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Biomedical subjects

Todd K Rosengart

Publications and source records attributed to Todd K Rosengart.

At least 19 recordsLinked to original sources
PubMed2006

Stable cognition after coronary artery bypass grafting: comparisons with percutaneous intervention and normal controls.

BACKGROUND: Cognitive decline has been associated with coronary artery bypass grafting (CABG), but the extent to which these findings are related to the natural history of cognitive deficits in elderly patients with cardiac disease or have been influenced by the research methods used to determine abnormalities warrants further study. METHODS: After excluding individuals with conditions known to cause brain dysfunction, individuals referred for percutaneous coronary intervention (n = 42) or CABG (n = 35) were compared with an age-matched and education-matched control group without clinical evidence of coronary artery disease (n = 44). These subjects underwent a battery of 14 neurocognitive tests at baseline (preoperatively) and at 3 weeks and 4 months postoperatively. RESULTS: The majority of test scores for all three cohorts were within nonimpaired ranges at baseline and 3 weeks later. Change in impairment status from baseline to 3-week assessment was not associated statistically with type of treatment as referenced to clinical norms, and was associated with type of treatment on only one measure as referenced to control group performances. A further overall improvement in impairment status from 3 weeks' to 4 months' follow-up was seen in both CABG and percutaneous coronary intervention patients. Mean test scores were significantly worse in CABG patients versus percutaneous coronary intervention patients in 4 of 13 measures at 3 weeks' follow-up, but significant de novo impairment at 3 weeks' follow-up in the CABG group compared with the percutaneous coronary intervention and control groups was present in only one test. As assessed by reliable change methodology, impairment was statistically associated with type of treatment for only 1 of 13 measures. CONCLUSIONS: As compared with changes seen in repeat testing of healthy control subjects and individuals who underwent percutaneous coronary intervention, clinically meaningful cognitive deterioration was not observed after CABG.

Adult↗
PubMed2005

An Egr-1 master switch for arteriogenesis: studies in Egr-1 homozygous negative and wild-type animals.

BACKGROUND: Arteriogenesis has been implicated as an important biologic response to acute vascular occlusion. The early growth response 1 (Egr-1) gene encodes an immediate-early response transcription factor that is upregulated by changes in vascular strain and that in turn upregulates a number of putative angiogenic and arteriogenic growth factors. We therefore hypothesized that early growth response 1 might be a critical arteriogenic messenger that induces revascularization in the setting of acute vascular occlusions. METHODS: Wild-type or Egr-1-/- (null) C57 BL mice, or Sprague-Dawley rats, underwent unilateral iliofemoral artery excision and subsequent analyses for angiogenesis and arteriogenesis through cell-specific immunohistochemistry. Rats were also administered an adenoviral vector encoding for Egr-1 (AdEgr group), noncoding vectors (AdNull group), or saline, after which these animals were assessed by means of serial laser Doppler perfusion imaging and morphologic examination of rat foot-pad ischemic lesions. RESULTS: Egr-1 wild-type mice demonstrated an equivalent number of capillaries but a greater number of arterioles following excision versus Egr-1 null mice. AdEgr group rats demonstrated greater distal perfusion from 7 to 21 days after excision compared with control animals (P < .02), which approximated normal perfusion at 21 days after excision. AdEgr group rats also demonstrated greater arteriolar density and less severe ischemic foot-pad lesions than control animals. CONCLUSION: These data suggest the importance of Egr-1 as a critical and potentially therapeutic mediator of revascularization after vascular occlusion and implicate arteriogenesis (collateral vessel formation) as a critical component of this process.

Animals↗
PubMed2005

Calcified rheumatic valve neoangiogenesis is associated with vascular endothelial growth factor expression and osteoblast-like bone formation.

