Clinical use of tissue plasminogen activator for systemic thrombolysis in dogs and cats.

INTRODUCTION: Systemic administration of tissue plasminogen activator (tPA) is seldomly reported in dogs and cats. ANIMALS: Client-owned animals receiving tPA (2010-2020). MATERIALS AND METHODS: Medical records of dogs and cats receiving tPA for distant known/suspected thrombus were reviewed. Fourteen dog visits (24 injections) and five cat visits (six injections) were included. RESULTS: Canine known/suspected thrombus included pulmonary thromboembolism (n=6), intracardiac thrombus (n=4), aortic thrombus (n=1), cranial vena cava thrombus (n=2), and femoral and iliac veins thrombus (n=1). Various canine primary diseases were represented, but open-heart surgery was the most common cause. Median time between diagnosis/suspicion of thrombus and tPA injection was 24.5 h (range, 3-150 h). Mean total tPA dose was 1.0±0.78 mg/kg. Clinical improvement occurred in 93% of dogs. Non-fatal complications were reported in 14% of dogs. Dogs' survival to discharge was 78.6% without identifiable non-survivor characteristics. Feline known/suspected thrombus included unilateral feline aortic thromboembolism (FATE) (n=2), bilateral FATE (n=2), and right renal artery thrombus. Feline primary diseases included cardiomyopathy (n=5). Median time between diagnosis/suspicion of thrombus and tPA injection was 4 h (range, 2-17 h) and median total tPA dose was 1.0 mg/kg (range, 0.6-1.4 mg/kg).Clinical improvement occurred during 40% of the visits. All cats (n=3) with acute kidney injury (AKI) at admission developed worsening AKI and reperfusion injury. Of the remaining two visits, one developed a non-fatal AKI. Cats' survival to discharge was 40%. CONCLUSIONS: Systemic thrombolysis with tPA seems to be effective and safe in dogs. More investigation is needed in cats.

Trifoliate left atrioventricular valve with and without intact septal structures in four dogs: echocardiographic findings and surgical repair.

Trifoliate left atrioventricular (AV) valve with common atrioventricular junction is considered part of the spectrum of atrioventricular septal defect. This valve morphology is typically associated with defects in the AV septum resulting in communication at the atrial or ventricular level, but has also been described as an isolated defect in the setting of a common AV junction without AV septal defect. Trifoliate left AV valve exhibits a line of apposition between the bridging leaflets that is directed toward the inlet interventricular septum, distinguishing it from isolated mitral valve cleft in which the orientation of the bridging leaflets are toward the left ventricular outflow tract. The echocardiographic findings of four dogs with trifoliate left AV valve are described; two with intact septal structures and two with large ostium primum defects. Three dogs underwent open surgical repair using different approaches depending on the presence or absence of a septal defect. One of these underwent concurrent surgical repair for right AV valve dysplasia. One dog with intact septal structures underwent interventional closure of a concurrent patent ductus arteriosus. Current terminology associated with trileaflet left AV valve malformations is reviewed.

Phase I clinical trial of an antithrombotic drug protocol combining apixaban and clopidogrel in dogs.

