Effects of the thyromimetic agent diiodothyropropionic acid on body weight, body mass index, and serum lipoproteins: a pilot prospective, randomized, controlled study.

CONTEXT: Widespread thyroid hormone actions offer the possibility of developing selective thyromimetic analogs with salutary metabolic properties. Consequently, effects of diiodothyropropionic acid (DITPA) on body weight, serum lipoproteins, and bone metabolism markers were studied in a prospective, controlled, double-blind 24-wk trial, which was primarily designed to assess treatment of stable chronic heart failure. DESIGN: Eighty-six patients (aged 66 +/- 11 yr, mean +/- sd) were randomized (1:2) to placebo or an escalating DITPA dose (90 to 180, 270, and 360 mg/d) over 8 wk until serum TSH was less than 0.02 mU/liter. Patients were studied at 2, 4, 6, 8, 16, and 24 wk and after 4 wk off study drug. Only 21 DITPA-treated and 27 placebo patients completed the full 24 wk of therapy. RESULTS: DITPA therapy lowered serum TSH levels and, to a lesser extent, serum T(3) and T(4), but there were no differences in clinical manifestations of thyrotoxicosis or hypothyroidism. Serum total and low-density lipoprotein cholesterol levels both decreased on DITPA; there was a transient decrease in triglycerides and no change in high-density lipoprotein cholesterol. DITPA therapy was associated with significant reduction in body weight, 12.5 lb at 24 wk. Increases in serum osteocalcin, N-telopeptide, and deoxypyridinoline levels were consistent with increased bone turnover on DITPA. CONCLUSION: This investigation of DITPA actions demonstrated its efficacy in reducing body weight and lowering total and low-density lipoprotein cholesterol levels. However, DITPA's adverse effects at doses used resulted in a high dropout rate and potentially dangerous skeletal actions were observed.

Effect of baseline or changes in adrenergic activity on clinical outcomes in the beta-blocker evaluation of survival trial.

BACKGROUND: Adrenergic activation is thought to be an important determinant of outcome in subjects with chronic heart failure (CHF), but baseline or serial changes in adrenergic activity have not been previously investigated in a large patient sample treated with a powerful antiadrenergic agent. METHODS AND RESULTS: Systemic venous norepinephrine was measured at baseline, 3 months, and 12 months in the beta-Blocker Evaluation of Survival Trial (BEST), which compared placebo treatment with the beta-blocker/sympatholytic agent bucindolol. Baseline norepinephrine level was associated with a progressive increase in rates of death or death plus CHF hospitalization that was independent of treatment group. On multivariate analysis, baseline norepinephrine was also a highly significant (P<0.001) independent predictor of death. In contrast, the relation of the change in norepinephrine at 3 months to subsequent clinical outcomes was complex and treatment group-dependent. In the placebo-treated group but not in the bucindolol-treated group, marked norepinephrine increase at 3 months was associated with increased subsequent risks of death or death plus CHF hospitalization. In the bucindolol-treated group but not in the placebo-treated group, the 1st quartile of marked norepinephrine reduction was associated with an increased mortality risk. A likelihood-based method indicated that 18% of the bucindolol group but only 1% of the placebo group were at an increased risk for death related to marked reduction in norepinephrine at 3 months. CONCLUSIONS: In BEST, a subset of patients treated with bucindolol had an increased risk of death as the result of sympatholysis, which compromised the efficacy of this third-generation beta-blocker.

Acute in vivo testing of an intravascular respiratory support catheter.

