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Biomedical subjects

Irving L Kron

Publications and source records attributed to Irving L Kron.

At least 55 records · Page 3Linked to original sources

Modern concepts in heart transplantation.

In 1967, Christian Barnard performed the first successful human-to-human heart transplant. Following this triumph, the ensuing decade saw a waning interest in heart transplantation given the complications related to rejection and immunosuppression. With the introduction of cyclosporine immunotherapy in the early 1980s, however, success was more the rule than the exception, and cardiac transplantation became an acceptable therapy. Currently, heart transplantation is considered the gold standard therapy for end-stage heart failure refractory to medical treatment. One-year survival is now approximately 85%, and 10-year survival approaches 60%. While the main obstacles in the early years of heart transplantation were immunosuppression, the current issue at hand is organ availability. Approximately 2500 heart transplants are done yearly, but the list of candidates exceeds 50,000. What is perhaps even more alarming is the fact that while the number of heart transplants performed in the United States has dropped every year since 1994, the prevalence of heart failure increases every year and is predicted to do so into the year 2030. Nevertheless, the last 20 years has seen dramatic improvements in the ways we diagnose rejection, the fine-tuning of immunosuppressive regimens, and the advent of better preservation techniques. We have a better understanding of the causes of acute and chronic rejection and ways to treat these problems. Undoubtedly, we will continue to fine-tune the therapy in the years to come. This article is a review of the current indications, techniques, and medical therapies involved with cardiac transplantation.

Female↗

Keratinocyte growth factor enhances post-pneumonectomy lung growth by alveolar proliferation.

BACKGROUND: Keratinocyte growth factor (KGF) has been shown to play an important role in pneumocyte proliferation and lung development. We hypothesized that exogenous KGF would enhance postpneumonectomy compensatory lung growth through alveolar proliferation. METHODS AND RESULTS: Adult Sprague-Dawley rats were used. Left pneumonectomy was performed in group P, sham thoracotomy in group S, and left pneumonectomy with administration of KGF (6.25 mg/week, intraperitoneally) in group PK. Lung weight index (LWI), lung volume index (LVI), and alveolar cell proliferation index (CPI) were measured in the right lung at 10 and 21 days after surgery. Morphometric analysis was used to determine alveolar surface density (Sv) and total volume of respiratory region (TVvr). As expected, LWI, LVI, and CPI were significantly increased after pneumonectomy at both time points in group P. The administration of KGF resulted in further significant enhancements of LWI, LVI, and CPI in group PK. TVvr was significantly increased in group P and further enhanced in group PK. Interestingly, Sv was not altered in group P but was significantly elevated in group PK. Administration of KGF to sham-operated animals did not alter LWI, LVI, or CPI. CONCLUSIONS: KGF enhances compensatory lung growth after pneumonectomy in adult rats as indicated by increased LWI, LVI, and CPI. KGF induces new alveolar formation, as indicated by increases in Sv and TVvr. We believe that this is the first evidence that KGF can induce new alveolar formation in mature lungs.

Animals↗

Beneficial effects of inhaled nitric oxide in adult cardiac surgical patients.

BACKGROUND: Pulmonary hypertension with associated right ventricular dysfunction may complicate the postoperative cardiac patient despite maximum pharmacologic and ventilatory support. The purpose of this study was to retrospectively review our experience with inhaled nitric oxide (INO) in adult postoperative cardiac patients with pulmonary hypertension. METHODS: We retrospectively reviewed the medical records of 17 adult cardiac patients treated with INO postoperatively between November 1998 and February 2000. The INO was used to manage pulmonary hypertension postoperatively in patients who had undergone coronary artery bypass graft (CABG) (n = 13), valve operation (n = 3), and combined CABG/aortic valve replacement (n = 1). Hemodynamic and respiratory measurements before INO and again 6 hours after administration were examined. Student's t test was used to analyze the data. RESULTS: Inhaled nitric oxide (20 ppm to 30 ppm) was administered for a median duration of 30.2 hours. The group, as a whole, demonstrated a significant decrease in both mean pulmonary artery pressure and right ventricular stroke work index. In addition, a significant increase in posttherapeutic cardiac index and Pao2/Fio2 ratio was observed. The vasodilatory effects of nitric oxide were specific to the pulmonary circulation as no significant change in mean arterial pressure was noted. Overall mortality was 6%. CONCLUSIONS: Inhaled nitric oxide effectively and selectively lowered right ventricular afterload and right ventricular work in critically ill adult cardiac patients with acute pulmonary hypertension.

