Invited commentary.
Explore the source record for details and available documents.
Aortic Valve Stenosis↗
Biomedical subjects
Patrick McCarthy
Publications and source records attributed to Patrick McCarthy.
Mechanical and electrical effects of cell-based gene therapy for ischemic cardiomyopathy are independent.
Cell-based gene therapy to alter the myocardial tissue microenvironment has been shown to improve mechanical cardiac function, but little is known regarding its effects on arrhythmogenic risk. Clinical studies with skeletal myoblasts (SKMBs) have suggested a potential increase in arrhythmogenic risk. Therefore, we studied the functional mechanical and electrical effects of transient reestablishment of stem cell homing via transplantation of stromal-cell derived factor-1 (SDF-1)-expressing SKMBs. Eight weeks after anterior myocardial infarction, rats received in five divided doses into the periinfarct zone 1 million SKMBs transfected with AdSDF-1 (n=15) or AdGFP (n=8). Echocardiography was used to quantify changes in cardiac function, and optical mapping was used to determine the arrhythmogenic risk. Eight weeks after cell therapy, we observed a 54% (p=0.004) increase in shortening fraction in AdSDF-1:SKMB-treated rats, but only an 18.8% increase (p=not significant) with GFP:SKMB. SDF-1-treated hearts exhibited an increase in vascular density compared with control SKMBs (34.9+/-7.1 vs. 20.7+/-5.6 vessels/mm2; p<0.01). Optical mapping performed 8 weeks after cell therapy revealed that all animals that received SKMBs regardless of viral transfection had inducible ventricular tachycardia (VT) whereas only 50% of saline-treated animals had inducible VT (p<0.05). Transient reestablishment of stem cell homing via transplantation of modified SKMBs is sufficient to improve cardiac function. However, despite improved mechanical function, the risk of ventricular tachycardia increased. We propose that future studies on functional effects of cell-based gene therapies should address both mechanical and electrical consequences.
Adenoviridae↗
Safety and feasibility of autologous myoblast transplantation in patients with ischemic cardiomyopathy: four-year follow-up.
BACKGROUND: Successful autologous skeletal myoblast transplantation into infarcted myocardium in a variety of animal models has demonstrated improvement in cardiac function. We evaluated the safety and feasibility of transplanting autologous myoblasts into infarcted myocardium of patients undergoing concurrent coronary artery bypass grafting (CABG) or left ventricular assist device (LVAD) implantation. In addition, we sought to gain preliminary information on graft survival and any associated changes in cardiac function. METHODS AND RESULTS: Thirty patients with a history of ischemic cardiomyopathy participated in a phase I, nonrandomized, multicenter pilot study of autologous skeletal myoblast transplantation concurrent with CABG or LVAD implantation. Twenty-four patients with a history of previous myocardial infarction and a left ventricular ejection fraction <40% were enrolled in the CABG arm. In a second arm, 6 patients underwent LVAD implantation as a bridge to heart transplantation, and patients donated their explanted native hearts for testing at the time of heart transplantation. Myoblasts were successfully transplanted in all patients without any acute injection-related complications or significant long-term, unexpected adverse events. Follow-up positron emission tomography scans showed new areas of glucose uptake within the infarct scar in CABG patients. Echocardiography measured an average change in left ventricular ejection fraction from 28% to 35% at 1 year and of 36% at 2 years. Histological evaluation in 4 of 6 patients who underwent heart transplantation documented survival and engraftment of the skeletal myoblasts within the infarcted myocardium. CONCLUSIONS: These results demonstrate the survival, feasibility, and safety of autologous myoblast transplantation and suggest that this modality offers a potential therapeutic treatment for end-stage heart disease.
Adult↗
Intravascular ultrasound evidence of angiographically silent progression in coronary atherosclerosis predicts long-term morbidity and mortality after cardiac transplantation.