Current treatment for acute respiratory failure (ARF) includes the use of mechanical ventilation and/or extracorporeal membrane oxygenation, both of which can exacerbate lung injury. Intravenous respiratory support, using hollow fiber membranes placed in the vena cava, represents an attractive potential treatment for ARF, which could help reduce or eliminate ventilator induced trauma and/or other problems. Our group has been developing a respiratory support catheter (the Hattler catheter [HC]) that consists of a constrained hollow fiber bundle with a centrally located balloon. The balloon can be pulsated rapidly to increase blood flow across the fibers and decrease diffusional transfer resistance there, thus increasing gas exchange. The purpose of this study was to evaluate the HC in acute animal implants and to compare performance with that achieved in previous ex vivo studies. The HC was implanted into four calves by means of the external jugular vein and placed in the superior and inferior vena cava spanning the right atrium. Gas exchange, hemodynamics, and hematologic parameters were assessed over a range of balloon pulsation rates from 30 to 300 beats/minute. A <10% reduction in cardiac output was associated with catheter insertion and operation. The maximum CO2 exchange rate occurred at the highest pulsation rate and averaged 56 +/- 3 ml/min, or 327 +/- 15 ml/min per m2 when averaged to catheter membrane area, a level comparable to that achieved in the previous ex vivo studies. Balloon pulsation did not produce significant levels of hemolysis, as plasma-free hemoglobin remained below 10-15 mg/dl.

Sustained angina relief 5 years after transmyocardial laser revascularization with a CO(2) laser.

BACKGROUND: Although transmyocardial laser revascularization (TMR) has provided symptomatic relief of angina over the short term, the long-term efficacy of the procedure is unknown. Angina symptoms as assessed independently by angina class and the Seattle Angina Questionnaire (SAQ) were prospectively collected up to 7 years after TMR. METHODS: Seventy-eight patients with severe angina not amenable to conventional revascularization were treated with a CO(2) laser. Their mean age was 61+/-10 years at the time of treatment. Preoperatively, 66% had unstable angina, 73% had had >/=1 myocardial infarction, 93% had undergone >/=1 CABG, 42% had >/=1 PTCA, 76% were in angina class IV, and 24% were in angina class III. Their average pre-TMR angina class was 3.7+/-0.4. RESULTS: After an average of 5 years (and up to 7 years) of follow-up, the average angina class was significantly improved to 1.6+/-1 (P=0.0001). This was unchanged from the 1.5+/-1 average angina class at 1 year postoperatively (P=NS). There was a marked redistribution according to angina class, with 81% of the patients in class II or better, and 17% of the patients had no angina 5 years after TMR. A decrease of >/=2 angina classes was considered significant, and by this criterion, 68% of the patients had successful long-term angina relief. The angina class results were further confirmed with the SAQ; 5-year SAQ scores revealed an average improvement of 170% over the baseline results. CONCLUSIONS: The long-term efficacy of TMR persists for >/=5 years. TMR with CO(2) laser as sole therapy for severe disabling angina provides significant long-term angina relief.

Ex vivo testing of the intravenous membrane oxygenator.

Intravenous oxygenation represents a potential respiratory support modality for patients with acute respiratory failure or with acute exacerbations of chronic respiratory conditions. Our group has been developing an intravenous oxygenator, the IMO, which uses a constrained fiber bundle and a rapidly pulsating balloon within the fiber bundle. Balloon pulsation drives blood flow past the fibers at greater relative velocities than would otherwise exist within the host vessel, and gas exchange rates are enhanced. The purpose of this study was twofold: (1) to characterize the gas exchange performance of the current IMO in an extracorporeal mock vena cava vessel under conditions of known fixed vessel geometry and controlled blood flow rates; and (2) to compare the IMO gas exchange performance to that reported for the clinically tested IVOX device within a comparable ex vivo set-up. The ex vivo flow loop consisted of a 1 inch ID tube as a mock vena cava that was perfused directly from an anesthetized calf at blood flow rates ranging from 1 to 4 1/2 L/min. O2 and CO2 exchange rates were measured for balloon pulsation rates, which ranged from 0 to 180 bpm. Balloon pulsation significantly increased gas exchange, by 200-300% at the lowest blood flow rate and 50-100% at the highest blood flow rate. Balloon pulsation eliminated much if not all of the dependence of the gas exchange rate on blood flow rate as seen in passive oxygenators. This suggests that in clinical application the IMO may exhibit less gas transfer variability due to differences in cardiac output Over the entire flow rate range studied, the CO2 and O2 gas exchange rates of the IMO at maximal balloon pulsation varied from approximately 250 to 350 ml/min/m2. At maximum balloon pulsation the IMO exchanged CO2 and O2 at rates from 50-500% greater, depending upon the blood flow rate, than the exchange rates reported for the IVOX device in ex vivo tests.