Administration, Inhalation↗

Ischemia-reperfusion injury after lung transplantation increases risk of late bronchiolitis obliterans syndrome.

BACKGROUND: Bronchiolitis obliterans syndrome (BOS) is the most common cause of long-term morbidity and mortality after lung transplantation. Our hypothesis was that early ischemia-reperfusion injury after lung transplantation increases the risk of BOS. METHODS: Data on 134 patients who had lung transplantation between January 1, 1990 and January 1, 2000, was used for univariate and multivariate logistic regression analysis. RESULTS: After lung transplantation, 115 patients (115 of 134, 86%) survived more than 3 months. In that group, 41 patients developed BOS, of which 23 had progressive disease. Univariate analysis revealed that ischemia-reperfusion injury (p = 0.017) and two or more acute rejection episodes (p = 0.032) were predictors of BOS onset, whereas ischemia-reperfusion injury (p = 0.011) and cytomegalovirus infection (p = 0.009) predicted progressive BOS. Multivariate logistic regression analysis showed that ischemia-reperfusion injury was an independent predictor for both BOS development and BOS progression. Two or more acute rejection episodes were also an independent predictor of BOS development, whereas cytomegalovirus infection was an independent predictor of progressive BOS. CONCLUSIONS: Ischemia-reperfusion injury increases the risk of BOS after lung transplantation.

Adolescent↗

Surgical relocation of the posterior papillary muscle in chronic ischemic mitral regurgitation.

Mitral annuloplasty is the preferred surgical treatment for chronic ischemic mitral regurgitation. Although this is usually successful, leaflet restriction by apical displacement of the posterior papillary muscle tip may cause residual mitral regurgitation. Ventricular remodeling surgery is an effective procedure for surgical relocation of the posterior papillary muscle tip in the setting of a severely dilated left ventricle. Direct relocation of the posterior papillary muscle may be useful for patients with a minimally dilated left ventricle or regional left ventricular geometric changes causing mitral regurgitation. Such a surgical procedure is described.

Cardiac Surgical Procedures↗

Adenosine A2A agonist reduces paralysis after spinal cord ischemia: correlation with A2A receptor expression on motor neurons.

BACKGROUND: The adenosine A2A agonist ATL-146e ameliorates reperfusion inflammation, reducing subsequent paralysis and neuronal apoptosis after spinal cord ischemia. We hypothesized that neuroprotection with ATL-146e involves inducible neuronal adenosine A2A receptors (A2A-R) that are upregulated after ischemia. METHODS: Eighteen rabbits underwent laparotomy, and 14 sustained spinal cord ischemia from cross-clamping the infrarenal aorta for 45 minutes. One group (ischemia-reperfusion [I/R] + ATL) received ATL-146e intravenously for 3 hours during spinal cord reperfusion. A second group (I/R) received equivolume intravenous saline solution for 3 hours and served as an ischemic control, and a third group (Sham) underwent sham laparotomy. At 48 hours, all subjects were assessed for motor impairment using the Tarlov scoring system (0 to 5). Lumbar spinal cord sections were immunolabeled for A2A-R and graded in a blinded fashion using light microscopy. RESULTS: There was a significant improvement in Tarlov scores in I/R + ATL animals compared with the I/R group. Sham-operated animals demonstrated no A2A-R immunoreactivity. There was a dramatic increase in A2A-R immunoreactivity in neurons of lumbar spinal cord sections from I/R compared with I/R + ATL and sham-operated animals. CONCLUSIONS: Reduction in paralysis in animals receiving ATL-146e correlates with the new finding of A2A-R expression on lumbar spinal cord motor neurons after ischemia. Adenosine A2A agonists may exert neuroprotective effects by binding to inducible neuronal A2A-R that are upregulated during spinal cord reperfusion, and reduced in response to administration of an A2A-R-specific agonist.

Animals↗

Coronary risk stratification in patients with end-stage lung disease.