OBJECTIVES: The aim of this study was to determine whether angiographically silent early coronary intimal thickening could predict long-term morbidity and mortality. BACKGROUND: Although intravascular ultrasound (IVUS) is widely used to detect early transplant coronary disease, its prognostic significance has not been well defined. METHODS: The study cohort consisted of 143 patients who underwent early multivessel (2.1 +/- 0.7 arteries/patient) IVUS examination 1.0 +/- 0.5 month and 12.0 +/- 1.0 month after transplantation. The change in intimal thickness was evaluated using paired analysis of 1,069 matched sites. Rapidly progressive vasculopathy was defined as the change in intimal thickness >/=0.5 mm. Patients were followed for a primary end point of all-cause mortality and a secondary composite end point of mortality and nonfatal myocardial infarction (MI). Angiographic disease, defined as any >/=50% diameter stenosis, was assessed in 126 patients. RESULTS: Intravascular ultrasound at one year demonstrated rapid progression in 54 (37%) of 143 patients and new lesions in 67 (47%) of 143 of patients. At a mean clinical follow-up of 5.9 years, more patients with rapidly progressive vasculopathy died, as compared with those without (26% vs. 11%, p = 0.03). Death and MI also occurred more frequently among those with rapid progression than in those without it (51% vs. 16%, p < 0.0001). There was no significant difference in outcome in patients with and without donor-transmitted lesions. Angiographic disease was found in 11 (22%) of 50 patients with and in 2 (2.1%) of 76 patients without (p = 0.003) rapidly progressive vasculopathy. The IVUS-defined rapid progression correlated highly with future development of angiographic disease (p = 0.0005). CONCLUSIONS: Rapidly progressive vasculopathy by IVUS, defined as an increase of >/=0.5 mm in intimal thickness within the first year after transplantation, is a powerful predictor of all-cause mortality, MI, and angiographic abnormalities. Accordingly, such patients may be candidates for more aggressive anti-atherosclerotic and/or immunosuppressive therapy.
Adult↗
Feasibility and safety of autologous myoblast transplantation in patients with ischemic cardiomyopathy.
Successful autologous skeletal myoblast transplantation into infarcted myocardium in a variety of animal models has demonstrated improvement in cardiac function. We evaluated the safety and feasibility of transplanting autologous myoblasts into infarcted myocardium of patients undergoing concurrent coronary artery bypass grafting (CABG) or left ventricular assist device implantation (LVAD). In addition, we sought to gain preliminary information on graft survival and any potential improvement of cardiac function. Eighteen patients with a history of ischemic cardiomyopathy participated in a phase I, nonrandomized, multicenter pilot study of autologous skeletal myoblast transplantation concurrent with CABG or LVAD implantation. Twelve patients with a history of previous myocardial infarction (MI) and a left ventricular ejection of less than 30% were enrolled in the CABG arm. In a second arm, six patients underwent LVAD implantation as a bridge to heart transplantation and were required to donate their heart for testing at the time of heart transplant. Myoblasts were successfully transplanted in all patients without any acute injection-related complications or significant long-term unexpected adverse events. Follow-up PET scans showed new areas of viability within the infarct scar in CABG patients. Echocardiography measured an average improvement in left ventricular ejection fraction (LVEF) from 25% to 34%. Histological evaluation in four out of five patients who underwent heart transplantation documented survival and engraftment of the skeletal myoblasts within the infarcted myocardium. These interim results demonstrate survival, feasibility, and safety of autologous myoblast transplantation and suggest that this modality may offer a potential therapeutic treatment for end-stage heart disease.
Adult↗
Sustained apoptosis in human cardiac allografts despite histologic resolution of rejection.
BACKGROUND: We investigated the occurrence of apoptosis during and after resolution of cardiac allograft rejection. Apoptosis could play different roles in graft survival depending on the target cells; thus, we also determined the cell types involved. METHODS: Endomyocardial biopsy specimens were evaluated during the first 6 months after transplantation as follows: group I, no current or prior rejection; group II, during an episode of moderate rejection; and group III, histologic resolution after an episode of moderate rejection. RESULTS: Groups II and III showed significantly increased apoptotic activity, indicated by increased caspase-8 and caspase-3 activity; however, activated caspase-3 was undetectable in group I. Activated caspase-3 was detected only in groups II and III. Terminal deoxynucleotide transferase-mediated dUTP nick-end labeling was detected in groups II and III but not group I and predominantly in inflammatory cells. CONCLUSIONS: Increased caspase activity and apoptosis of infiltrating cells not only occurs during acute cardiac allograft rejection but persists after histologic resolution. Thus, programmed cell death occurs beyond the period of histologic resolution and may play a role in regulation of the rejection process.
Adult↗
Successful cardiac transplantation in an HIV-1-infected patient with advanced disease.
Explore the source record for details and available documents.