Effects of donor bone marrow infusion in clinical lung transplantation.

BACKGROUND: We have demonstrated that donor cell chimerism is associated with a lower incidence of obliterative bronchiolitis (OB) in lung recipients, and that donor chimerism is augmented by the infusion of donor bone marrow (BM). We herein report the intermediate results of a trial combining the infusion of donor BM and lung transplantation. METHODS: Clinical and in vitro data of 26 lung recipients receiving concurrent infusion of donor bone marrow (3.0 to 6.0 x 10(8) cells/kg) were compared with those of 13 patients receiving lung transplant alone. RESULTS: Patient survival and freedom from acute rejection were similar between groups. Of the patients whose graft survived greater than 4 months, 5% (1 of 22) of BM and 33% (4 of 12) of control patients, developed histologic evidence of OB (p = 0.04). A higher proportion (but not statistically significant) of BM recipients (7 of 10, 70%) exhibited donor-specific hyporeactivity by mixed lymphocyte reaction assays as compared with the controls (2 of 7, 28%). CONCLUSIONS: Infusion of donor BM at the time of lung transplantation is safe, and is associated with recipients' immune modulation and a lower rate of obliterative bronchiolitis.

A clinical trial combining donor bone marrow infusion and heart transplantation: intermediate-term results.

BACKGROUND: Donor chimerism (the presence of donor cells of bone marrow origin) is present for years after transplantation in recipients of solid organs. In lung recipients, chimerism is associated with a lower incidence of chronic rejection. To augment donor chimerism with the aim to enhance graft acceptance and to reduce immunosuppression, we initiated a trial combining infusion of donor bone marrow with heart transplantation. Reported herein are the intermediate-term results of this ongoing trial. METHODS: Between September 1993 and August 1998, 28 patients received concurrent heart transplantation and infusion of donor bone marrow at 3.0 x 10(8) cells/kg (study group). Twenty-four contemporaneous heart recipients who did not receive bone marrow served as controls. All patients received an immunosuppressive regimen consisting of tacrolimus and steroids. RESULTS: Patient survival was similar between the study and control groups (86% and 87% at 3 years, respectively). However, the proportion of patients free from grade 3A rejection was higher in the study group (64% at 6 months) than in the control group (40%; P =.03). The prevalence of coronary artery disease was similar between the two groups (freedom from disease at 3 years was 78% in study patients and 69% in controls). Similar proportions of study (18%) and control (15%) patients exhibited in vitro evidence of donor-specific hyporesponsiveness. CONCLUSIONS: The infusion of donor bone marrow reduces the rate of acute rejection in heart recipients. Donor bone marrow may play an important role in strategies aiming to enhance the graft acceptance.

Experimental evaluation of a model for oxygen exchange in a pulsating intravascular artificial lung.

Intravascular oxygenation and carbon dioxide removal remains a potentially attractive means for respiratory support in patients with acute or chronic respiratory failure. Our group has been developing an intravascular hollow fiber artificial lung that uses a pulsating balloon located within the fiber bundle to augment gas transfer. We previously reported on a simple compartmental model for simulating O2 exchange in pulsating intravascular artificial lungs. In this study we evaluate the O2 exchange model with gas exchange and PO2 measurements performed on an idealized intravascular artificial lung (IIVAL) tested in a water perfusion loop. The IIVAL has well-defined bundle geometry and can be operated in balloon pulsation mode, or a steady perfusion mode for determining the mass transfer correlation required by the model. The O2 exchange rates and compartmental O2 tensions measured with balloon pulsation in the IIVAL are within 10% of model predictions for flow and pulsation conditions relevant to intravascular oxygenation. The experiments confirmed that a significant buildup of PO2 occurs within the fiber bundle, which reduces the O2 exchange rate. The agreement between experiments and predictions suggests that the model captures the cardinal processes dictating gas transfer in pulsating intravascular artificial lungs.