BACKGROUND: Significant coronary artery disease (CAD) has been a contraindication for listing patients for lung transplantation. We hypothesize that coronary risk stratification can help identify a sub-set of patients who need additional diagnostic tools and intervention. METHODS: We performed a retrospective review of 72 consecutive patients who underwent lung transplantation at our institution from 1995 to 2000. Further, a review of patients who are currently listed for transplantation yielded 48 patients. We then identified the various risk factors for CAD, the diagnostic tools used, and pre-operative intervention. Risk factors identified included smoking history, diabetes, hypertension, hypercholesterolemia, CAD, congestive heart failure, age >50, and arrhythmias. Based on these risk factors, the patients were then classified into 2 groups: low risk (< or =1 risk factors) and high risk (> or =2 risk factors). We identified the patients in each group who underwent coronary angiography (CA), those with angiographic evidence of CAD, and those who received pre-operative intervention. RESULTS: Of the 72 patients who underwent lung transplantation, 48 were identified as at high risk for CAD. Of these, 5 patients had CAD diagnosed before surgery using CA, and 1 patient received pre-operative intervention. Of the 48 patients currently on the lung transplant list, we identified 28 patients as high risk for CAD, 12 of whom were noted to have CA, and 2 of whom received pre-operative intervention. CONCLUSIONS: Although CAD was once a contraindication for lung transplantation, pre-operative risk stratification allows identification of CAD with CA in a high-risk group. We believe that by using appropriate pre-operative cardiac intervention, patients with severe CAD could successfully undergo lung transplantation.

Adolescent↗

Controlled perfusion decreases reperfusion injury after high-flow reperfusion.

INTRODUCTION: Some investigators have suggested that high pulmonary artery flow rates increase the risk of severe reperfusion injury after lung transplantation. We hypothesized that controlling the initial flow rate and pulmonary artery pressure would decrease the severity of lung dysfunction in the setting of high-flow reperfusion. METHODS: Using our isolated, ventilated, blood-perfused rabbit lung model, all groups underwent lung harvest, 4-hour storage (4 degrees C), and blood reperfusion. We measured pulmonary artery pressure, peak inspiratory pressure, arterial oxygenation, and wet-to-dry weight ratio. Group 1 (control, n = 8) underwent reperfusion at 60 ml/min for 30 minutes. Group 2 (high flow, n = 8) underwent reperfusion at 120 ml/min for 30 minutes. Group 3 (controlled flow, n = 8) underwent initial reperfusion at 60 ml/min for 5 minutes, followed by reperfusion at 120 ml/min for 25 minutes. RESULTS: Group 1 had significantly improved pulmonary artery pressure, peak inspiratory pressure, arterial oxygenation, and wet-to-dry weight ratio measurements compared with groups 2 and 3 after 30 minutes of reperfusion. However, Group 3 had improved pulmonary artery pressure, peak inspiratory pressure, arterial oxygenation, and wet-to-dry weight ratio measurements compared with Group 2. CONCLUSIONS: High-flow reperfusion results in severe reperfusion injury after lung transplantation. Controlled reperfusion using a low initial flow rate decreases the severity of reperfusion injury associated with high-flow rates.

Animals↗

Percutaneous transluminal angioplasty and stenting in the treatment of chronic mesenteric ischemia: results and longterm followup.

