Outcomes after heart transplantation in patients with and without pretransplant renal dysfunction.

OBJECTIVE: To compare long-term survival and incidence of ESRD between patients with and without preoperative renal dysfunction following heart transplantation. DESIGN: Fifty consecutive patients with preoperative estimated GFR < or = than 50 ml/min were compared with 50 age-matched patients with estimated GFR > or = than 80 ml/min who underwent heart transplantation between 1994 and 1998. We investigated two primary outcomes: death and development of ESRD. We also analyzed risk factors. RESULTS: Eight patients (16%) developed ESRD and 19 (38%) died in the control group whereas 10 patients (20%) developed ESRD and 26 (52%) died in the renal failure group during a mean follow-up period of 6.74 +/- 3.31 years. Survival and time to ESRD were not significantly different. In univariate and multivariate analysis, waiting time was the only risk factor found to predict mortality but not ESRD. High cyclosporine levels were only found to be associated with lower estimated GFR (p < 0.009). Among the control group, mortality was significantly higher in the subgroup of patients that developed > or = 50% reduction of estimated GFR at the end of the first post transplant year (p < 0.05). CONCLUSIONS: This study suggests that low pre-transplant estimated GFR may not accurately predict long-term development of ESRD.

Novel experimental model of pressure overload hypertrophy in rats.

BACKGROUND: We studied a novel animal model of pressure overload hypertrophy in transition to heart failure following ascending aortic constriction. We sought to assess chronologic changes in hemodynamic parameters, echocardiographic signs of left ventricular (LV) remodeling, exercise tolerance, and profiles of systemic and local inflammation. MATERIALS AND METHODS: A cohort of Sprague Dawley rats underwent aortic constriction proximal to the innominate artery and were followed by echocardiography. A group of animals were euthanized 20 wk after aortic constriction, before any detectable decline in fractional shortening (normal fractional shortening (FS) or control group; n = 6). When additional animals reached an absolute 25% decline in fractional shortening, they were randomized to be euthanized on d 0 (25% downward arrow FS group; n = 5), or d 21 (>25% downward arrow FS group; n = 6). Hemodynamic and echocardiographic assessment, swim testing to exhaustion, and measurement of systemic and local inflammatory markers was performed at each time interval. RESULTS: An absolute decline of 25% in FS after aortic constriction was observed between 24 and 28 wk for most animals. The transition from compensated to decompensated hypertrophy was associated with markedly decreased dP/dt(max) and dP/dt(min), increased LV end-systolic diameter and LV end-diastolic diameter, stabilization of LV free wall diameter, decreased exercise performance and up-regulation in expression of interleukin-1, interleukin-6, tumor necrosis factor-alpha, and atrial natriuretic peptide. All animals developed heart failure. CONCLUSIONS: This study demonstrates that proximal aortic constriction in young rats represents an excellent experimental model of pressure overload hypertrophy that may be useful for testing the efficacy of novel therapies for the treatment of heart failure.

Intracystic breast carcinoma in a male: Unusual case presentation and literature review.

Breast carcinoma in males is rare and accounts for 0.5-1.5% of all breast carcinomas. Intracystic breast carcinoma is distinctly uncommon and represents approximately 5-7.5% of all breast cancers in males. On physical examination and radiologic imaging, these lesions often appear benign; however, the presence of an intracystic solid component is typical and should raise the suspicion of carcinoma. We report an unusual case of intracystic breast carcinoma presenting in a male and review the literature.

Right ventricular beneficial effects of beta adrenergic receptor kinase inhibitor (betaARKct) gene transfer in a rat model of severe pressure overload.

Heart failure is associated with abnormalities in betaAR cascade regulation, calcium cycling, expression of inflammatory mediators and apoptosis. Adenoviral mediated gene transfer of betaARKct has beneficial indirect effects on these pathologic processes upon the left ventricular myocardium. The concomitant biochemical changes that occur in the right ventricle have not been well characterized. Sprague-Dawley rats underwent aortic banding and were followed by echocardiography. After a decrease in fractional shortening of 25% from baseline, intracoronary injection of adenoviral-betaARKct (n=14) or adenoviral-beta-galactosidase (control, n=13) was performed. Rats were randomly euthanized on post-operative day 7, 14 or 21. Protein analysis including RV myocardial levels of betaARKct, betaARK1, SERCA(2a), inflammatory tissue mediators (IL-1, IL-6 and TNF-alpha), apoptotic markers (bax and bak), and MAP kinases (jnk, p38 and erk) was performed. ANOVA was employed for group comparison. Adenoviral-betaARKct treated animals showed increased expression of betaARKct and decreased levels of betaARK1 compared with controls. This treatment group also demonstrated normalization of SERCA(2a) expression and decreased levels of the inflammatory markers IL-1, IL-6 and TNF-alpha. The pro-apoptotic markers bax and bak were similarly improved. Ventricular levels of the MAP kinase jnk were increased. Differences were most significant 7 days after gene transfer, but the majority of these changes persisted at 21 days. These results suggest that attenuation of the pathologic mechanisms of beta adrenergic receptor desensitization, SERCA(2a) expression, inflammation and apoptosis, not only occur in the left ventricle but also in the right ventricular myocardium after intracoronary gene transfer of betaARKct during heart failure.