Validation of a model for flow-dependent carbon dioxide exchange in artificial lungs.

The exchange rate of CO2 in artificial lungs depends on the sweep gas flow rate. Control of the amount of CO2 removed by an artificial lung requires quantitative knowledge of the flow dependence. A simple model of the dependence of CO2 exchange on sweep gas flow rate in artificial lungs has been previously presented (1). For a given partial pressure of CO2 in the blood phase, sweep gas flow rate, and CO2 exchange rate, the model indicates how close the CO2 exchange rate is to the maximum level attainable by the artificial lung. The focus of this study was to validate the model experimentally by testing 2 commercial artificial lungs in an in vitro test loop. The CO2 exchange rate for each artificial lung was measured over a range of sweep gas flow rates. Linear regression was used to fit the data to the model and estimate the maximum possible CO2 exchange rate and the average water-side PCO2 (PCO2w). The difference between the measured and regressed values of PCO2w was used as an indicator of the ability of the model to quantitatively predict the dependence of CO2 exchange on gas flow rate. This difference was less than 5% for each experiment, indicating that the model can be used to guide control of CO2 exchange rates in artificial lungs.

Native heart complications after heterotopic heart transplantation: insight into the potential risk of left ventricular assist device.

BACKGROUND: In heterotopic heart transplantation, the donor heart is connected parallel to the recipient's diseased heart. Recipients continue to have risks, such as arrhythmia, thromboembolism, valvular heart disease, and ischemic heart disease which can develop in the native heart. It may serve as a clinical model to study long-term pathophysiologic processes in the native heart of patients with a left ventricular assist device. METHOD: We analyzed the prevalence of long-term complications related to the native heart in the heterotopic heart transplant and attempted to gain insight into the potential risk to a native heart after receiving a left ventricular assist device. RESULTS: Between December 1984 and December 1994, 16 patients (13 men, 3 women, ranging in age from 37 to 60 years) underwent heterotopic heart transplant at the University of Pittsburgh. The 1- and 5-year survival rate after the transplant was 81% and 44%, respectively. Actuarial freedom from complications related to the native heart after 1 year and 4 years was ventricular arrhythmia: 85%, 75%; ischemic disease: 85%, 64%; valvular disease: 100%, 88%; and thromboembolism: 85%, 58%. Of these complications, thromboembolism was not considered in determining actuarial freedom from complications because thromboembolism should be regarded as a device-related complication rather than as a native-heart-related complication for left ventricular assist device recipients. Consequently, actuarial freedom from all complications excluding thromboembolism was 70% after 1 year and 50% after 4 years. In addition, the hazard function curve remains constant up to 80 months after the operation without significant differences among the yearly ratios. CONCLUSIONS: This analysis suggests that cautious observation of the native heart's long-term performance is necessary for the left ventricular assist device recipient.

Transmyocardial laser revascularization in the patient with unmanageable unstable angina.