BACKGROUND: The purpose of this study was to review the results of percutaneous transluminal angioplasty (PTA), stenting, or both in the treatment of patients who present with symptoms and angiographic findings most consistent with chronic mesenteric ischemia. STUDY DESIGN: A retrospective analysis of 33 consecutive patients from a single institution who underwent PTA, stenting, or both for treatment of symptoms most characteristic of chronic mesenteric ischemia was performed. RESULTS: There were 12 men and 21 women with a mean age of 63 years (range 40 to 89 years). Median weight loss was 28 lb (range 6 to 80 lb). Postprandial pain was present in 88% of the patients (29 of 33). All lesions treated were stenoses. PTA alone was performed in 21 patients (32 vessels), and PTA and stenting were performed in 12 patients (15 vessels). PTA was technically successful in 26 of 32 vessels (81.3%); PTA plus stenting was technically successful in 15 of 15 vessels (100%) (p = 0.073). Complete alleviation of symptoms occurred immediately in 27 of the patients (82%), and 2 patients (6%) had significant improvement in symptoms. There were four immediate clinical failures (12%): two patients were found to have occult malignancy and one had immediate relief of symptoms after surgical release of the median arcuate ligament. Followup data were obtained in all patients with clinically successful procedures (mean 38 months, median 25 months, range 1 to 123 months). Angiographic followup was available in 52% of the patients (15 of 29), at a mean of 20 months. The primary longterm clinical success rate was 83.3% (24 of 29). Four of the five patients with recurrent symptoms were successfully retreated with endovascular therapy. The primary assisted longterm clinical success rate was 96.6% (28 of 29). The 5-year survival rate was 76.1%. Major complications occurred in 13% of the procedures, with a 30-day mortality rate of 0%. CONCLUSION: Endovascular therapy for treatment of mesenteric arterial stenoses is effective in the treatment of patients with symptoms and angiographic findings characteristic of chronic mesenteric ischemia.

Abdominal Pain↗

Complications of coarctation repair.

Surgery's role in the treatment of coarctation has been established, and the benefit to life expectancy and quality of life is undeniable. Three postaortic coarctation repair complications are discussed, with review of existing literature: recurrent or residual aortic coarctation, postrepair aneurysm formation, and spinal cord ischemia. Incidence, potential causative factors, and outcome of surgical or transcatheter treatment for recurrent and residual aortic coarctation are reviewed. A literature review of postrepair aneurysm formation focuses on etiologic factors such as use of patch aortoplasty repair techniques, aortic arch hypoplasia, congenital abnormality of the aortic wall, and persistent hypertension after repair. The spectrum, onset, incidence, and potential risk factors for postcoarctation repair spinal cord ischemia are reviewed. Use of adenosine receptor agonists to achieve a state of ischemic resistance is under investigation to address this potential hazard of coarctation repair. Complications after surgery do occur in certain subsets of patients, but the risk of subsequent intervention is still lower than the hazards associated with the natural course of the defect.

Aneurysm↗

Contrasting natures of lung growth after transplantation and lobectomy.

OBJECTIVE: We hypothesized that posttransplantation lung growth in an immature recipient and postlobectomy compensatory lung growth are two distinct processes. METHODS: Mature swine underwent left upper lobectomy, and growth of the left lower lobe was studied after 2 weeks and after 3 months. Left lower lobes from another set of mature pigs were transplanted into immature animals, and growth of the transplanted lobe was then studied after 2 weeks and after 3 months. Left lower lobes from mature animals that did not undergo operation were used as normal control lobes. The lobes were weighed on removal and fixed intrabronchially. Sections stained with hematoxylin and eosin were used to determine alveolar surface density and percentage volume of respiratory region. Immunostaining for 5-bromo-2'-deoxyuridine was used to determine alveolar cell proliferation index, and epidermal growth factor receptor expression was detected by Western blot. RESULTS: Postlobectomy lung growth (increase in lobe weight) reached statistical significance at 2 weeks, with a concomitant rise in cell proliferation index. The transplanted lobe, in contrast, exhibited a gradual growth response, with a statistically significant increase in cell proliferation index at 3 months. Volume of respiratory region was noted to increase only in the transplanted lobe at 3 months. Epidermal growth factor receptor expression was upwardly regulated relative to that in normal control lobes in the 2-week postlobectomy and 3-month posttransplantation lobes. CONCLUSIONS: Postlobectomy lung growth appears to be regulated by a different mechanism than is posttransplantation lung growth and is a more rapid and restorative process. The growth peaks in both processes correlate with upward regulation of cell proliferation index and epidermal growth factor receptor expression.

Animals↗

Adenosine A2A receptor activation decreases reperfusion injury associated with high-flow reperfusion.