AIDS-Related Opportunistic Infections↗
Myocardial ischemic injury after heart transplantation is associated with upregulation of vitronectin receptor (alpha(v)beta3), activation of the matrix metalloproteinase induction system, and subsequent development of coronary vasculopathy.
BACKGROUND: Myocardial ischemic injury after heart transplantation is associated with subsequent development of graft vasculopathy. Both vitronectin receptor (integrin alpha(v)beta3) and tissue factor play key roles in vascular endothelial cell injury. Matrix metalloproteinases (MMPs) are activated in ischemic injury models. METHODS AND RESULTS: Thirteen patients developed myocardial ischemic injury within 2 weeks of cardiac transplantation (ischemia group). These were compared with 10 transplantation patients who had no evidence of ischemia (control group). Endomyocardial biopsies were evaluated within 2 weeks of transplantation for alpha(v)beta3, tissue factor, and extracellular MMP inducer (EMMPRIN). At 1 year, MMPs were evaluated, and interstitial myocardial fibrosis was quantified. All patients underwent intravascular ultrasound at 1 month and 1 year after transplantation. Compared with control, the ischemia group demonstrated evidence of significant increased expression of alpha(v)beta3 (3.2-fold, P<0.001), tissue factor (2.5-fold, P<0.001), and EMMPRIN (1.9-fold, P=0.01). At 1 year, the ischemia group had a significant increase in myocardial fibrosis (24+/-1.8% versus 14+/-1.1%, P<0.001) and zymographic activity of MMP-2 (1.4-fold, P<0.001), MMP-3 (1.2-fold, P<0.001), and MMP-9 (1.3-fold, P=0.01). Coronary vasculopathy progression was also more advanced in the ischemia group (change in coronary maximal intimal thickness over 1 year 0.54+/-0.1 versus 0.26+/-0.06 mm; P=0.031). CONCLUSIONS: Myocardial ischemic injury after cardiac transplantation is associated with upregulation of alpha(v)beta3, tissue factor, and activation of the MMP induction system, which may contribute to the subsequent development of allograft remodeling and vasculopathy.
Adult↗
Patterns of myocardial endothelin-1 expression and outcome after cardiac transplantation.
BACKGROUND: Endothelin-1 (ET-1), a potent vasoconstrictor, is released in response to several inflammatory cytokines after heart transplantation. The present study correlated patterns of myocardial ET-1 expression in heart biopsies with acute rejection, post-transplantation ischemic injury, and subsequent development of coronary vasculopathy. METHODS AND RESULTS: Patterns of myocardial ET-1 expression were evaluated in 47 heart transplant recipients at 3 months after transplant. Transplant vasculopathy was documented by coronary angiography at 2 years after transplant. Expression of ET-1 was tabulated for both blood vessels and the interstitium. Vascular ET-1 expression was positive in 7/17 (41%) of patients with greater than grade 2 (International Society Heart Lung Transplant) rejection compared with 3/30 (10%) of patients with grade 0 and grade 1A rejection (P=0.02). Compared with patients with negative interstitial ET-1 expression (n=22), patients with positive interstitial ET-1 expression (n=25) had higher incidence of post-transplantation ischemic injury (52% versus 9%, P=0.002), lower mean episodes of acute rejection (> or = grade 2) during the first 3 months of transplant (1.09+/-0.66 versus 1.86+/-1.6, P=0.048), and more common vasculopathy at 2 years (50% versus 15%, P=0.02), and they tended to have worse survival (83.2% versus 100%, P=0.058). CONCLUSIONS: Vascular ET-1 expression is likely to be associated with acute rejection. Interstitial ET-1 expression, however, is more likely to be associated with post-transplantation ischemic injury and subsequent development of coronary vasculopathy.
Coronary Angiography↗
Usefulness of plasma vitamin B(6), B(12), folate, homocysteine, and creatinine in predicting outcomes in heart transplant recipients.