BACKGROUND: Transmyocardial laser revascularization (TMR) provides relief for patients with chronic angina, nonamenable to direct coronary revascularization. Unmanageable, unstable angina (UUA) defines a subset of patients with refractory angina who are at high risk for myocardial infarction and death. Patients were classified in the UUA group when they had been admitted to the critical care unit with unstable angina for 7 days with three failed attempts at weaning them off intravenous antianginal medications. METHODS: Seventy-six treated patients were analyzed to determine if TMR is a viable option for patients with unmanageable unstable angina. These patients were compared with 91 routine protocol patients (protocol group [PG]) undergoing TMR for chronic angina not amenable to standard revascularization. The procedure was performed through a left thoracotomy without cardiopulmonary bypass. These patients were followed for 12 months after the TMR procedure. Both unmanageable and chronic angina patients had a high incidence of at least one prior surgical revascularization (87% and 91%, respectively). RESULTS: Perioperative mortality (< or = 30 days post-TMR) was higher in the UUAG versus PG (16% vs 3%, p = 0.005). Late mortality, up to 1 year of follow-up, was similar (13% vs 11%, UUAG vs PG; p = 0.83). A majority of the adverse events in the UUAG occurred within the first 3 months post-TMR, and patients surviving this interval did well, with reduced angina of at least two classes occurring in 69%, 82%, and 82% of patients at 3, 6, and 12 months, respectively. The percent improvement in angina class from baseline was statistically significant at 3, 6, and 12 months. A comparable improvement in angina was found in the protocol group of patients. CONCLUSIONS: TMR carried a significantly higher risk in unmanageable, unstable angina than in patients with chronic angina. In the later follow-up intervals, however, both groups demonstrated similar and persistent improvement in their angina up to 12 months after the procedure. TMR may be considered in the therapy of patients with unmanageable, unstable angina who otherwise have no recourse to effective therapy in the control of their disabling angina.

Lung transplantation for end-stage pulmonary sarcoidosis.

BACKGROUND: Sarcoidosis is a multi-system granulomatous disease which can cause significant pulmonary morbidity and occasionally be fatal. The long term benefit of lung transplantation for this disorder are unknown. METHODS: A retrospective review was made of nine single lung transplant procedures performed at the University of Pittsburgh between March 1991 and March 1995 in patients with end-stage lung disease secondary to sarcoidosis. Two contemporaneous groups of recipients receiving transplants for COPD (n = 30) and inflammatory lung disease (n = 13) served as control groups. Surviving recipients underwent sequential surveillance bronchoscopy with transbronchial biopsy. RESULTS: All recipients survived beyond post-operative day (POD) 30, with 5 recipients currently alive. One year survival for this group was 6/9 (67%). Eight of the 9 sarcoidosis recipients had sequential lung biopsy procedures. Five of these 8 recipients (62.5%) had recurrence of granulomata in the lung allograft with the mean time to diagnosis of recurrent sarcoidosis being POD 224.2 +/- 291.3 (range POD 21-719). None of these 5 recipients had radiographic evidence or clinical symptoms related to granulomatous inflammation in the allograft. Pre-operative and post-operative spirometric values were available on 8 recipients. Vital capacity significantly improved in all recipients from 1.54 +/- 0.43 litres to 2.55 +/- 0.63 litres by POD 180 and was maintained through the fourth postoperative year (p < 0.05 Wilcoxon Signed Rank). Spirometric values were also compared before and after transplantation in the 5 recipients with granulomata in the allograft. Vital capacity significantly improved in these 5 recipients from 1.53 +/- 0.48 litres to 2.71 +/- 0.71 litres by POD 180 and was maintained throughout the first postoperative year (p < 0.05, Wilcoxon Signed Rank). The prevalence of high grade acute cellular rejection [ACR (histologic grades III and IV)] did not differ from that seen in a contemporaneous group of 30 single lung recipients who received allografts for COPD (p < 0.05 Mann-Whitney U), nor when compared to a group of 13 single lung recipients who received allografts for immunologically mediated lung disease (p < 0.05 Mann-Whitney U). The prevalence of chronic rejection (histologic obliterative bronchiolitis [OB]) in the sarcoidosis recipients was 4/8 (50%). In the controls with COPD recipients the prevalence of OB was 10/30 (33.3%), and in the 13 controls with immunologic disease it was 6/13 (46.2%). There was no significant difference in the prevalence of OB between the sarcoidosis recipients and controls. When analyzed to the fifth year after transplantation, freedom from the development of OB also failed to differ between these 3 groups (p = 0.25, Logrank, Mantel-Cox). CONCLUSIONS: Although granulomatous inflammation in the lung allograft is common following transplantation for sarcoidosis, it is not clinically or radiographically relevant. In addition, the prevalence of high grade ACR and histologic OB is no different when compared to other single lung recipients. For these reasons lung transplantation is a viable alternative for end-stage lung disease secondary to sarcoidosis.