BACKGROUND: Rheumatic heart disease is the most common cause of valvular disease in developing countries. Despite the high prevalence of this disease, the cellular mechanisms are not well known. We hypothesized that rheumatic valve calcification is associated with an osteoblast bone formation and neoangiogenesis. METHODS AND RESULTS: To test this hypothesis, we examined human rheumatic valves replaced at surgery (n=23), normal human valves (n=20) removed at cardiac transplantation, and degenerative mitral valve leaflets removed during surgical valve repair (n=15). Microcomputed tomography was used to assess mineralization fronts to reconstruct the extents of mineralization. Immunohistochemistry was used to localize osteopontin protein, alpha-actin, osteocalcin, vascular endothelial growth factor, von Willebrand factor, and CD68 (human macrophage). Microcomputed tomography demonstrated complex calcification developing within the heavily calcified rheumatic valves, not in the degenerative mitral valves and control valves. Immunohistochemistry localized osteopontin and osteocalcin to areas of smooth muscle cells within microvessels and proliferating myofibroblasts. Vascular endothelial growth factor was present in areas of inflammation and colocalized with the CD68 stain primarily in the calcified rheumatic valves. Alizarin red, osteopontin, and osteocalcin protein expression was upregulated in the calcified rheumatic valves and was present at low levels in the degenerative mitral valves. CONCLUSIONS: These findings support the concept that rheumatic valve calcification is not a random passive process but a regulated, inflammatory cellular process associated with the expression of osteoblast markers and neoangiogenesis.

Adult↗
PubMed2005

Recommendations of the National Heart, Lung, and Blood Institute Working Group on Future Direction in Cardiac Surgery.

New surgical procedures, imaging modalities, and medical devices have improved therapy for many patients and made treatment possible for others who have had few options in the past. In February 2004, the National Heart, Lung, and Blood Institute's (NHLBI) Advisory Council proposed that the institute evaluate the status and future directions in cardiac surgery. In response to this recommendation, the NHLBI convened a working group of cardiac surgeons on May 7 and 8, 2004, to assess the state of cardiac surgery research, identify critical gaps in current knowledge, determine areas of opportunity, and obtain specific recommendations for future research activities. The working group discussed surgical revascularization, novel surgical approaches, valvular research directions, biotechnology and cell-based therapy, heart failure, imaging modalities, and barriers to clinical research and presents its recommendations here.

Cardiac Surgical Procedures↗
PubMed2005

Surgical revision after percutaneous mitral valve repair with a clip: initial multicenter experience.

PURPOSE: Almost 50,000 mitral valve operations are performed annually in the United States, with an increasing number of repairs. Recently, a percutaneous mitral valve repair option that achieves edge-to-edge approximation with a clip has been described in patients with mitral regurgitation. DESCRIPTION: We describe 6 patients from three centers with mitral regurgitation after percutaneous repair who underwent reintervention. During open surgical revision, the clips were uneventfully removed in all patients with no limitation in surgical options. Five patients underwent repair and 1 underwent replacement. EVALUATION: After surgical revision, mitral regurgitation was significantly decreased, and all but 1 patient underwent uneventful recovery. One patient developed ilio-femoral deep venous thrombosis that was treated successfully with anticoagulation. CONCLUSIONS: Preserving standard of care options is critical with any evolving technology in the event of initial treatment failure. Standard surgical options were preserved in all of the patients who underwent percutaneous mitral valve edge-to-edge repair. Furthermore, a thorough understanding of the clip design, in particular its unlocking mechanism, is essential and facilitates surgical clip removal.

Adult↗
PubMed2005

Neurocognitive functioning in patients undergoing coronary artery bypass graft surgery or percutaneous coronary intervention: evidence of impairment before intervention compared with normal controls.

BACKGROUND: Cognitive deficits have been reported to occur in a significant proportion of patients undergoing coronary artery bypass grafting (CABG), but the extent to which these deficits were preexistent or related to the natural history of cognitive decline in this patient population remains poorly defined. METHODS: After excluding patients with conditions known to cause brain dysfunction (eg, hepatic dysfunction, stroke), a group of patients referred for percutaneous coronary intervention (PCI) or CABG (n = 82) was compared with an age- and education-matched control group that did not have clinical evidence of coronary artery disease (n = 41). These subjects underwent a battery of neurocognitive and emotional testing. RESULTS: Test score means for 5 of 14 different measures were significantly greater (impaired) in cardiac compared with control group subjects. Of cardiac subjects, 20% demonstrated clinical impairment (test result > or = 1 SD worse than mean for normative standards) in 6 of 14 tests, compared with 10% of the controls. By clinical standards, 46% of cardiac subjects would be considered to be impaired (score 1 SD or more below the control group mean) on 3 or more neuropsychologic measures, compared with 29% of the controls. By this (control group mean) standard, cardiac subjects demonstrated impaired scores on 3.06 +/- 2.6 tests compared with impairment in 2.0 +/- 2.35 tests for the control group (p = 0.01). CONCLUSIONS: Even excluding patients at high risk for brain dysfunction, cognitive impairment is found in patients with coronary artery disease before interventional therapy. Baseline impairment must be considered when evaluating outcomes after intervention.