Atherothrombotic complications are frequently seen in patients undergoing heart transplantation. These patients have high plasma total homocysteine concentrations associated with lower folate and vitamin B(6) levels. The relation between these metabolic abnormalities and the development of vascular complications, however, remains unclear. Fasting plasma total homocysteine, folate, vitamin B(12), vitamin B(6), and creatinine were measured in 160 cardiac transplant recipients who were followed for a mean duration of 28 +/- 9 months after blood draw (mean 59 +/- 28 months after transplant). Cardiovascular events and causes of mortality were determined and Cox proportional-hazards regression analysis was used to identify the independent predictors for cardiovascular events and mortality. Twenty-five patients developed cardiovascular events and 17 died (11 cardiovascular deaths). Mean +/- SD total homocysteine value was 18.4 +/- 8.5 (range 4.3 to 63.5 micromol/L). Hyperhomocysteinemia (> or =15 micromol/L) was seen in 99 patients (62%). Levels were no different in patients with or without cardiovascular complications/death (16.8 +/- 6.2 vs 18.9 +/- 9 micromol/L, p = 0.4). However, vitamin B(6) deficiency was seen in 21% of recipients with and in 9% without cardiovascular complications/death (p = 0.05). The relative risk for cardiovascular events, including cardiovascular death, increased 2.7 times (confidence interval 1.2 to 5.9) for B(6) levels < or =20 nmol/L compared with those with normal B(6) levels (p = 0.02). Thus, hyperhomocysteinemia is common in transplant recipients but may have no causal role in the atherothrombotic vascular complications of transplantation. Deficiency of vitamin B(6), however, may predict adverse outcomes, suggesting a possible role for supplementation with this vitamin.
Adult↗
Myocardial ischemic-fibrotic injury after human heart transplantation is associated with increased progression of vasculopathy, decreased cellular rejection and poor long-term outcome.
OBJECTIVES: We sought to assess the influence of peritransplant ischemia and fibrosis on the development of allograft vasculopathy, acute cellular rejection and long-term outcome. BACKGROUND: Allograft vasculopathy is a common long-term complication of cardiac transplantation. One of the potential risk factors is peritransplant allograft ischemia. METHODS: One hundred forty heart transplant recipients had baseline and one-year intravascular ultrasound analysis done to assess the progression of allograft vasculopathy. Serial endomyocardial biopsies were evaluated for cellular rejection, vascular rejection, ischemia and fibrosis. Based on histology, patients were classified into one of the following groups: nonischemic (n = 32), ischemia (n = 24), fibrosis (n = 62) or vascular rejection (n = 22). Three-color flow cytometry crossmatching (FCXM) was used to assess donor-specific human lymphocyte antigens (HLA) sensitization. Long-term outcome of patients in each group was assessed by estimating incidence of graft failure or deaths over a seven-year follow up. RESULTS: Patients in the fibrosis group had the lowest incidence of donor-specific HLA sensitization (40%, p = 0.008) and lowest average episodes of cellular rejection (1.7 +/- 1.4, p = 0.04), but they had increased coronary vasculopathy progression (change in coronary intimal thickness = 0.59 +/- 0.28 mm, p < 0.0001) and poor seven-year event-free survival (49%, p = 0.01). CONCLUSIONS: The development of fibrosis after cardiac transplantation is associated with advanced coronary vasculopathy, although a low incidence of acute cellular rejection is noted, suggesting the presence of nonimmune mechanisms in mediating the pathogenesis of allograft vasculopathy.
Adolescent↗
Acute vascular rejection is associated with up-regulation of vitronectin receptor (alphavbeta3), increased expression of tissue factor, and activation of the extracellular matrix metalloproteinase induction system.
BACKGROUND: A cascade of inflammatory reactions characterize acute vascular rejection after heart transplantation. This study was undertaken to test the hypothesis that acute vascular rejection is associated with up-regulation of vitronectin receptor (alphavbeta3), increased expression of tissue factor, and activation of the extracellular matrix metalloproteinase induction system. METHODS: Acute vascular rejection developed in 14 heart transplant recipients within 2 weeks of transplantation, confirmed by immunofluorescence (AVR group). We compared these patients with 10 transplant recipients who had no evidence of acute vascular rejection or peritransplant ischemic injury (control group). We evaluated endomyocardial biopsy specimens for alphavbeta3, tissue factor, and extracellular matrix metalloproteinase inducer (EMMPRIN). RESULTS: Compared with the control group, the AVR group demonstrated evidence of significantly increased expression of alphavbeta3 (1.9-fold, p < 0.001), tissue factor (1.8-fold, p < 0.001), and EMMPRIN (1.5-fold, p < 0.001). All patients in the AVR group received plasmapheresis; 11 of 14 patients had evidence of ischemic necrosis on biopsy specimens, and 3 of 14 patients experienced hemodynamic compromise and graft dysfunction and died within 3 weeks of transplant. Another patient died at 10 months after transplant. CONCLUSIONS: Acute vascular rejection is associated with up-regulation of alphavbeta3, tissue factor, and activation of the matrix metalloproteinase induction system, which may contribute to the lethal morbidity associated with this disease.