Effect of ischemic time on survival in clinical lung transplantation.

BACKGROUND: While there is convincing evidence that prolonged ischemic times correlate with reduced long-term survival in heart transplantation, the effect of ischemic time on outcome in clinical lung transplantation remains controversial. To assess the effect of ischemic time on outcomes in lung transplantation, we reviewed our experience. METHODS: The study was performed by retrospective chart review. RESULTS: First-time lung transplantation was performed on 392 patients between 1988 and 1998. All grafts were flushed with cold crystalloid preservation solution and stored on ice. Ischemic time data were available for 352 of 392 (90%) patients. Ischemic times were grouped as follows: 0 to 4 hours (n = 91), 4 to 6 hours (n = 201), more than 6 hours (n = 60). Ischemic time did not correlate with survival: 3-year actuarial survival = 56% (0 to 4 hours), 58% (4 to 6 hours), 68% (> 6 hours), p = 0.58. There was no significant difference in the incidence of biopsy-proven diffuse alveolar damage in the first 30 days after transplantation (31%, 32%, 38%), episodes of acute rejection in the first 100 days after transplantation (1.9, 1.8, 1.7), duration of intubation (median 3, 4, 3 days), or incidence of obliterative bronchiolitis (23%, 28%, 26%) between the three groups (0 to 4 hours, 4 to 6 hours, > 6 hours, respectively). A diagnosis of diffuse alveolar damage was associated with a significantly worse outcome (1-year survival = 82% versus 54%, p < 0.0001). CONCLUSIONS: In contrast to heart transplantation, pulmonary allograft ischemic time up to 9 hours does not appear to have a significant impact on early graft function or survival. The presence of diffuse alveolar damage on biopsy early after transplantation does not correlate with prolonged ischemic time, but is associated with substantially reduced posttransplantation survival.

Traumatic aortic rupture: diagnosis and management.

BACKGROUND: Traumatic aortic rupture is a relatively uncommon lesion that presents the cardiothoracic surgeon with unique challenges in diagnosis and management. To address controversial aspects of this disease, we reviewed our experience. METHODS: The study was performed by retrospective chart review. RESULTS: Forty-two patients with traumatic thoracic aortic ruptures were managed between January 1988 and June 1997. Nine arrived without vital signs and died in the emergency department. Admission chest radiographs were normal in 3 patients (12%) and caused significant delays in diagnosis. Four of 30 patients admitted with vital signs had rupture before thoracotomy and died. Twenty-six underwent aortic repair. In 1 patient repair was performed with simple aortic cross-clamping, whereas a second was managed with a Gott shunt. The remaining 24 patients had repair with partial left heart bypass. In 1 patient hypothermic circulatory arrest was required. Two patients (7.7%) died. There were no cases of new postoperative paraplegia in the bypass group. There was no morbidity directly attributable to the administration of heparin for cardiopulmonary bypass. CONCLUSIONS: In a discrete group of patients with traumatic rupture of the aorta, the rupture will become complete during the first few hours of hospital admission; aggressive medical treatment with beta-blockade and vasodilators in the interval before the operation is an essential aspect of management. Active distal circulatory support with partial left-heart bypass provides the optimal means of preventing spinal cord ischemia during repair of acute traumatic aortic rupture.

Surgical treatment of lipomatous hypertrophy of the interatrial septum.

