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There are limited data regarding the surgical management of primary pulmonary artery sarcomas (PPAS) because of their rarity and complicated diagnostic history. The objective of this study was to analyze our institution’s long-term surgical management outcomes for PPAS in the absence of a care pathway. From May 1997 to June 2013, 8 patients (mean age 60.6 ± 11.8 years; range, 40-73 years; 5 women and 3 men) underwent surgical intervention for PPAS at our institution. The most common computed tomography finding was a luminal filling defect obstructing the pulmonary artery (PA), without evidence of extraluminal extension. Three patients underwent debulking/pulmonary endarterectomy alone and 5 patients underwent a more radical resection with PA patch angioplasty, PA resection and reconstruction, pulmonary valve replacement, and unilateral pneumonectomy. The mean postoperative survival in this series was 3.8 ± 3.6 years (range, 1-11.9 years), with 2 radical surgical resection patients alive at 4.9 and 11.9 years, respectively. For those patients with incomplete resection, 3-dimensional (3D) models were created to demonstrate the advantage of a preoperative guide for a more complete resection and what it would entail. Six patients had local recurrences with mean disease-free interval of 14 ± 10.9 months (range, 2 months-2.5 years), and 2 patients with re-resections had an overall postoperative survival of 2.8 and 11.9 years, respectively. In our small cohort of PPAS, patients treated with radical surgical resection had better survival. The small number of PPAS cases in this series makes proving this association unlikely but warrants consideration.

Bioprosthetic leaflets made from animal tissues are used in the majority of surgical and transcatheter cardiac valve replacements. This study develops a new surgical bioprosthesis, using porcine pericardial leaflets. Porcine pericardium was obtained from genetically engineered pigs with a mutation in the GGTA-1 gene (GTKO) and fixed in 0.6% glutaraldehyde, and used to develop a new surgical valve design. The valves underwent in vitro hydrodynamic test in a pulse duplicator and high-cycled accelerated wear testing and were evaluated for acute haemodynamics and thrombogenicity in a juvenile sheep implant study for 48 h. The porcine surgical pericardial heart valves (pSPHVs) exhibited excellent hydrodynamics and reached 200 million cycles of in vitro durability, with no observable damage. Juvenile sheep implants demonstrated normal valve function with no acute thrombogenic response for either material. The pSPHV incorporates a minimalistic construction method using a tissue-to-tissue design to cover the stent. This new design is a proof of concept alternative to the use of bovine pericardium and synthetic fabric in surgical bioprosthetic heart valves.

OBJECTIVES Surgical strategies to treat drug refractory left ventricular outflow tract obstruction (LVOTO) in hypertrophic cardiomyopathy include septal myectomy (SM) and, less frequently, mitral valve (MV) repair or replacement. The primary aim of this study was to report the surgical technique and management outcomes in a consecutive group of patients with variable phenotypes of hypertrophic cardiomyopathy in a broad national specialist practice. METHODS A total of 203 consecutive patients, 132 men (mean age 48.6 ± 14.6 years) underwent surgery for the management of LVOTO. Surgical approaches included SM (n = 159), SM with MV repair (n = 25), SM with MV replacement (n = 9) and MV replacement alone (n = 10). Specific surgical approaches were performed based on the underlying mechanism of obstruction. Eleven (5.4%) patients had previous alcohol septal ablation for the management of LVOTO. Concomitant non-mitral cardiac procedures were carried out in 22 (10.8%) patients. RESULTS Operative survival rate was 99.0% with 2 deaths within 30 days. The mean bypass time was 92.9 ± 47.8 min, with a mean length of hospital stay of 10.5 ± 7.8 days. Surgical complications included 3 ventricular septal defects requiring repair (1.5%), 1 Gerbode defect surgically repaired, 2 aortic valve repairs (1.0%), 2 transient ischaemic attacks (1.0%) and 4 strokes (2.0%). Thirty-nine (19.2%) patients had perioperative new-onset atrial fibrillation and 8 (3.9%) patients had unexpected atrioventricular block requiring a permanent pacemaker. Mean resting left ventricular outflow tract gradient improved from 70.6 ± 40.3 mmHg preoperatively to 11.0 ± 10.5 mmHg at 1 year postoperatively (P