Acute Disease↗
Acute cellular rejection following human heart transplantation is associated with increased expression of vitronectin receptor (integrin alphavbeta3).
The vitronectin receptor (integrin alphavbeta3), a cell-surface adhesion receptor, has been shown to play a significant role in endothelial cell migration, apoptosis, atherosclerosis, and T-lymphocyte activation. This study was undertaken to test the hypothesis that cardiac allograft rejection is associated with increased expression of alphavbeta3. We also determined whether fibronectin receptor (alpha5beta1) and tissue factor are up-regulated in the presence of acute cellular rejection. We evaluated endomyocardial biopsy specimens with histologic evidence of different degrees of acute cellular rejection (grade 0, n = 10; grade 1A, n = 10; grade 2, n = 10; grade 3A, n = 10). Biopsies were obtained 2-4weeks after cardiac transplantation. Immunoperoxidase staining was performed for alphavbeta3, tissue factor, and alpha5beta1, and protein levels were further determined by Western blot analysis. Specimens with grade 2 and grade 3A rejection showed positive staining of alphavbeta3 in lymphocytic aggregates and vascular endothelial cells. By immunoblotting, we identified significantly increased expression of alphavbeta3 in the presence of acute rejection, grade 2 (3-fold, p = 0.01) and grade 3A (3.6-fold, p = 0.005) compared to grade 0 and 1 A specimens. There was no evidence of increased expression of alpha5beta1 or tissue factor. Acute cellular rejection, a process characterized by T-lymphocyte activation and release of inflammatory cytokines, is associated with increased expression of alphavbeta3.
Acute Disease↗
Capillary electrophoretic separation by double-strand polyaniline-coate capillaries of the advanced glycation endproducts formed from N-alpha-acetyl-L-lysine with reducing sugars.
Capillary electrophoresis using a capillary coated with a double-strand coating of polyaniline:poly(methyacrylate-co-acrylic acid) (PAN:P[MA-AAI) was used to separate advanced glycation endproducts (AGEs) formed at 37 degrees C from model systems containing either glucose (Glc), fructose (Fru), or glyceraldehyde (GA) and N-alpha-acetyl-L-lysine (NALys). The presence of the P(MA-AA) as a second strand in the polymer allows the maintenance of the conductive state of the PAN at a wide pH range. Effects of buffer pH and coating concentration on the electroosmotic flow (EOF) were investigated. More AGE species can be detected for the GA/NALys mixtures using this coated capillary than upon an uncoated capillary. The coating procedure is simple and the stability of the coated capillary is good.
Carbohydrates↗
Association of sternal wound infection with parasternal muscle sutures.
BACKGROUND: Sternal wound infection complicating open-heart surgery is a potentially devastating complication that has been associated with a number of risk factors. We recently consulted on three consecutive patients with this complication who had heavy nonabsorbable parasternal sutures placed in muscle tissue adjacent to the sternum. The aim of this report is to document our findings and caution that this technique to control bleeding from the parasternal intercostal muscles my increase risk of infection. METHODS: The pathology, surgical findings, and microbiology of these three cases are analyzed for similarity and possible cause of infection. RESULTS: By surgical observation and culture reports, each infection appeared to have originated at the site of nonabsorbable suture in devascularized parasternal muscle tissue. Sinus tracts could be probed to a similar site in each patient. CONCLUSION: Placement of sutures in the parasternal muscles where the sternal wires wrap around the bone leads to compression and necrosis of muscle tissue. We caution that this technique to control bleeding may cause a nidus of infection and increase the risk of deep sternal wound infection.
Adult↗
Reading and writing in the field of mechanical circulatory support.
Today there is a multiplicity of options for publishing scientific research work. In a specialized field like blood pump studies it is readily established that a very small number of journals publish the vast majority of work. Reading and publishing in those journals will provide the quickest exposure of the work to the most specifically interested and relevant people, even if the "impact factors" of those journals do not have stratospheric values.
Heart, Artificial↗