppler probe placed directly on the graft. RESULTS: There was immediate perfect patency with brisk flow in 91% of patients (32 of 35). A normal Doppler study, defined as a diastolic predominant pattern with a diastolic flow velocity of greater than 15 cm/second, was found in all patients with normal angiograms. All patients with abnormal angiograms also had abnormal Doppler flow. Thus, Doppler analysis was 100% accurate for confirming graft patency and for detecting failed grafts. All abnormal grafts were successfully revised, which allowed 100% early patency. Operative mortality was 2.8% (1 of 35) and there have been no late deaths at a follow-up of more than 2 years. One patient required angioplasty of the anastomosis (1 of 34, 2.9%), but none have required subsequent surgical intervention. CONCLUSIONS: Objective analysis of graft flow in the operating room is necessary to achieve 100% early graft patency with minimally invasive direct coronary artery bypass operations. Doppler analysis is the preferred initial method, because it is safe, accurate, and rapid.

Adult↗
PubMed2000

Reduced incidence of atrial fibrillation with minimally invasive direct coronary artery bypass.

BACKGROUND: Atrial fibrillation (AF) is a frequent complication after coronary artery bypass graft (CABG) surgery. The purpose of this study was to determine the incidence of postoperative AF after minimally invasive direct coronary artery bypass (MIDCAB) in comparison with CABG. METHODS: Between November 1995 and May 1997, 96 MIDCAB procedures were performed. During the same period, 42 patients underwent traditional single CABG using the left internal mammary artery graft (S-CABG). The incidence of in-hospital AF, defined as a sustained episode requiring treatment, was compared between the two groups. RESULTS: There was no difference in age, ejection fraction, or preoperative risk score between the groups. The use of beta-blockers before or after surgery was not different. The incidence of postoperative AF in the first 6 weeks after surgery was 4% (4 of 96) for MIDCAB and 28% (12 of 42) for S-CABG (p = 0.003). Patients with postoperati

Aged↗
PubMed1999

Copulsation balloon for right ventricular assistance: preliminary trials.

BACKGROUND: Options for management of acute right ventricular (RV) failure are limited. This report describes preliminary testing of a temporary RV assist device that acts by direct compression of the RV. The system comprises a pancake-shaped silicone balloon (5 cm diameter) connected to a drive console that delivers a 65-mL pneumatic pulse during cardiac systole. METHODS AND RESULTS: Initial in vivo tests were performed on 6 pigs (weight, 41+/-4 kg). RV wall motion and stroke volume were monitored via transesophageal echocardiography. Acute RV failure was created by graded right coronary ligation, which yielded a 63% reduction in RV stroke volume (39.9+/-8.2 to 14.7+/-1.9 mL; P<0.002). We secured the balloon over the RV free wall by attaching it to the edges of the opened pericardium. The sternum was then reapproximated, and data were collected with the device off and on (every beat). Device placement had no deleterious effect on RV function. Balloon activation returned RV stroke volumes to normal (37.8+/-9.2 mL) and increased mean pulmonary artery pressures from 13+/-2 to 16+/-3 mm Hg (P<0.01). RV compression did not induce or exacerbate tricuspid regurgitation. Mean aortic pressure improved from postinfarction levels but did not return to normal. CONCLUSIONS: We conclude that the pulmonary circulation can be supported in the short term via cardiac compression and that balloon copulsation techniques for short-term RV failure should be tested in long-term models.

Angioplasty, Balloon↗
PubMed1999

Results of graft patency by immediate angiography in minimally invasive coronary artery surgery.

BACKGROUND: Although minimally invasive direct coronary artery bypass (MIDCAB) is being employed for revascularization of the left anterior descending coronary artery (LAD) with the left internal mammary artery (LIMA), little objective data exist regarding graft patency. Because the procedure is performed on a beating heart through a limited access approach, concerns have been raised regarding the ability to perform as accurate an anastomosis compared with conventional coronary artery bypass (CAB). METHODS: A prospective study of consecutive patients undergoing MIDCAB LIMA to LAD was undertaken. All procedures were performed through a limited anterior thoracotomy incision with a stabilization device. Selective angiography of the LIMA graft was performed intraoperatively or in the immediate postoperative period. RESULTS: One hundred and three patients underwent the MICAB procedure. Angiographic evaluation of the anastomosis was obtained in 100 patients (97%). Angiographic graft patency was 99%, with perfect graft patency (no stenosis greater than 50%) being 91%. Three grafts were revised in the operating room. One patient underwent reoperation and 3 more underwent percutaneous transluminal coronary angioplasty. There were two noncardiac mortalities (1.9%), both with patent grafts. CONCLUSIONS: Immediate graft patency after MIDCAB is acceptable, and comparable with conventional CAB data, although meaningful comparison is difficult. The significance of early angiographic findings and the role for early angiography remain to be defined.

Adult↗
PubMed1999

Finding the LAD during MIDCAB operations.