We report a case of lipomatous hypertrophy of the interatrial septum in a patient with a recent syncopal episode and shortness of breath. Preoperative transesophageal echocardiography demonstrated a large tumor protruding from the interatrial septum. In addition, the patient was found to have significant coronary artery disease and a right internal carotid artery stenosis. The patient underwent successful resection of the mass with septal reconstruction, aortocoronary bypass, and right carotid endarterectomy. Histology of the mass was consistent with lipomatous hypertrophy.

Cardiopulmonary bypass is associated with early allograft dysfunction but not death after double-lung transplantation.

OBJECTIVES: To assess the effect of cardiopulmonary bypass on allograft function and recipient survival in double-lung transplantation. METHODS: Retrospective review of 94 double-lung transplantations. RESULTS: Cardiopulmonary bypass was used in 37 patients (CPB); 57 transplantations were accomplished without bypass (no-CPB). Bypass was routinely used for patients with pulmonary hypertension (n = 27) and for two recipients undergoing en bloc transplantation. Cardiopulmonary bypass was required in eight (12.3%) of the remaining 65 patients. Mean ischemic time was longer in the CPB group (346 vs 315 minutes, p = 0.04). The CPB group required more perioperative blood (11.4 vs 6.0 units, p = 0.01). Allograft function, assessed by the arterial/alveolar oxygen tension ratio, was better in the no-CPB group at 12 and 24 hours after operation (0.54 vs 0.39 at 12 hours, p = 0.002; and 0.63 vs 0.38 at 24 hours, p = 0.001). The CPB group had more severe pulmonary infiltrates at both 1 and 24 hours (p = 0.005). Diffuse alveolar damage was more common in the CPB group (69% vs 35%, p = 0.002). Median duration of intubation was longer in the CPB group (10 days) than in the no-CPB group (2 days, p = 0.002). The 30-day mortality rate (13.5% vs 7.0% in the CPB and no-CPB groups) and 1-year survival (65% vs 67%, CPB and no-CPB) were not significantly different. CONCLUSIONS: In the absence of pulmonary hypertension, cardiopulmonary bypass is only occasionally necessary in double-lung transplantation. Bypass is associated with substantial early allograft dysfunction after transplantation.

Retinoic acid regulation of renal tubular epithelial and vascular smooth muscle cell function.

Vitamin A and its derivatives have been postulated to play an important role in renal tubulogenesis and compensatory hypertrophy. This study examined the effects of two carboxylic derivatives of vitamin A on Lewis lung carcinoma-porcine kidney-1 (LLC-PK1) renal tubular epithelial cell mito- and motogenesis and cell size. It was found that all-trans and 13-cis retinoic acids exerted modest, dose-dependent effects to stimulate incorporation of 3H-thymidine into acid-precipitable material of LLC-PK1 cells. The effects of all-trans retinoic acid to promote 3H-thymidine uptake in LLC-PK1 cells modestly enhanced that seen with acidic fibroblastic growth factor. Similar findings of these two retinoic acid derivatives to promote 3H-thymidine uptake and to enhance 3H-thymidine uptake stimulated by another growth factor (platelet-derived growth factor BB) were also observed in cultured bovine aortic smooth muscle cells. Both retinoic acids promoted healing of denuded areas made within confluent monolayers of serum-starved LLC-PK1 cells. All-trans retinoic acid also stimulated recovery of mechanically denuded areas within bovine aortic smooth muscle monolayers. Neither all-trans nor 13-cis retinoic acids s affected cell size as assessed by forward light scatter with flow cytometry, suggesting lack of effect to induce hypertrophy. These results demonstrate that two carboxylic acid derivatives of vitamin A are capable of stimulation of basal and growth factor-induced incorporation of 3H-thymidine uptake into acid-precipitable material and healing of denuded areas in disparate cell types. These findings are compatible with a role for vitamin A and its analogues in the tissue repair process.