Aged↗
PubMed2005

Alteration of splicing signals in a genomic/cDNA hybrid VEGF gene to modify the ratio of expressed VEGF isoforms enhances safety of angiogenic gene therapy.

Vascular endothelial growth factor (VEGF)-mediated physiological angiogenesis results from the concerted action of three major VEGF isoforms (VEGF121, 165, 189), which arise from alternate splicing. We have previously shown that expression of a mixture of VEGF isoforms via gene transfer is considerably more potent than expression of a single VEGF isoform. To test the hypothesis that different mixtures of VEGF isoforms may offer the same therapeutic benefit with a better safety profile, we compared the efficacy and safety of an adenovirus gene transfer vector expressing the three major VEGF isoforms (AdVEGF-All) in the normal ratio to those of AdVEGF-All6A+, in which the splicing sequences for exon 6A were altered to promote expression of VEGF189 at the expense of VEGF121. Both vectors were equally potent in mediating recovery of hind-limb blood flow following experimental ischemia. By contrast, intravenous administration of AdVEGF-All6A+ yielded enhanced survival and a lower capacity to support tumor growth compared to AdVEGF-All, and intratracheal administration of AdVEGF-All6A+ resulted in less pulmonary edema than that of AdVEGF-All. We conclude that AdVEGF-All and AdVEGF-All6A+ are similar in potency but that AdVEGF-All6A+ is safer. This suggests that AdVEGF-All6A+ may be the preferred candidate for clinical development.

Adenoviridae↗
PubMed2005

Gene therapy for heart failure.

Congestive heart failure (CHF) remains a leading cause of morbidity and mortality in the United States and in many other countries. Current heart failure therapies, including multidrug treatment regimens, biventricular pacing, and mechanical support such as left ventricular assist devices, are often hindered by limited benefits or significant associated procedural complications or side effects. Therefore, new forms of treatment, which could ideally target the underlying biological processes affecting the ailing cardiomyocyte, would be of significant potential benefit to the population of individuals with CHF. Gene transfer strategies, including modification of cellular contractile signaling and regulatory pathways, represent a promising new form of such biologic therapy for heart disease.

Adenylyl Cyclases↗
PubMed2004

Adenoviral-mediated transfer of vascular endothelial growth factor 121 cDNA enhances myocardial perfusion and exercise performance in the nonischemic state.

BACKGROUND: Angiogenic gene therapy has been demonstrated to enhance perfusion to ischemic tissues, but it is unknown whether the administration of angiogenic growth factors will increase blood flow to nonischemic tissues. This study investigates whether enhanced myocardial perfusion can be mediated by adenovirus-mediated transfer of vascular endothelial growth factor 121 cDNA to nonischemic myocardium. METHODS: New Zealand White rabbits received adenovirus (5 x 10(10) particle units) encoding for vascular endothelial growth factor 121 (n = 14) or a control vector without a transgene (n = 13) or saline solution (n = 9) via direct myocardial injection. Fluorescent microsphere perfusion studies and histologic analyses were performed 4 weeks later. In a parallel study, exercise treadmill testing was performed to assess the functional effects of this therapy in Sprague-Dawley rats. RESULTS: Microsphere assessment of myocardial perfusion in rabbits 4 weeks after adenovirus-encoding vascular endothelial growth factor administration was greater than that for rats injected with control vector without a transgene or saline solution (3.2 +/- 0.5 vs 2.7 +/- 0.7 and 2.4 +/- 0.4, respectively; P <.03). The endothelial cell count per high power field was increased in animals injected with adenovirus-encoding vascular endothelial growth factor versus animals injected with control vector without a transgene or saline solution (147 +/- 27 vs 123 +/- 14 and 125 +/- 16 cells, respectively), although this did not reach statistical significance (P =.12). Rats treated with adenovirus-encoding vascular endothelial growth factor also demonstrated prolonged exercise tolerance compared with rats injected with control vector without a transgene or saline solution (exhaustion time: 26 +/- 5 minutes vs 19 +/- 2 minutes and 20 +/- 3 minutes, respectively; P =.006). CONCLUSIONS: Adenovirus encoding-mediated transfer of vascular endothelial growth factor 121 induces an enhancement in regional perfusion in nonischemic myocardium that corresponds to changes in exercise tolerance. Adenovirus-encoding vascular endothelial growth factor therapy may be useful for inducing angiogenesis in the nonischemic state, such as for prophylactic therapy of early coronary artery disease.