Reverse remodeling is associated with changes in extracellular matrix proteases and tissue inhibitors after mesenchymal stem cell (MSC) treatment of pressure overload hypertrophy.

Changes in ventricular extracellular matrix (ECM) composition of pressure overload hypertrophy determine clinical outcomes. The effects of mesenchymal stem cell (MSC) transplantation upon determinants of ECM composition in pressure overload hypertrophy have not been studied. Sprague-Dawley rats underwent aortic banding and were followed by echocardiography. After an absolute decrease in fractional shortening of 25% from baseline, 1 x 10(6) MSC (n = 28) or PBS (n = 20) was randomly injected intracoronarily. LV protein analysis, including matrix metalloproteinases (MMP-2, MMP-3, MMP-6, MMP-9) and tissue inhibitors of metalloproteinases (TIMP-1, TIMP-2, TIMP-3), was performed after sacrifice on postoperative day 7, 14, 21 or 28. Left ventricular levels of MMP-3, MMP-6, MMP-9, TIMP-1 and TIMP-3 were demonstrated to be decreased in the MSC group compared with controls after 28 days. Expression of MMP-2 and TIMP-2 remained relatively stable in both groups. Successful MSCs delivery was confirmed by histological analysis and visualization of labelled MSCs. In this model of pressure overload hypertrophy, intracoronary delivery of MSCs during heart failure was associated with specific changes in determinants of ECM composition. LV reverse remodeling was associated with decreased ventricular levels of MMP-3, MMP-6, MMP-9, TIMP-1 and TIMP-3, which were upregulated in the control group as heart failure progressed. These effects were most significant at 28 days following injection.

Right ventricular effects of intracoronary delivery of mesenchymal stem cells (MSC) in an animal model of pressure overload heart failure.

In a rat model of left ventricular pressure overload hypertrophy with biventricular failure, we studied the effects of intracoronary delivery of mesenchymal stem cells (MCS) upon right ventricular hemodynamic performance, profiles of local inflammation and apoptosis, and determinants of extracellular matrix remodeling. Sprague-Dawley rats underwent aortic banding and were followed by echocardiography. After a decrease in left ventricular fractional shortening of 25% from the baseline (relative 50% reduction), animals were randomized to an intracoronary injection of MSC (n=28) or PBS (n=20). Right ventricular hemodynamic assessment and measurement of local inflammatory markers, proapoptotic factors, and determinants of extracellular matrix remodeling were performed on post-transplantation day 7, 14, 21 or 28. MSC injection improved right ventricular systolic function in the MSC group compared to the control group (mean+/-SD, max dP/dt 772+/-272 mm Hg/s vs. 392+/-132 at 28 days, P<0.01). Diastolic function was similarly improved (mean+/-SD, max -dP/dt -558+/-171 mm Hg/s vs. -327+/-131 at 28 days, P<0.05). Right ventricular levels of IL-1, IL-6, TNF-alpha, bax, bak and p38 were significantly decreased in the MSC treated animals. Expression of MMP-3, MMP-6, MMP-9, TIMP-1 and TIMP-3 declined in the MSC group compared with controls after 28 days. In this model of left ventricular pressure overload hypertrophy and biventricular failure, intracoronary delivery of MSC was associated with an improvement in the right ventricular hemodynamic performance, profiles of local inflammation and apoptosis, and determinants of extracellular matrix remodeling.

Improved exercise capacity and reduced systemic inflammation after adenoviral-mediated SERCA-2a gene transfer.