INTRODUCTION: Combining an antiplatelet drug, clopidogrel, with the direct oral Factor Xa inhibitor, apixaban, could provide an effective antithrombotic strategy in dogs. Thus, a limited 3 + 3 phase I dose-escalation clinical trial in healthy dogs was conducted to evaluate bleeding (primary end-point) and pharmacodynamic (PD)/pharmacokinetic (PK) parameters (secondary end-point). ANIMALS: Eleven beagle dogs, median body weight 10.2 kg (9.7-10.9 kg), were enrolled. METHODS: Four doses of apixaban (three dogs/dose) administered for eight days. Clopidogrel dose was fixed at 18.75 mg per os (PO) q 24 h with escalation of apixaban dose at 5 mg PO q 12 h, 5 mg PO q 8 h, 10 mg PO q 12 h, and 10 mg PO q 8 h. Laboratory testing included fecal occult blood, coagulation parameters, Factor X activity, apixaban concentration, platelet aggregometry, and thromboelastography on days 1, 3, and 8. RESULTS: Evidence of bleeding was not observed at any dosage. Dose-dependent changes in PD/PK parameters between baseline and 3 h post-medication were observed including a prolongation of prothrombin time, a prolongation of activated partial thromboplastin time, a decrease of Factor X activity level, and increased apixaban concentration. CONCLUSIONS: The combination of apixaban at a dosage range of approximately 0.5 mg/kg PO q 12 h to 1 mg/kg PO q 8 h and clopidogrel at approximately 1.8 mg/kg PO q 24 h did not cause bleeding over a one-week period in healthy dogs. Clinically relevant changes in PD/PK data occur at all dosage levels. This study provides a starting point for longer-term clinical trials to determine safety and efficacy.

Dilatable pulmonary artery banding for ventricular septal defect: surgical technique and case report of three cats.

Pulmonary artery banding (PAB) is a viable but underreported palliative option for hemodynamically significant ventricular septal defect in small animals. A significant challenge associated with PAB is judging the degree of band tightening, which can be further complicated when animals are immature and still growing at the time of PAB. If a pulmonary artery band is overtightened or becomes progressively too tight after surgery, the result can be reversal of shunt flow with potentially devastating consequences. Placement of a band that could be percutaneously dilated using a balloon catheter affords a minimally invasive option for partially or completely relieving the band should it become too tight after PAB. This report describes a surgical technique for placement of a dilatable pulmonary artery band, reviews guidelines for tightening the band, and reports the outcome of three cats undergoing the procedure. All three cats showed evidence of reduced hemodynamic load after PAB for a period of up to three years after PAB.

Open surgical repair of tetralogy of Fallot in dogs.

Tetralogy of Fallot is a congenital heart defect that causes cyanosis, severe progressive weakness and activity intolerance, polycythemia, and shortened life span in dogs. Open surgical repair of tetralogy of Fallot consisting of closure of the ventricular septal defect and reconstruction of the right ventricular outflow tract via a right ventriculotomy during cardiopulmonary bypass is feasible in severely affected dogs. Successful surgical repair can completely resolve clinical signs associated with the defect.

Intrapericardial cyst causing cardiac tamponade in a cat.

A two-year-old cat with episodic dyspnea was diagnosed with an intrapericardial cyst via two-dimensional echocardiography. The cyst directly compressed the right ventricle, resulting in cardiac tamponade. Centesis of the cyst was performed to reduce tamponade prior to surgery. At surgery, a large, fluid-filled cystic structure was found within the pericardium. The cystic structure was continuous with a pedicle of liver that passed through a small peritoneopericardial diaphragmatic hernia. Surgical resolution was achieved by median sternotomy, midline pericardotomy, resection of the cyst, and diaphragmatic herniorrhaphy.

Influence of open surgical correction on intermediate-term outcome in dogs with subvalvular aortic stenosis: 44 cases (1991-1998).

OBJECTIVE: To compare outcome and intermediate-term survival for dogs undergoing open surgical correction of subvalvular aortic stenosis (SAS) with those for dogs with SAS that did not undergo surgery. DESIGN: Retrospective study. ANIMALS: 44 dogs with congenital SAS. PROCEDURE: Maximum instantaneous systolic pressure gradients were determined by use of Doppler echocardiography. Cardiopulmonary bypass and open surgical correction of SAS (membranectomy with or without septal myectomy) was performed in 22 dogs, whereas 22 dogs did not undergo surgical correction. Cumulative survival was compared between surgical and nonsurgical groups, using Kaplan-Meier nonparametric analysis and a Mantel-Cox log-rank test. RESULTS: Initial systolic pressure gradients were not significantly different for dogs undergoing surgery (128 +/- 55 mm Hg), compared with those that did not undergo surgery (117 +/- 57 mm Hg). Systolic pressure gradients were significantly decreased after surgery in dogs that underwent surgery (54 +/- 27 mm Hg). Cumulative survival was not significantly different between dogs in the surgical and nonsurgical groups. Censoring surgery-related mortality in the analysis still did not reveal a significant difference in cumulative survival between the surgical and nonsurgical groups. CONCLUSIONS AND CLINICAL RELEVANCE: Despite reductions in the systolic pressure gradient and possible associated improvement in exercise tolerance, a palliative benefit on survival was not documented in dogs undergoing surgery for SAS.