Minimally invasive direct coronary artery bypass (MIDCAB) is a new surgical procedure that revascularizes the left anterior descending coronary artery (LAD) without the need for a median sternotomy or cardiopulmonary bypass. This operation is performed through a small left anterior thoracotomy. With this exposure, it can be difficult to locate the left anterior descending coronary artery. We have identified anatomic features on the surface of the pericardium that can serve as a landmark for finding the left anterior descending coronary artery.

Coronary Artery Bypass↗
PubMed1999

Partial versus full sternotomy for aortic valve replacement.

BACKGROUND: Recent trends suggest that smaller incisions reduce postoperative morbidity. This study tests the hypothesis that a partial upper sternotomy improves patient outcome for aortic valve replacement. METHODS: A group of 50 patients who underwent aortic valve surgery through a partial upper sternotomy (group I) were compared to 50 patients who underwent aortic valve replacement through a median sternotomy during the same time period (group II). The mean age (60+/-2 versus 63+/-2 years; mean +/- SEM) and preoperative ejection fractions (53+/-2 versus 54+/-2) were similar. Operations were performed with central cannulation, and antegrade/retrograde blood cardioplegia. RESULTS: There was one death in each group. No differences were found in aortic occlusion time, mediastinal drainage, transfusion incidence, narcotic requirement, length of stay, or cost. The incidence of pleural and pericardial effusions was increased (18.4% versus 3.9%, p < 0.03), and the need for postoperative inotropic support was higher (38.7% versus 19.6%, p < 0.03) in the partial sternotomy group. CONCLUSIONS: Aortic valve replacement can be performed through a partial sternotomy with results comparable to full sternotomy. The partial sternotomy offers a cosmetic benefit, but does not significantly reduce postoperative pain, length of stay, or cost.

Adult↗
PubMed1999

Genetic evolutionary staging of early non-small cell lung cancer: the P53 --> HER-2/NEU --> ras sequence.

INTRODUCTION: The sequence of genetic evolutionary abnormalities that have occurred in a given lung cancer tumor before tumor sampling can be inferred from patterns of intracellular co-occurrence of these abnormalities in tumor cell subpopulations at the time of sampling. The same evolutionary sequences that are present within each lung cancer were evident in intertumor comparisons. METHODS: Correlated cell by cell measurements of cell DNA content, p53, Her-2/neu, and ras proteins were obtained by multiparameter flow cytometry on 46 surgically resected stage I-III primary non-small cell lung cancers. Early evolutionary changes were identified by the fact that they could appear alone in individual cells. Later appearing abnormalities were identified by the fact that they were accompanied by early abnormalities in the same cells. Patients were followed prospectively. Evolutionary patterns observed in individual tumors were correlated with subsequent clinical outcome of patients undergoing surgical resection. RESULTS: Three common patterns were identified: (I) a diploid DNA pathway consisting of the sequence p53 overexpression --> Her-2/neu overexpression --> ras overexpression, (II) an aneuploid DNA pathway with the same p53 --> Her-2/neu --> ras sequence, and (III) a pathway in which none of the intracellular protein measurements made here were abnormal. Fourteen tumors recurred after 11.5 months' median study time. Nine of 12 recurrences in pathways I and II occurred in patients whose tumors were far advanced along these molecular genetic pathways. CONCLUSIONS: Multiparameter cell-based genetic evolutionary studies may be a promising approach for identifying patients with stage I-III non-small cell lung cancer at high risk for recurrence.

Adult↗
PubMed1999

Mechanical analysis of midline sternotomy wound closure.

OBJECTIVE: Unstable median sternotomy closure can lead to postoperative morbidity. This study tests the hypothesis that separation of the sternotomy site occurs when physiologic forces act on the closure. METHODS: Median sternotomy was performed in 4 human cadavers (2 male) and closed with 7 interrupted stainless steel wires. The chest wall was instrumented to apply 4 types of distracting force: (1) lateral, (2) anterior-posterior, (3) rostral-caudal, and (4) a simulated Valsalva force. Forces were applied in each direction and were limited to physiologic levels (< 400 N). Four sets of sonomicrometry crystals were placed equidistantly along the sternum to measure separation at the closure site. RESULTS: Sternal separation occurred as a result of the wires cutting through the bone. Less force was needed to achieve 2.0-mm distraction in the lateral direction (220 +/- 40 N) than in the anterior-posterior (263 +/- 74 N) and rostral-caudal (325 +/- 30 N) directions. More separation occurred at the lower end of the sternum than the upper. During lateral distraction, xiphoid and manubrial displacement averaged 1.85 +/- 0.14 and 0.35 +/- 0.12 mm, respectively. Anterior-posterior distraction caused 1.99 +/- 0.04-mm xiphoid displacement and 0.26 +/- 0.12-mm manubrial displacement. During a simulated Valsalva force, more separation occurred in the lateral (2.14 +/- 0.11 mm) than in the anterior-posterior (0.46 +/- 0.29 mm) or rostral-caudal (0.25 +/- 0.15 mm) directions. CONCLUSIONS: These data suggest that sternal dehiscence can occur under physiologic loads and that improved sternal stability may be readily achieved via mechanical reinforcement near the xiphoid. Closure techniques designed to minimize wire migration into the sternum should also be developed.

Bone Wires↗