BACKGROUND: We hypothesized that sarcoplasmic reticulum Ca2+ ATPase pump (SERCA-2a) gene delivery would have beneficial effects upon exercise capacity and markers of inflammation in the setting of heart failure. MATERIALS AND METHODS: A pressure-overload model of experimental heart failure was used in rats. Following a decrease in fractional shortening of >or=25%, animals underwent intracoronary adenoviral-mediated gene transfection using SERCA-2a. Heart failure animals were randomized to receive the SERCA-2a gene, the beta galactosidase (control) gene, or followed without any further intervention. Exercise and hemodynamic testing were performed, and myocardial and systemic markers of inflammation were assayed after 7 and 21 d. RESULTS: Animals receiving Ad.SERCA-2a showed an increase in exercise tolerance (499.0 +/- 14.9 versus 312.8 +/- 10.5 s, P < 0.0001) relative to Ad.Gal group. Groups treated with Ad.SERCA-2a had significantly decreased serum levels of the inflammatory markers interleukin-1, interleukin-6, and tumor necrosis factor-alpha compared with Ad.Gal-treated animals. Serum levels of atrial natriuretic peptide were decreased in animals receiving Ad.SERCA-2a compared with animals receiving Ad.Gal at day 7 (0.35 +/- 0.03 versus 0.52 +/- 0.11 pg/mL, P = 0.001). Myocardial levels of the proapoptotic protein bax were reduced in Ad.SERCA-2a -treated animals compared with those receiving Ad.Gal at day 7 (protein level/actin: 0.24 +/- 0.05 versus 0.33 +/- 0.04, P = 0.04) and day 21 (protein level/actin: 0.61 +/- 0.04 versus 0.69 +/- 0.01, P = 0.001). CONCLUSIONS: Genetic modulation of heart failure using the SERCA-2a gene was associated with improvement in cardiac function and exercise capacity as well as improvements in heart-failure associated inflammatory markers.

Adenoviral beta-adrenergic receptor kinase inhibitor gene transfer improves exercise capacity, cardiac contractility, and systemic inflammation in a model of pressure overload hypertrophy.

OBJECTIVE: We hypothesized that intracoronary adenoviral-mediated delivery of betaARKct would improve heart failure associated pathophysiologic abnormalities related to exercise capacity, cardiac contractility, systemic inflammation and volume overload. METHODS: After aortic banding, a cohort of Sprague-Dawley rats was followed by echocardiography. When an absolute decline of 25% in fractional shortening was detected, animals were randomized to intracoronary delivery of Ad.ssARKct (n=14), Ad.beta-Gal (n=13), or followed without any other further intervention (n=18). Assessment of exercise tolerance and hemodynamic profile and measurement of markers of systemic inflammation and volume overload was performed at 7, 14, and 21 days after gene delivery. Data were analyzed using ANOVA. RESULTS: Animals receiving Ad.ssARKct showed improved exercise tolerance compared to Ad.Gal-treated animals at 14 days (507+/-26 s vs. 408+/-19 s, P=0.01) and 21 days (526+/-55 s vs. 323+/-19 s, P<0.001) following injection. Animals receiving Ad.ssARKct demonstrated improved +dP/dtmax (mean+/-SD, 5,581+/-960 mmHg/s vs. 3,134+/-438 mmHg/s, P<0.01) and -dP/dtmax (mean+/-SD, -3,494+/-1,269 mmHg/s vs. -1,925+/-638 mmHg/s, P<0.01) compared to Ad.Gal-treated animals at 7 days. These differences were observed up to 21 days following injection. Serum levels of IL-1, IL-6, and TNF-alpha, as well as ANP were also decreased in animals receiving Ad.betaARKct. CONCLUSIONS: Genetic modulation of heart failure using the betaARKct gene was associated with improved exercise capacity and cardiac function as well as amelioration in heart failure-associated profiles of systemic inflammation and volume overload.

Improvement in hemodynamic performance, exercise capacity, inflammatory profile, and left ventricular reverse remodeling after intracoronary delivery of mesenchymal stem cells in an experimental model of pressure overload hypertrophy.