Neuromuscular function of the latissimus dorsi muscle in goats after dynamic cardiomyoplasty.

Skeletal muscle deterioration is emerging as a limitation to long-term cardiac assist by dynamic cardiomyoplasty. Chronic electrical stimulation of in situ skeletal muscle showed that ischemia, decreased muscle preload, muscle overuse, and chronic electrical stimulation are factors for muscle deterioration. Transposition around the heart has been associated with signs of muscle denervation after chronic electrical stimulation. To evaluate latissimus dorsi muscle neuromuscular function after longterm dynamic cardiomyoplasty, we performed neuromuscular functional analysis and histology on the latissimus dorsi muscle and thoracodorsal nerve of six normal goats and six goats after 6 months of dynamic cardiomyoplasty. Electromyographic analysis showed positive sharp waves and fibrillation potentials in the latissimus dorsi of three goats from the dynamic cardiomyoplasty group. Conduction velocity of the thoracodorsal nerve of goats from the dynamic cardiomyoplasty group (58.32+/-9.80 m/s) was reduced compared to the goats from the control group (71.48+/-5.71 m/s, P = 0.02). Histologic changes in skeletal muscle were compatible with denervation. Loss of myelin sheaths, collapse of endoneurial connective tissue, and solitary foci of axonophagia and myelinophagia further documented severe injury to the thoracodorsal nerve in goats from the dynamic cardiomyoplasty group. The latissimus dorsi muscle wrap was denervated after long-term dynamic cardiomyoplasty. Traction on the neurovascular pedicle at each contraction of the transposed muscle may induce afferent axonal injury of the thoracodorsal nerve resulting in diminished muscular function.

A canine model of heart failure by intracoronary adriamycin injection: hemodynamic and energetic results.

BACKGROUND: To eliminate the noncardiac toxicities associated with Adriamycin (Pharmacia Upjohn, Kalamazoo, MI) and to avoid the need for surgical implantation of a coronary artery catheter, we proposed serial intracoronary infusions of Adriamycin (Pharmacia Upjohn) with a Judkins catheter to develop a nonsurgical but selective model of dilated cardiomyopathy in dogs. METHODS AND RESULTS: Twenty-two dogs were entered onto the study. Each dog received four weekly injections of Adriamycin (Pharmacia Upjohn; 15 mg/wk) through a Judkins catheter and verapamil orally (5 mg/kg twice daily) for 4 weeks. Dogs were evaluated with echocardiography, right-sided cardiac catheterization, and endomyocardial biopsy at times 0 and 10 weeks. The left ventricular ejection fraction decreased from 0.65 +/- 0.04 to 0.48 +/- 0.11 (P = .0006). The left ventricular end-diastolic and end-systolic diameter indices increased from 42.00 +/- 2.17 to 46.92 +/- 5.81 mm (P = .0029) and from 27.65 +/- 2.59 to 35.00 +/- 6.84 mm, respectively (P = .0210). The mechanical cardiac efficiency decreased from 28.55% +/- 13.30% at baseline and 15.64% +/- 9.09% at 10 weeks (P = .001). Cardiac myocyte vacuolation was present on histological examination at 10 weeks. The mortality rate was 41%. Minimal systemic Adriamycin (Pharmacia Upjohn) toxicity was noticed. CONCLUSION: Intracoronary injection of Adriamycin (Pharmacia Upjohn) in dogs induced a chronic dilated cardiomyopathy.