Aims Surgical intervention is used to treat dynamic left ventricular outflow tract obstruction (LVOTO) in hypertrophic cardiomyopathy. This study assesses the effect of different surgical strategies on long-term mortality and morbidity. Methods and results In total, 347 patients underwent surgical intervention for LVOTO (1988-2015). Group A (n = 272) underwent septal myectomy; Group B (n = 33), septal myectomy and mitral valve (MV) repair; Group C (n = 22), myectomy and MV replacement; and Group D (n = 20), MV replacement alone. Median follow-up was 5.2 years (interquartile range 1.9-7.9). The mean resting LVOT gradient improved post-operatively from 71.9 ± 39.6 mmHg to 13.4 ± 18.5 mmHg (P 1 New York Heart Association (NYHA) class; 58.9% of patients undergoing MV replacement alone did not improve their NYHA class. There were 5 perioperative deaths and 20 late deaths (>30 days). Survival rates at 1, 5 and 10 years respectively were 98.4, 96.9, 91.9% in Group A; 97.0, 92.4, 61.6% in Group B; 100.0, 100.0, 55.6% in Group C; and 94.7, 85.3, 85.3% in Group D (log-rank, P 30 days) complications included atrial fibrillation (29.6%), transient ischaemic attack/stroke (2.4%) and heart failure hospitalisation (3.2%). There were 16 repeat surgical interventions at 3.0 years. Conclusion Septal myectomy is a safe procedure resulting in symptomatic improvement in the majority of patients. The annual incidence of non-fatal disease-related complications after surgical treatment of LVOTO is relatively high. Patients who underwent MV replacements had poorer outcomes with less symptomatic benefit in spite of a similar reduction in LVOT gradients.

Background This report studies the early and medium-term clinical and echocardiographic outcomes of the Alfieri edge-to-edge mitral valve repair, as adjunctive therapy, to prevent and treat systolic anterior motion (SAM) at the time of septal myectomy (SM) for left ventricular outflow tract obstruction in hypertrophic cardiomyopathy. Methods From 2009-2015, 11 consecutive patients had a trans-atrial Alfieri repair, to prevent (n = 7) or treat (n = 4) SAM at the time of SM. Results No patients were lost to follow-up. There were no perioperative or late deaths. Pre-bypass, the mean left ventricular outflow tract gradient, measured directly by simultaneous needle insertion, was 40.7 ± 19.9 mmHg at rest and 115.8 ± 30.4 mmHg on provocation with Isoproterenol, which reduced after SM and Alfieri repair and discontinuation of bypass, to a mean gradient of 8.3 ± 9.8 mmHg at rest and 25.8 ± 9.2 mmHg on provocation. One patient who required mitral valve replacement on day 4, was hospitalized at 2.7 years with heart failure requiring diuresis and remains well at 6 years. One patient developed postoperative atrial fibrillation. There were no other early or late complications. At a median follow-up of 6.6 years (international quartile range 1.2-7.4), clinical and echocardiographic data demonstrated maintained improvement in mean New York Heart Association class from 2.6 ± 0.9 preoperatively to 1.7 ± 0.4 and reduction in mean grade of mitral regurgitation from 2.7 ± 0.8 preoperatively to 0.7 ± 0.6. Conclusions The Alfieri repair, as adjunctive therapy, for the prevention or treatment of SAM at the time of SM demonstrates satisfactory early and medium-term clinical and echocardiographic outcomes supporting the ongoing utility of this approach.

We report the management of an acquired Gerbode defect, from the left ventricle to the coronary sinus, following mechanical mitral valve replacement. Following a failed percutaneous closure, surgical patch closure of the defect was performed.

Background: Hypertrophic cardiomyopathy (HCM) is a clinically heterogeneous genetic heart disease characterized by left ventricular hypertrophy in the absence of another disease that could explain the wall thickening. Elucidation of the genetic basis of HCM lead to the identification of several genes encoding sarcomeric proteins, such as MYH7, MYBPC3, TPM1, TNNT2, and TNNI3. Sarcomeric genes are mutated in approximately 40% of HCM patients and a possible explanation for the incomplete yield of mutation-positive HCM may be somatic mutations. Methods and Results: We studied 104 unrelated patients with non-familial HCM. Patients underwent clinical evaluation and mutation screening of 5 genes implicated in HCM (MYH7, MYBPC3, TPM1, TNNT2, and TNNI3) in genomic DNA isolated from resected cardiac tissue; 41 of 104 were found to carry a mutation, but as several patients carried the same mutations, the total amount of different mutations was 37; 20 of these mutations have been previously described, and pathogenicity has been assessed. To determine the effect of the 17 new mutations an in silico assay was performed and it predicted that 4 variants were damaging mutations. All identified variants were also seen in the DNA isolated from the corresponding blood, which demonstrated the absence of somatic mutations. Conclusions: Somatic mutations in MYH7, MYBPC3, TPM1, TNNT2, and TNNI3 do not represent an important etiologic pathway in HCM. (Circ J 2013; 77: 2358–2365)