OBJECTIVES: In a rat model of pressure overload hypertrophy, we studied the effects of intracoronary delivery of mesenchymal stem cells on hemodynamic performance, exercise capacity, systemic inflammation, and left ventricular reverse remodeling. METHODS: Sprague-Dawley rats underwent aortic banding and were followed up by echocardiographic scanning. After a decrease in fractional shortening of 25% from baseline, animals were randomized to intracoronary injection of mesenchymal stem cells (MSC group; n = 28) or phosphate-buffered saline solution (control group; n = 20). Hemodynamic and echocardiographic assessment, swim testing to exhaustion, and measurement of inflammatory markers were performed before the rats were humanely killed on postoperative day 7, 14, 21, or 28. RESULTS: Injection of mesenchymal stem cells improved systolic function in the MSC group compared with the control group (mean +/- standard deviation: maximum dP/dt 3048 +/- 230 mm Hg/s vs 2169 +/- 97 mm Hg/s at 21 days and 3573 +/- 741 mm Hg/s vs 1363 +/- 322 mm Hg/s at 28 days: P < .001). Time to exhaustion was similarly increased in the MSC group compared with controls (487 +/- 35 seconds vs 306 +/- 27 seconds at 28 days; P < .01). Serum levels of interleukins 1 and 6, tumor necrosis factor-alpha, and brain natriuretic peptide-32 were significantly decreased in animals treated with mesenchymal stem cells. Stem cell transplantation improved left ventricular fractional shortening at 21 and 28 days. Left ventricular end-systolic and end-diastolic diameters were also improved at 28 days. CONCLUSIONS: In this model of pressure overload hypertrophy, intracoronary delivery of mesenchymal stem cells during heart failure was associated with an improvement in hemodynamic performance, maximal exercise tolerance, systemic inflammation, and left ventricular reverse remodeling. This study suggests a potential role of this treatment strategy for the management of hypertrophic heart failure resulting from pressure overload.

Congenital heart disease manifested as acute abdominal pain.

We present a case of a 53-year-old man with complaints of severe abdominal pain and nausea. Emergency department abdominal workup was non-diagnostic. Physical examination revealed signs of right- and left-heart failure. A past medical history of dysrhythmias and chronic abdominal complaints prompted hospital admission. Subsequent right heart catheterization revealed a significant left-to-right shunt. CT scan of the chest and angiography confirmed the diagnosis of an abnormal ascending vein between the innominate vein and the left superior pulmonary vein. After the anomalous vein was ligated, the patient's abdominal pain resolved.

Massive right atrial myxoma presenting with syncope.

A 65-year-old man presented to the emergency room following an episode of syncope. His vital signs and physical examination were unremarkable. A chest X-ray and an ECG were also normal. He was admitted to the hospital for further work-up. A computed tomography scan of his brain did not reveal any evidence of stroke, hemorrhage, or mass effect. A transesophageal echocardiogram, however, revealed tricuspid regurgitation and a right atrial mass with finger-like projections, which appeared to originate from the tricuspid valve. Left heart catheterization was performed, showing a 99% proximal right coronary artery stenosis. The patient was scheduled to undergo atrial mass resection, tricuspid valve annuloplasty, and coronary bypass. During the procedure, a large myxoma was found to be adherent to the right side of the atrial septum, adjacent to the fossa ovalis. The mass was friable and was attached to the endocardium by a pedicle. Following resection of the atrial mass and tricuspid valve annuloplasty, a single saphenous vein graft bypass to the right coronary artery was performed. The patient's postoperative course was unremarkable and he was discharged home on postoperative day 6.

The surgical management of superior sulcus tumors: a retrospective review with long-term follow-up.

BACKGROUND: We reviewed our experience with multimodality therapy for superior sulcus tumors to identify aspects of treatment that impact survival. METHODS: We retrospectively analyzed the records of 39 consecutive patients who underwent surgical resection in a single institution between 1993 and 2000. RESULTS: Median age at presentation was 59 years (range, 40 to 77). Twenty-five patients (64%) were men. At presentation, 36 patients (92%) had clinical T3 tumors and 3 (8%) had clinical T4 tumors. Mediastinoscopy was negative in all patients. Thirty-one patients (79%) received preoperative radiotherapy (median dose, 4500 cGy). Chemotherapy was administered concurrently with radiotherapy in 27 patients (69%). Complete surgical resection was performed in 34 patients (87%). There were 2 (5%) postoperative deaths. Of the 31 patients who received preoperative therapy, 14 (45%) had their tumors downstaged and 9 (29%) demonstrated a complete pathologic response. Median follow-up (100%) was 69 months. Overall 5-year survival was 47.9%. Five-year survival was 52.1% in patients with negative resection margins (p = 0.005), and 60.6% in patients who demonstrated a response to induction chemoradiation therapy (p = 0.008). Independently, margin status and response to induction therapy are predictors of overall survival (p = 0.01 and p = 0.02, respectively). Multivariable analysis identified margin status as the only factor significantly associated with overall survival. Negative margins strongly correlated with the response to preoperative therapy (p = 0.004). Disease-free survival correlated well with the response to induction therapy (p = 0.03). The chemotherapy regimen, T status, operative procedure, and complete pathologic response did not correlate with survival. CONCLUSIONS: The use of chemoradiation induction therapy may downstage tumors, enhance the ability to obtain a complete surgical resection, and prolong survival.