Adenoviridae↗
PubMed2004

Angiogenic pretreatment improves the efficacy of cellular cardiomyoplasty performed with fetal cardiomyocyte implantation.

BACKGROUND: Cell implantation into areas of myocardial infarction (cellular cardiomyoplasty) may be limited in efficacy because of the lack of blood supply to these areas of myocardium, resulting in early loss of transplanted cells. We therefore tested the hypothesis that pretreatment of infarcted myocardium with angiogenic therapy, followed by cell transplant, would be more effective than the application of either strategy alone. METHODS: Fischer 344 rats underwent left coronary artery ligation and injection of an adenovirus encoding VEGF 121, an empty expression cassette control vector, or saline solution. Capillary density in the infarcted region was determined in preliminary studies. Cardiomyocytes harvested from syngeneic Fischer rat fetuses were prelabeled and then injected directly into the infarct area 3 weeks after vector administration. Exercise treadmill testing was performed 2 weeks after cell transplantation, after which a cell viability index was calculated as the number of implanted (prelabeled) nuclei divided by the number of coadministered microspheres detected in sections of implanted myocardium. RESULTS: Capillary density in the area of infarction was significantly greater in adenovirus encoding VEGF 121 compared with rats injected with saline solution (P =.001). The cell survival index was also greater in adenovirus encoding VEGF 121 compared with animals injected with empty expression cassette control or saline solution (P =.0045). Exercise tolerance was nearly doubled in animals receiving adenovirus encoding VEGF 121 3 weeks prior to cell implantation compared with animals receiving adenovirus encoding VEGF 121 or cells alone or those receiving adenovirus encoding VEGF 121 at the time of cell implantation (P <.001). CONCLUSIONS: Pretreatment of an infarcted region of the heart with angiogenic mediators such as VEGF can enhance the efficacy of cellular cardiomyoplasty, presumably by creating a more favorable environment for the survival of transplanted cells.

Animals↗
PubMed2004

Homozygous deletion of early growth response 1 gene and critical limb ischemia after vascular ligation in mice: evidence for a central role in vascular homeostasis.

BACKGROUND: The early growth response 1 gene (Egr1) encodes for an immediate to early response transcription factor that is upregulated by changes in vascular strain and hypoxia and in turn upregulates the downstream expressions of a number of angiogenic growth factors. We therefore hypothesized that early growth response 1 may be a critical early messenger governing revascularization in the setting of acute vascular occlusions. METHODS: C57 BL/6 mice deficient in the Egr1 gene (knockout) and their wild-type litter mates underwent ligation and excision of the femoral artery with or without the previous administration of 2.7 x 10(9) particle units of an adenoviral vector coding for the vascular endothelial growth factor gene (VEGF) or Egr1. Distal hind limb perfusion was serially measured in these animals with laser Doppler perfusion imaging. RESULTS: Wild-type mice (n = 9) had nearly complete restitution of hind limb perfusion by day 35 after ligation. In contrast, all noninjected Egr1 knockout mice (n = 5) had severe ipsilateral limb necrosis develop between 1 and 4 days after ligation (P <.0001). Egr1 knockout mice injected with VEGF vector (n = 4) demonstrated significantly improved perfusion relative to baseline by postligation day 28, which persisted to postligation day 35 (P <.05). Egr1 knockout animals injected with Egr1 vector (n = 7) demonstrated a partial recovery of hind limb perfusion relative to VEGF vector-treated knockout animals at postligation day 4 (P <.01), which persisted to day 35. CONCLUSIONS: These findings suggest that early growth response 1 plays a pivotal role in reperfusion responses to vascular occlusion in mice and possibly other mammals.

Adenoviridae↗
PubMed2004

Adenovirus-mediated transfer of a minigene expressing multiple isoforms of VEGF is more effective at inducing angiogenesis than comparable vectors expressing individual VEGF cDNAs.