Clinical characteristics of 53 dogs with Doppler-derived evidence of pulmonary hypertension: 1992-1996.

Pulmonary hypertension occurs as a primary or secondary disorder of the pulmonary vasculature. Doppler echocardiography provides a noninvasive tool for the estimation of pulmonary arterial pressure when tricuspid regurgitation or pulmonic insufficiency is present. The cardiology database at Colorado State University was reviewed, and echocardiographic records from cases diagnosed with pulmonary hypertension were evaluated. Application of the modified Bernoulli equation to the maximal instantaneous velocity of a right-sided regurgitant jet provided evidence of pulmonary hypertension in 53 dogs over a 4-year period. Tricuspid regurgitant velocity > or = 2.8 m/second or pulmonic insufficiency velocity > or = 2.2 m/second was considered abnormal and indicative of pulmonary hypertension. Tricuspid regurgitant gradients in 51 dogs ranged from 32 to 145 mm Hg (mean, 63.0 mm Hg; median, 57.0 mm Hg; 25th-75th percentiles, 45.2-76.5 mm Hg). Pulmonic insufficiency gradients in 8 dogs ranged from 20 to 100 mm Hg (mean, 59.5 mm Hg; median, 61.5 mm Hg; 25th-75th percentiles, 32.0-84.5 mm Hg). Affected dogs ranged in age from 2 months to 16 years. Clinical signs were characteristic of cardiopulmonary disease, but a relatively high frequency of syncope was noted (12 of 53 dogs, 23%). Pulmonary hypertension was probably due to increased pulmonary vascular resistance in 23 dogs, pulmonary overcirculation in 2 dogs, and pulmonary venous hypertension in 23 dogs. Five dogs lacked a clinically recognizable cardiopulmonary cause of pulmonary vascular disease. Our results suggest that pulmonary hypertension can occur as a complication of commonly encountered cardiopulmonary diseases, and that Doppler echocardiography can facilitate recognition of this condition.

Fluoroscopic determination of latissimus dorsi muscle shortening fraction after dynamic cardiomyoplasty.

Optimization of the skeletal muscle contraction during cardiac assist is important to achieve maximal cardiac assist and yet avoid overstimulation that may injure skeletal muscle. Dynamic cardiomyoplasty suffers from lack of an objective, reproducible, and accurate technique to measure skeletal muscle shortening fraction after wrap and training of the muscle. A recruitment curve is considered the best way to select the proper stimulation level to achieve supramaximal contraction without overstimulating the muscle. A fluoroscopic technique of determining latissimus dorsi recruitment curve was evaluated in five goats undergoing dynamic cardiomyoplasty with an anterior cardio-subcutaneous wrap. Two pairs of stainless steel targets (0.5 and 1 cm of diameter) were implanted on each side of the muscle wrap. One pair of sonomicrometer crystals was also implanted. Displacement of the targets was measured under fluoroscopy at five different stimulation levels. Correlation coefficients between targets on the inside surface of the wrap and the sonomicrometer crystals, and targets on the outside surface of the wrap and the sonomicrometer crystals were 0.71 (P < 0.05) and 0.60 (P < 0.05), respectively. Targets on the inside surface of the wrap were more accurate than targets on the outside surface of the wrap for measurement of skeletal muscle shortening fraction and establishment of a recruitment curve. Adverse effects from the targets were not observed.

Atrioventricular septal defects in three llamas (Lama glama).

Two half-sibling neonatal llamas (Lama glama) and one unrelated adult llama were presented with various complaints, including failure to thrive, respiratory distress, and excessive recumbency. The related camelids were born in successive years to the same dam but from unrelated sires. Thoracic auscultation revealed significant systolic and diastolic murmurs on both sides of the chest in all three llamas, and arterial blood gas evaluation revealed hypoxemia in two llamas. Echocardiographic examinations revealed large atrioventricular septal (AVS) defects in all three llamas. Two llamas were euthanized after diagnosis and the third died 4 mo later. Postmortem examination confirmed large AVS defects in all animals. There also was marked cardiomegaly in each animal. The discovery of such a cardiac anomaly in these three camelids suggests that it may be common in this species and may have a genetic basis.