INTRODUCTION: High pulmonary artery flow rates can result in severe reperfusion injury after lung transplantation. Our hypothesis was that selective activation of the adenosine A(2A) receptor with a highly specific analog (ATL-146e) would inhibit leukocyte activation and decrease reperfusion injury after high-flow reperfusion. METHODS: Using our isolated, ventilated, blood-perfused rabbit lung model, all groups (n = 8 per group) underwent lung harvest, 4 hours of cold storage, and blood reperfusion for 30 minutes. Measurements of pulmonary artery pressure (in millimeters of mercury), arterial oxygenation (in millimeters of mercury), myeloperoxidase, peak inspiratory pressure, and wet/dry weight ratio were obtained. Groups 1 (high flow) and 2 (high flow ATL-146e) underwent reperfusion at 120 mL/min for 30 minutes. Groups 3 (controlled high flow) and 4 (controlled high flow ATL-146e) underwent controlled reperfusion with an initial reperfusion of 60 mL/min for the first 5 minutes, followed by a rate of 120 mL/min for 25 minutes. During reperfusion, groups 2 and 4 received ATL-146e at 4 microg. kg(-1). min(-1). RESULTS: ATL-146e significantly improved lung physiologic measurements under both high-flow (group 1 vs group 2) and controlled high-flow (group 3 vs group 4) conditions after 30 minutes. CONCLUSIONS: The adenosine A(2A) receptor analogue ATL-146e significantly decreases the severity of reperfusion injury in the setting of both high-flow and controlled high-flow reperfusion.

Animals↗

Adenosine A2A analogue ATL-146e reduces systemic tumor necrosing factor-alpha and spinal cord capillary platelet-endothelial cell adhesion molecule-1 expression after spinal cord ischemia.

OBJECTIVE: Inflammation is likely a major contributor to spinal cord reperfusion injury after aortic reconstruction. Systemic 4-(3-[6-amino-9-(5-ethylcarbamoyl-3,4-dihydroxy-tetrahydro-furan-2-yl)-9H-purin-2-yl]-prop-2-ynyl)-cyclohexanecarboxylic acid methyl ester (ATL-146e), a selective adenosine A(2A) agonist, has been shown to reduce paralysis after spinal cord ischemia. We hypothesized that ATL-146e reduces cytokine production during spinal cord reperfusion, curtailing inflammation and decreasing spinal cord capillary platelet-endothelial cell adhesion molecule-1 (PECAM-1) expression. STUDY DESIGN: New Zealand White rabbits sustained spinal cord ischemia with 45-minute cross-clamping of the infrarenal aorta. One group of animals received intravenous ATL-146e at 0.06 microg/kg/min for 3 hours during reperfusion, beginning after 30 minutes of ischemia. A second group received saline solution vehicle alone for 3 hours, serving as an ischemic control. A third group served as sham-operated animals, undergoing laparotomy with anesthesia. Serum was assayed with enzyme-linked immunosorbent assay for tumor necrosing factor-alpha (TNF-alpha). Animals were allowed to recover for 48 hours and were evaluated for hind-limb motor function with the Tarlov (0 to 5) scoring system. At necropsy, animals from each group yielded spinal cords for immunohistochemical staining for PECAM-1. Data are expressed as mean +/- standard error of the mean, with statistical analysis with Student t test and Kruskal-Wallis nonparametric test. RESULTS: Markedly improved Tarlov scores were seen in rabbits with ATL-146e (P <.001) during spinal cord reperfusion as compared with ischemic control animals. A significant reduction was found in TNF-alpha in the sera of rabbits with ATL-146e infusion (P <.01) as compared with ischemic control animals. Significantly reduced endothelial PECAM-1 staining intensity (P <.05) was seen in microscopic spinal cord sections from rabbits with ATL-146e. CONCLUSION: ATL-146e, an adenosine A(2A) agonist, reduces spinal cord reperfusion injury. The mechanism of the protection may involve a reduction in circulating TNF-alpha during a critical 3-hour reperfusion interval and reduction in spinal cord endothelial PECAM-1 upregulation.

Animals↗

Ventricular reconstruction results in improved left ventricular function and amelioration of mitral insufficiency.

