Biomedical subjects
Publications and source records attributed to T J Gardner.
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BACKGROUND: Coronary revascularization entails obligatory myocardial ischemia followed by reperfusion with occasional resultant postischemic contractile dysfunction, a state associated with significant morbidity and mortality. This injury is attributed in part to oxygen free radicals and has been partially ameliorated with exogenous antioxidants, a strategy limited by agent instability, low titer, and inadequate cardiomyocyte uptake. Cardiac gene transfer with antioxidant encoding vectors may significantly enhance intracellular free radical scavenger activity. METHODS AND RESULTS: C57/BL6 neonatal mice (age, 2 days; n = 131) underwent intrapericardial delivery of recombinant adenoviruses encoding superoxide dismutase (SOD) and catalase (Cat) (n = 76) or beta-galactosidase (LacZ) as a control (n = 55). After 3 days, hearts were explanted, and SOD and Cat transgene expression was detected by Western blot analysis. Spectrophotometric enzyme assays demonstrated enhanced SOD activity 1.6-fold (P < 0.0001) and Cat 3.6-fold (P < 0.00001) in experimental versus LacZ hearts. Isolated perfused hearts were subjected to 5 minutes of warm ischemia, and at 5, 10, and 15 minutes after initiation of reperfusion, LacZ controls lost 24%, 33%, and 41% of peak systolic apicobasal force, respectively, whereas experimental hearts lost 5%, 12%, and 20% (P < 0.001, each time point). In controls, rate of force generation diminished 8%, 17%, and 35%; in experimental hearts, it increased 1% at 5 minutes and decreased 5% and 15% and 10 and 15 minutes (P < 0.01, P < 0.05, P < 0.05). LacZ hearts exhibited dysfunction similar to hearts from uninjected animals (P = NS, each time point). CONCLUSIONS: Adenovirus-mediated cardiac gene transfer and expression of SOD and Cat augment antioxidant enzyme activity and minimize contractile dysfunction after ischemic reperfusion in the isolated perfused neonatal mouse heart.
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BACKGROUND: The relationship among the maternal, placental, and uniquely shunted embryonic circulation was explored to provide access to the embryonic cardiovascular system in utero. Manipulation of gene expression in the developing heart would be particularly useful for studying the effects of altered gene expression on cardiac development and in the etiology of congenital cardiac anomalies. METHODS AND RESULTS: Dye studies demonstrated that intraplacental injection allows direct access to the embryonic cardiac and systemic circulation. To evaluate the efficacy of cardiac gene transfer using this approach, replication-deficient recombinant adenoviral vectors encoding luciferase or beta-galactosidase as reporter genes were injected intraplacentally into embryonic day (E)12.5 murine embryos, an age at which the mass of the heart was observed to be large compared with other organs. Embryos were assayed for transgene expression at E15.5 and at birth. Survival rates at these times were similar among vector-injected and control groups. At E15.5 and at birth, luciferase activity within the heart was 9- and 23-fold higher, respectively, than in the remainder of the embryo, although levels of expression were generally lower at birth than during embryonic life. Beta-galactosidase expression was observed within all regions of the embryonic heart and was localized to approximately 15% of atrial and ventricular cells. CONCLUSIONS: Intraplacental delivery of adenovirus at embryonic day 12.5 results in somatic gene transfer to the murine embryonic heart, which persists at least until birth. The combination of intraplacental injection to directly access the fetal coronary circulation and injection at E12.5 when the mass of the heart is large compared with other organs results in transgene expression in cardiac cells. Intraplacental injections early in embryonic life may thus be useful to study the effects of temporal manipulation of gene expression on cardiac development and disease.
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Two pediatric cases of cervical aortic arch with aneurysm formation are reported. Only female patients with cervical aortic arch have developed aneurysms, which may influence risk counseling of such patients.
BACKGROUND: Cognitive deficits have been reported in patients after coronary artery bypass grafting, but the incidence of these deficits varies widely. We studied prospectively the incidence of cognitive change and whether the changes persisted over time. METHODS: Cognitive testing was done preoperatively and 1 month and 1 year postoperatively in 127 patients undergoing coronary artery bypass grafting. Tests were grouped into eight cognitive domains. A change of 0.5 standard deviation or more at 1 month and 1 year from patient's preoperative Z score was the outcome measure. RESULTS: We identified four main outcomes for each cognitive domain: no decline; decline and improvement; persistent decline; and late decline. Only 12% of patients showed no decline across all domains tested; 82% to 90% of patients had no decline in visual memory, psychomotor speed, motor speed, and executive function; 21% and 26% had decline and improvement in verbal memory and language; approximately 10% had persistent decline in the domains of verbal memory, visual memory, attention, and visuoconstruction; and 24% had late decline (between 1 month and 1 year) in visuoconstruction. CONCLUSIONS: This study establishes that the incidence of cognitive decline varies according to the cognitive domain studied and that some patients have persistent and late cognitive changes in specific domains after coronary artery bypass grafting.
BACKGROUND: Stroke occurs after coronary artery bypass grafting with an incidence ranging between 0.8% and 5.2%. To identify factors associated with stroke, we prospectively examined a study cohort and tested findings in an independent validation sample. METHODS: The study cohort comprised 456 patients undergoing coronary artery bypass grafting only, and the validation sample comprised 1,298 patients. Stroke was detected postoperatively by the study team and confirmed by neurologic consultation and computed tomographic scanning. RESULTS: Five factors taken together were correlated with stroke: previous stroke, presence of carotid bruit, history of hypertension, increasing age, and history of diabetes mellitus. The only significant intraoperative factor was cardiopulmonary bypass time. Probabilities were calculated, and patients were placed into low, medium, and high stroke-risk groups. In the validation sample, this model was able to rank the majority of patients with stroke into the high-risk group. CONCLUSIONS: These five factors taken together can identify the risk of stroke in patients having coronary artery bypass grafting. Recognition of the high-risk group will aid studies on the mechanism and prevention of stroke by modification of surgical procedures or pharmacologic intervention.