Lung endothelial cell proliferation in normal and pulmonary hypertensive neonatal calves.

Tremendous changes in pressure and flow occur in the pulmonary and systemic circulations after birth, and these hemodynamic changes should markedly affect endothelial cell replication. However, in vivo endothelial replication rates in the neonatal period have not been reported. To label replicating endothelial cells, we administered the thymidine analog bromodeoxyuridine to calves approximately 1, 4, 7, 10, and 14 days old before they were killed. Because we expected the ratio of replicating to nonreplicating cells to vary with vascular segment, we examined the main pulmonary artery, a large elastic artery, three sizes of intrapulmonary arteries, the aorta, and the carotid artery. In normoxia for arteries < 1,500 micron, approximately 27% of the endothelial cells were labeled on day 1 but only approximately 2% on day 14. In the main pulmonary artery, only approximately 4% of the endothelial cells were labeled on day 1 and approximately 2% on day 14. In contrast, in the aorta, approximately 12% of the endothelial cells were labeled on day 1 and approximately 2% on day 14. In chronically hypoxic animals, only approximately 14% of the endothelial cells were labeled on day 1 in small lung arteries and approximately 8% were still labeled on day 14. We conclude that the postnatal circulatory adaptation to extrauterine life includes significant changes in endothelial cell proliferation that vary dramatically with time and vascular location and that these changes are altered in chronic hypoxia.

Surgical correction of cor triatriatum sinister in a kitten.

A seven-month-old, male domestic shorthair was presented for respiratory distress. Cor triatriatum sinister was diagnosed based on echocardiography. Surgical dilatation and tearing of the anomalous membrane dividing the left atrium resulted in resolution of clinical signs. Intraoperative echocardiography was used to evaluate the adequacy of the repair.

Analysis of prognostic indicators for dogs with pericardial effusion: 46 cases (1985-1996).

OBJECTIVE: To determine factors associated with disease-free interval and survival time for dogs with pericardial effusion. DESIGN: Retrospective study. ANIMALS: 46 dogs. PROCEDURE: Signalment, history, results of physical examination, electrocardiography, echocardiography, and thoracic radiography; disease-free interval; and survival time were obtained from medical records or telephone conversations with owners and referring veterinarians. RESULTS: Dogs that had ascites at the time of the initial physical examination were significantly less likely, and dogs that had evidence of pulmonary metastases on thoracic radiographs or that had echocardiographic evidence of a right atrial mass were significantly more likely, to have died of pericardial effusion or the underlying cause of effusion than were dogs that did not. Median survival time was 15.3 months for dogs with idiopathic pericardial effusion, 16 days for dogs with hemangiosarcoma, and 13.6 months for dogs with mesothelioma. Dogs that had a nonspecific extracardiac mass and underwent pericardiectomy were significantly less likely to have had recurrence of signs than were dogs that did not. However, dogs with mesothelioma or hemangiosarcoma that underwent pericardiectomy did not have a significantly different risk of recurrence of signs or survival time, compared with dogs that did not. CLINICAL IMPLICATIONS: Results suggest that pericardiectomy will not affect risk of recurrence or survival time in dogs with pericardial effusion secondary to hemangiosarcoma or mesothelioma. However, pericardiectomy is still needed to differentiate dogs with neoplastic pericardial effusion from dogs with idiopathic pericardial effusion.

Myocardial oxygen consumption is affected by dynamic cardiomyoplasty in dogs with adriamycin-induced cardiomyopathy.