To assess the hypothesis that angiogenic gene therapy with the genomic form of vascular endothelial growth factor (VEGF) expressing the three major isoforms could be more potent than a vector expressing a single isoform, we designed an adenovirus vector (AdVEGF-All) expressing a VEGF cDNA/genomic hybrid gene. AdVEGF-All expressed all three major isoforms (121, 165, 189) in a 2:2:1 ratio. AdVEGF-All was 100-fold more potent than cDNA vectors expressing VEGF 121, 165, or 189 in restoring blood flow to the ischemic mouse hind limb. Interestingly, a mixture of Ad vectors individually expressing the VEGF 121, 165, and 189 cDNAs was equipotent to an equivalent dose of AdVEGF-All. Thus, a mixture of VEGF isoforms provides a more potent angiogenic response than a single isoform, suggesting that the individual isoforms function synergistically, an observation with important implications for gene and recombinant protein therapy.

Adenoviridae↗
PubMed2004

Therapeutic angiogenesis: a biologic bypass.

The use of angiogenic factors to effect therapeutic angiogenesis may be an attractive treatment modality for a substantial number of patients who have diffuse coronary artery disease and who are not candidates for traditional revascularization procedures. Delivery of angiogenic factors as a protein or gene encoding for the respective protein product has been shown to induce angiogenesis in numerous animal models, and expression of a functioning product has been demonstrated. Various early clinical trials of therapeutic angiogenesis have shown reduction in anginal symptoms and increases in exercise time, as well as objective evidence of improved perfusion, left ventricular function and angiographic appearance following such angiogenic treatments.

Angiogenesis Inducing Agents↗
PubMed2004

The failure of retrograde autologous priming of the cardiopulmonary bypass circuit to reduce blood use after cardiac surgical procedures.

UNLABELLED: Hemodilution during cardiopulmonary bypass (CPB) is a primary risk factor for blood transfusion in cardiac surgical patients. Priming of the CPB circuit with the patients' own blood (retrograde autologous priming, RAP) is a technique used to limit hemodilution and reduce transfusion requirements. We designed this study to examine the impact of RAP on perioperative blood product use. Using a retrospective cohort study design, the medical records of all patients undergoing CPB (excluding circulatory arrest cases) by a single surgeon were examined. Data were collected over a 24-mo period when RAP was routinely used as a blood conservation strategy (RAP group, n = 257). This group was compared with a cohort of patients during the 24 mo immediately preceding the introduction of RAP into clinical practice (no RAP group, n = 288). A small, statistically insignificant reduction in the percentage of patients receiving packed red blood cells was observed in the RAP group (44% versus 51% no RAP, P = 0.083). No differences were found between the groups in the number of units of packed red blood cells, platelets, or fresh frozen plasma transfused throughout the perioperative period. These results suggest that overall, RAP does not offer a clinically important benefit as a blood conservation technique. IMPLICATIONS: Priming of the cardiopulmonary bypass circuit with the patients' own blood (retrograde autologous priming) resulted in insignificant reductions in blood use in a large, unselected group of patients undergoing cardiac surgical procedures.

Adult↗
PubMed2003

Recovery of neuromuscular function after cardiac surgery: pancuronium versus rocuronium.

UNLABELLED: The use of pancuronium in fast-track cardiac surgical patients may be associated with delays in clinical recovery. Our objective in this study was to evaluate the incidence and severity of residual neuromuscular blockade after cardiac surgery in patients randomized to receive either pancuronium (0.08-0.1 mg/kg) or rocuronium (0.6-0.8 mg/kg). Eighty-two patients undergoing cardiopulmonary bypass were randomized to a pancuronium (n = 41) or rocuronium (n = 41) group. Intraoperative and postoperative management was standardized. In the intensive care unit, train-of-four (TOF) ratios were measured each hour until weaning off ventilatory support was initiated. Neuromuscular blockade was not reversed. After tracheal extubation, patients were examined for signs and symptoms of residual paresis. When weaning of ventilatory support was initiated, significant neuromuscular blockade was present in the pancuronium subjects (TOF ratio: median, 0.14; range, 0.00-1.11) compared with the rocuronium subjects (TOF ratio: median, 0.99; range, 0.87-1.21) (P < 0.05). Patients in the rocuronium group were more likely to be free of signs and symptoms of residual paresis than patients in the pancuronium group. Our findings suggest that the use of longer-acting muscle relaxants in cardiac surgical patients is associated not only with impaired neuromuscular recovery, but also with signs and symptoms of residual muscle weakness in the early postoperative period. IMPLICATIONS: The use of long-acting muscle relaxants in fast-track cardiac surgical patients is associated with significant residual neuromuscular block in the intensive care unit, including signs and symptoms of residual paresis.

Adult↗