Use of LeVeen pleuroperitoneal shunt for refractory high-volume chylothorax.

We present a case of intractable high-volume (> 2L/d) chylothorax after transhiatal esophagectomy treated successfully with the simultaneous insertion of both Denver (Denver Biomedical, Golden, CO) and LeVeen (Becton-Dickinson, Rutherford, NJ) pleuroperitoneal shunts. The patient initially had chemoradiotherapy for a T4N1 squamous cell carcinoma of the thoracic esophagus. Re-staging showed a dramatic shrinkage of tumor, and a transhiatal esophagectomy was performed. Sequential bilateral thoracotomies were performed on postoperative days 19 and 26 for attempted control of high-volume chylothorax, but these were unsuccessful. Subsequent pleuroperitoneal shunt insertion was used, which immediately controlled the effusion. A shunt study was performed shortly after hospital discharge, which showed an occluded Denver shunt and a patent LeVeen shunt. The patient succumbed to metastatic carcinoma 18 months after discharge, but no pleural effusion had recurred.

Successful treatment of esophageal cancer with transhiatal esophagectomy after heart transplantation.

A 55-year-old heart transplant recipient with reflux esophagitis presented for routine endoscopic surveillance of an area of Barrett's metaplasia initially seen 3 years previously. Esophagogastroduodenoscopy revealed adenocarcinoma at 33 cm from the incisors. The preoperative clinical stage was T1N0M0 by endoscopic ultrasound. Transhiatal esophagectomy was performed with R0 resection of the cancer, and the patient recovered uneventfully. Pathologic examination confirmed esophageal adenocarcinoma (T1N0M0) in Barrett's mucosa. The patient is doing well, and has no evidence of disease after 18 months.

Effect of older donor age on risk for mortality after heart transplantation.

BACKGROUND: Despite the increasingly common use of donor hearts at least 50 years of age, controversy still remains regarding long-term outcome. Our goal was to determine if older donor age is associated with an increased risk of mortality and specifically if the use of donor hearts at least 50 years of age reduces survival. METHODS: We retrospectively studied records of all primary heart transplants performed between January 1990 and July 2002. Fifty-six patients who had received donor hearts at least 50 years of age were compared with 611 recipients of donor hearts less than 50 years of age. Clinicopathologic parameters were analyzed for their effect on mortality using the Cox proportional hazard model with calculation of hazard ratios (HR). Cut-point analysis of donor age was used to determine which donor age is associated with the greatest risk of mortality after transplant. RESULTS: Recipients of donor hearts at least 50 years of age were older (58.5 years +/- 7.0 vs 53.2 +/- 11.6; mean +/- standard deviation [SD]; p < 0.0001), suffered more often from ischemic cardiomyopathy (69% vs 50%, p = 0.01), and experienced a longer waiting time (192.2 days +/- 301.0 vs 138.6 +/- 190.8, p < 0.0001). Donor hearts at least 50 years of age (age 54.1 +/- 3.5 years) were more often female (50% vs 34%, p = 0.03), died less often of "head trauma" (9% vs 42%, p < 0.0001), and exhibited fewer cytomegalovirus (CMV) mismatches (29% vs 39%, p = 0.04) than donor hearts less than 50 years of age (age 26.8 +/- 12.3 years). Multivariate predictors of mortality were rejection index (HR 1.90 per unit [rejections/100 survival days], p < 0.0001), donor age (HR 1.16 per 10-year increment, p = 0.002), and recipient age (HR 1.24 per 10-year increment, p = 0.04). Recipients of donor hearts at least 50 years of age had reduced 1-year and 5-year survival ([65.7% vs 81.7%, p < 0.05] and [48.3% vs 68.4%, p < 0.05], respectively), as well as a higher proportion of deaths occurring within 1 month of transplant (41% of total deaths vs 23%, p = 0.06). Cut-point analysis indicated the characteristic of donor age of at least 40 years (categorical variable) to predict mortality with the same degree of fit as age used as a continuous variable. CONCLUSIONS: Although we observed a substantial reduction in survival among patients who were allocated donor hearts at least 50 years of age, this difference was not solely attributable to the categorical variable of donor age 50 in this group. Donor age as a continuous variable, however, was determined to be a notable predictor of survival and use of the donor age cut-point of 40 years (categorical variable) allowed risk stratification with similar accuracy. The use of a donor age cut-point of 40 years may be a useful clinical criterion for graft-related risk assessment.