The purpose of the study was to investigate a possible myocardial sparing effect by dynamic cardiomyoplasty. We directly measured cardiac work and myocardial oxygen consumption after dynamic cardiomyopathy in dogs with adriamycin-induced cardiomyopathy. Ten dogs with cardiomyopathy induced by 4 weekly intracoronary infusions of adriamycin were studied. Five dogs underwent right latissimus dorsi cardiomyoplasty with progressive myostimulation, and five served as controls. Right heart and coronary sinus catheterizations were performed at 0, 10, and 15 weeks. Four and two dogs, respectively, the cardiomyoplasty and the control group, survived until 15 weeks. Cardiac work was not different between the control and the cardiomyoplasty groups (p = 0.42). Myocardial oxygen consumption was less in the cardiomyoplasty group (185.70 +/- 37.22; 165.75 +/- 25.86; 161.40 +/- 54.14 J/min at 0, 10, and 15 weeks, respectively) compared to the control group (147.80 +/- 70.99; 275.00 +/- 103.24; 263.50 +/- 52.75 J/min at 0, 10, and 15 weeks, respectively, p = 0.019). Mechanical cardiac efficiency was not meaningfully different between the cardiomyoplasty group (16.08% +/- 5.39%; 20.51% +/- 5.89%; 20.67% +/- 11.98% at 0, 10, and 15 weeks, respectively) compared to the control group (15.29% +/- 8.06%; 9.40% +/- 1.22%; 13.40% +/- 2.29% at 0, 10, and 15 weeks, respectively, p = 0.093). Acute changes of the cardiosynchronization ratio (2:1, 1:1, OFF) did not affect myocardial oxygen consumption or cardiac work within the cardiomyoplasty group. Dynamic cardiomyoplasty reduced myocardial oxygen consumption in dogs with adriamycin-induced cardiomyopathy.

Diagnosis and surgical repair of partial atrioventricular septal defects in two dogs.

Partial atrioventricular (AV) septal defects consist of an ostium primum defect and malformation of the septal cusp of the mitral valve. A partial AV septal defect was diagnosed by means of echo-cardiography in 2 dogs. Transatrial septal blood flow was high enough in both dogs to warrant surgical correction. Defects were repaired through right fifth intercostal thoracotomies, with the aid of cardiopulmonary bypass. An incision was made in the right atrium to expose the AV septal defect, and the mitral valve was inspected through the septal defect. The cleft in the septal cusp of the mitral valve was repaired with mattress sutures of 6-0 polypropylene. The septal defect was closed with autogenous pericardium harvested from the right aspect of the pericardial sac. Both dogs survived surgery and were alive 15 and 42 months, respectively, after surgery, however, 1 dog developed progressive mitral regurgitation after surgery. Partial AV septal defects can be successfully repaired in dogs. Long-term prognosis probably depends on the adequacy of the mitral valve repair.

Hypoxia increases bromodeoxyuridine labeling indices in bovine neonatal pulmonary arteries.

Thickening of peripheral pulmonary arteries (PA) in the pulmonary hypertensive neonate has been well described morphologically, but less is known regarding the role of cell proliferation in either the normal or hypertensive neonatal PA. Thus we studied DNA synthetic indices in the tunica media and tunica adventitia of four different sizes/generations of PA in normoxic calves (n = 15) and calves exposed to hypobaric hypoxia (n = 15) during the first 14 days of life. DNA synthetic indices were determined by incorporation of the thymidine analogue bromodeoxyuridine (BrdU). Hemodynamic studies confirmed a steady decline in PA pressure in normal neonatal calves during the first 2 wk of life and progressive pulmonary hypertension in the hypoxic group. Lungs were perfusion-fixed and pulmonary arteries were evaluated for BrdU incorporation by immunohistochemistry. DNA synthetic indices (BrdU-labeled cells/1,000 cells) in the tunica media from normoxic calves were highest between 4 and 7 days postpartum and decreased to their lowest levels by day 14. The highest indices were observed in smaller generations of PA in the normoxic newborn. Adventitial cells exhibited the same general pattern of BrdU incorporation except that the postpartum peak occurred earlier, at 1 to 4 days. Exposure to hypoxia significantly increased (P = 0.001) DNA synthetic indices in both the tunica media and adventitia. The highest DNA synthetic indices were observed in smaller-generation vessels. These findings indicate that the fraction of cells traversing the S phase (i.e., actively replicating in the cell cycle) in the normal neonatal pulmonary vasculature during transition are initially high compared to reported rates in hilar PA from adult rats, but then decrease by 14 days after birth. Further, exposure to hypoxia during transition dramatically increases and prolongs pulmonary vascular cell proliferation. We conclude that structural remodeling in the hypertensive neonatal PA is due partly to increased cell proliferation in the tunica media and adventitia.