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The objective of this work was to determine whether normothermic global cardiac ischemia in a porcine model was associated with a change in the density (Bmax) of voltage-dependent calcium channels in myocardial sarcolemmal membranes. Pigs were anesthetized, a thoracotomy was performed, and samples were taken of the left and right ventricles from control and ischemic hearts. Dihydropyridine-binding sites were quantified using [3H]isradipine, and 5'-nucleotidase activity was measured by the liberation of inorganic phosphate from adenosine monophosphate. Bmax and dissociation constants and 5'-nucleotidase activity for control and ischemic tissues, respectively, were compared by using Student's t-test for unpaired samples. After normothermic global ischemia, the Bmax of [3H]isradipine binding increased in the left ventricle by 81% (299% +/- 1.7% to 540% +/- 11% fmoles/mg, P < 0.01) and in the right ventricle by 33% (387% +/- 9.9% to 515% +/- 38% fmoles/mg, P < 0.01) compared with control. 5'-nucleotidase activity increased by 48% in the left ventricle and by 96% in the right ventricle (p < 0.05). Fifteen minutes of normothermic ischemia in the pig is associated with marked sarcolemmal abnormalities, including increases in specific dihydropyridine binding and 5'-nucleotidase activity, which reflect global changes in membrane function, which might contribute to the increase in myoplasmic calcium during ischemia.
OBJECTIVE: The current study was undertaken to determine long-term results of aortic valve replacement (AVR) in the elderly, to ascertain predictors of poor outcome, and to assess quality of life. SUMMARY BACKGROUND DATA: Aortic valve replacement is the procedure of choice for elderly patients with aortic valve disease. The number of patients aged 70 and older requiring AVR continues to increase. However, controversy exists as to whether surgery devoted to this subset reflect a cost-effective approach to attaining a meaningful quality of life. METHODS: This study reviews data on 247 patients aged 70 to 89 years who underwent isolated AVR between 1980 and 1995; there were 126 men (51%) and 121 women (49%). Follow-up was 97% complete (239/247 patients) for a total of 974.9 patient-years. Mean age was 76.2 +/- 4.8 years. Operative mortality and actuarial survival were determined. Patient age, gender, symptoms, associated diseases, prior conditions, New York Health Association class congestive heart failure, native valve disease, prosthetic valve type, preoperative catheterization data, and early postoperative conditions were analyzed as possible predictors of outcome. Functional recovery was evaluated using the SF-36 quality assessment tool. RESULTS: Operative mortality was 6.1% (15/247). Multivariate logistic regression showed that poor left ventricular function and preoperative pacemaker insertion were independent predictors of early mortality. After surgery, infection was predictive of early mortality. Overall actuarial survival at 1, 5, and 10 years was 89.5 +/- 2% (198 patients at risk), 69.3 +/- 3.4% (89 patients at risk), and 41.2 +/- 6% (13 patients at risk), respectively. Cox proportional hazards model showed that chronic obstructive pulmonary disease and urgency of operation were independent predictors of poor long-term survival. Postoperative renal failure also was predictive of poor outcome. Using the SF-36 quality assessment tool, elderly patients who underwent AVR scored comparably to their age-matched population norms in seven of eight dimensions of overall health. The exception is mental health. CONCLUSIONS: Aortic valve replacement in the elderly can be performed with acceptable mortality. Significant preoperative risk factors for early mortality include poor left ventricular function and preoperative pacemaker insertion. Predictors of late mortality include chronic obstructive pulmonary disease and urgency of operation. These results stress the importance of operating on the elderly with aortic valve disease; both long-term survival and functional recovery are excellent.
BACKGROUND: Cerebral circulation during urgent repair of acute type A aortic dissection has traditionally been managed with cardiopulmonary bypass and aortic cross clamping proximal to the innominate artery or by the use of hypothermic circulatory arrest (HCA). The more recently introduced retrograde cerebral perfusion (RCP) may confer additional cerebral protection during elective aortic arch reconstruction. The purpose of this study was to demonstrate the efficacy of RCP in the urgent repair of acute type A aortic dissection. METHODS AND RESULTS: We evaluated 60 consecutive patients who underwent repair of acute type A aortic dissection over a 6-year period. Patients were grouped according to intraoperative circulatory management strategies. Group 1 consisted of 41 patients operated on early in the series who were managed by cardiopulmonary bypass and standard aortic cross clamping (n = 21) with conversion to HCA (n = 20) if the intimal tear extended into the aortic arch. Since 1993, 19 patients, who make up group 2, were managed with routine open distal anastomosis and HCA with RCP. Data were analyzed for clinically evident, radiographically confirmed cerebrovascular accidents and 60-day mortality and evaluated by chi 2 analysis. Stroke and mortality rates of patients managed with either cardiopulmonary bypass or HCA were 26.3% and 29.3%, respectively. Patients undergoing RCP experienced statistically significant reductions in rates of confirmed cerebrovascular accidents (0%, P = .015) and mortality (5.3%, P = .04). CONCLUSIONS: We conclude that the introduction of circulatory management using RCP with HCA during urgent operative repair of acute type A aortic dissection has significantly improved both stroke and mortality rates.