INTRODUCTION: Surgical restoration of the left ventricular wall (Dor procedure) has been advocated as a therapy for left ventricular dysfunction due to ischemic cardiomyopathy. This procedure involves placement of an endoventricular patch through a ventriculotomy. METHODS: We reviewed our series of patients that underwent the Dor procedure within the past 4 years and examined their pre and postoperative ventricular function and mitral valve function. Pre and postoperative ejection fraction and degree of mitral regurgitation were analyzed using the paired Student t-test. We hypothesized that this procedure would result in improved ventricular function and that it would also help improve mitral valve function. RESULTS: Thirty-four patients underwent this procedure, with one death. Of these, 30 patients underwent concomitant coronary artery bypass grafting and 8 patients had mitral intervention (seven had an Alfieri repair of the mitral valve, and one had mitral valve annuloplasty). The average preoperative ejection fraction among these patients was 26.8% (range 10-45%). The postoperative ejection fraction was significantly higher at 35.4% (range 25-52%) (P <.001). We noted an improvement in ejection fraction in 27 patients (82%). We also noted that 21 of 33 patients (64%) had improvement in the degree of mitral regurgitation based on echocardiography data (P <.001). CONCLUSIONS: We conclude that the Dor procedure results in improvement in the left ventricular function. Furthermore, we also note that this procedure ameliorates mitral regurgitation in a majority of these patients even in the absence of associated mitral valve procedures, probably due to reduction in the size of the ventricle and improved orientation of the papillary muscles.

Cardiac Surgical Procedures↗

Complete versus partial atrioventricular canal: equal risks of repair in the modern era.

OBJECTIVE: To assess the authors' hypothesis that with modern techniques, the current risks of repair for both complete and partial atrioventricular canal (AVC) are equal. SUMMARY BACKGROUND DATA: Repair of complete AVC in infancy has traditionally carried a substantial mortality. In contrast, partial AVC has been considered low-risk for repair and can be performed later in childhood. METHODS: This was a retrospective review of 63 infants and children who underwent complete (n = 40) or partial AVC repair (n = 23) from 1990 to 2001. Among complete AVC patients, the ventriculoseptal defect was repaired via an individualized approach according to each patient's specific anatomy: direct suturing without a patch (n = 5) and/or interposition of a small pericardial patch with a running suture (n = 35). In all 63 patients the left AV valve cleft was closed with interrupted sutures, and all atrial defects were closed with a pericardial patch. Data were analyzed with the Student test and Fisher exact test. RESULTS: Results are expressed as the mean +/- SEM. Age at operation was 6.3 +/- 2.0 months for complete AVC and 47.5 +/- 6.1 months for partial AVC (P <.001). Bypass time was 65.2 +/- 2.3 minutes for complete AVC and 58.3 +/- 3.9 minutes for partial AVC ( P=.1). Reoperation rate was 7.5% (3/40) for complete AVC and 13.0% (3/23) for partial AVC ( P=.6). Early mortality was 2.5% (1/40) for complete AVC and 0% (0/23) for partial AVC ( P=.6). CONCLUSIONS: Compared to partial AVC, patients presenting for complete AVC repair are significantly younger and manifest more complex anatomy and pathophysiology. However, utilizing modern techniques, including an individualized surgical approach to the ventricular component, repair of complete AVC yields reoperation and early mortality rates similar to those of partial AVC.

Child, Preschool↗

Adenosine A2A analogue improves neurologic outcome after spinal cord trauma in the rabbit.

BACKGROUND: ATL-146e, an adenosine A2A agonist, reduces paralysis after spinal cord ischemia-reperfusion. We hypothesized that systemic ATL-146e could improve neurologic outcome after blunt spinal cord trauma. METHODS: Twenty rabbits survived a thoracic spinal cord impact of 30 g-cm. One group received 0.06 microg/kg/min ATL-146e for the first 3 hours after impact (A2A group), whereas a second group received saline carrier (T/C group). Neurologic outcome was measured using the Tarlov scale (0-5). Histologic sections from the A2A and T/C groups were compared for neuronal viability. RESULTS: There was significant improvement in Tarlov scores of A2A animals compared with T/C animals at 12 hours (p = 0.007), with a trend toward improvement at 36 (p = 0.08) and 48 (p = 0.09) hours after injury. There was decreased neuronal attrition in A2A animals (p = 0.06). CONCLUSION: Systemic ATL-146e given after spinal cord trauma results in improved neurologic outcome. Adenosine A2A agonists may hold promise as a rapidly acting alternative to steroids in the early treatment of the spinal cord injured patient.

Animals↗