Open resection for subvalvular aortic stenosis in dogs.

OBJECTIVE: To describe the surgical technique for open resection of congenital subvalvular aortic stenosis in dogs and to determine outcome of dogs undergoing the procedure. DESIGN: Uncontrolled clinical trial. ANIMALS: 17 dogs with congenital discrete subvalvular aortic stenosis. PROCEDURE: Dogs were placed on cardiopulmonary bypass by catheterizing the femoral artery and both vena cavae. The aorta was cross clamped, and cold cardioplegia solution was administered. The aortic root then was opened with a curvilinear incision. A subvalvular discrete fibrous ring was resected in all dogs. Septal myectomy was performed simultaneously on 11 dogs. RESULTS: 15 of 17 dogs survived the operation and were discharged from the hospital. Mean +/- SD maximal instantaneous aortic systolic pressure gradient measured by means of Doppler echocardiography was significantly reduced from 119 +/- 42 mm of Hg before surgery to 41 +/- 10 mm of Hg 12 months after surgery. Despite substantial reduction in the systolic pressure gradient, 4 of 15 dogs died suddenly between 7 days and 30 months after surgery. Three of the 4 dogs that died suddenly had pressure gradients > or = 180 mm of Hg and ventricular tachycardia before surgery. Eleven dogs were still alive between 1 and 48 months after surgery. CLINICAL IMPLICATIONS: The procedure resulted in substantial reductions in systolic pressure gradients in dogs with severe congenital subvalvular aortic stenosis. However, some dogs with severe aortic stenosis died suddenly after surgery. Thus, this surgery should not be considered curative. Proof of a survival benefit in dogs undergoing this surgery will have to await longer term follow-up.

Tropoelastin gene expression in individual vascular smooth muscle cells. Relationship to DNA synthesis during vascular development and after arterial injury.

After vascular injury, quiescent adult smooth muscle cells (SMCs) revert to a more immature synthetic-state phenotype concomitant with the onset of cell replication. The relationship between SMC proliferation and the reexpression of genes characteristic of immature SMCs (eg,tropoelastin [TE]), on an individual cell basis, has not been determined. Using a combined bromodeoxyuridine (BrdU) immunocytochemistry-TE in situ hybridization technique, we determined the relationship between DNA synthesis and TE gene expression in the rat vascular wall during development of the aortic media (embryonic days 13 to 18), low but detectable levels of TE expression occurred equally in both replicating and nonreplicating SMCs. TE message levels dramatically increased in the late fetal and early postnatal periods (fetal day 19 to 1 month postpartum), after a precipitous drop in SMC replication, and then decreased to undetectable levels by postpartum day 60. After a balloon catheter injury in the adult, a developmental sequence of SMC replication followed by TE gene expression was reiterated in both the media and in the developing neointima. On an individual cell basis, adult SMCs replicating after injury expressed little or no TE message; detectable TE gene expression occurred only in nonreplicating SMCs. The most important implications of these data are that (1) adult SMCs replicating after injury appear to revert to a pre-elastogenic embryonic phenotype; (2) maximal TE expression occurs in SMCs only after the cessation of cell replication; and (3) in both the media and the neointima, adult SMCs responding to injury undergo temporarily sequential changes in phenotype reflective of SMC development.