Objectives Human subjects and Old World primates have high levels of antibody to galactose-α-1,3 galactose β-1,4-N-acetylglucosamine (α-Gal). Commercially available bioprosthetic heart valves of porcine and bovine origin retain the Gal antigen despite current processing techniques. Gal-deficient pigs eliminate this xenoantigen. This study tests whether binding of human anti-Gal antibody effects calcification of wild-type and Gal-deficient glutaraldehyde-fixed porcine pericardium by using a standard subcutaneous implant model. Methods Expression of α-Gal was characterized by lectin Griffonia simplicifolia –IB4 staining. Glutaraldehyde-fixed pericardial disks from Gal-positive and Gal-deficient pigs were implanted into 12-day-old Wistar rats and 1.5-kg rabbits with and without prelabeling with affinity-purified human anti-Gal antibody. Calcification of the implants was determined after 3 weeks by using inductively coupled plasma spectroscopy. Results The α-Gal antigen was detected in wild-type but not Gal-deficient porcine pericardium. Wild-type disks prelabeled with human anti-Gal antibody exhibited significantly greater calcification compared with that seen in antibody-free wild-type samples (mean ± standard error of the mean: 111 ± 8.4 and 74 ± 9.6 mg/g, respectively; P = .01). In the presence of anti-Gal antibody, a significantly greater level of calcification was detected in wild-type compared with GTKO porcine pericardium (111 ± 8.4 and 55 ± 11.8 mg/g, respectively; P = .005). Calcification of Gal-deficient pericardium was not affected by the presence of anti-Gal antibody (51 ± 9.1 and 55 ± 11.8 mg/g). Conclusions In this model anti-Gal antibody accelerates calcification of wild-type but not Gal-deficient glutaraldehyde-fixed pericardium. This study suggests that preformed anti-Gal antibody present in all patients might contribute to calcification of currently used bioprosthetic heart valves. Gal-deficient pigs might become the preferred source for new, potentially calcium-resistant bioprosthetic heart valves.

Background Cardiac allograft vasculopathy (CAV) is primarily immune-mediated. We investigated the role of cellular rejection in CAV development. Methods The study comprised 252 cardiac transplant recipients (mean age, 49.02 ± 17.05 years; mean follow-up, 7.61 ± 4.49 years). Total rejection score (TRS) based on the 2004 International Society of Heart and Lung Transplantation R grading system (0R = 0, 1R=1, 2R=2, 3R=3) and any rejection score (ARS; calculated as 0R=0, 1R=1, 2R=1; 3R=1, or the number of rejections of any grade) were normalized for the total number of biopsy specimens. CAV was defined as coronary stenosis of 40% or more and/or distal pruning of secondary side branches. Thirty-two patients had undergone 3-dimensional intravascular ultrasound (IVUS) at baseline and with virtual histology (VH) IVUS at 24 months. Results In univariate analysis, 6-month TRS (hazard ratio [HR], 1.9; 95% confidence interval [CI], 0.99–3.90, p = 0.05) and ARS (HR, 2.22; 95% CI, 1.01–4.95; p = 0.047) were associated with increased risk of CAV. In multivariate analysis, 6-month TRS (HR, 2.84; 95% CI, 1.44–6.91, p = 0.02) was significantly associated with increased risk of CAV onset. The 12- and 24-month rejection scores were not risk factors for the onset of CAV. By Kaplan-Meier analysis, 6-month TRS exceeding 0.3 was associated with a significantly shorter time to CAV onset ( p = 0.018). There was direct correlation ( r = 0.44, p = 0.012) between TRS at 6 months and the percentage of necrotic core demonstrated by VH-IVUS at 24 months. Conclusion Recurrent cellular rejection has a cumulative effect on the onset of CAV. The mechanism may be due to increased inflammation resulting in increased plaque burden suggesting a relationship between the immune basis of cellular rejection and CAV.

ObjectiveImproved durability of bioprostheses has led some surgeons to recommend biologic rather than mechanical prostheses for patients younger than 65 years. We compared late results of contemporary bioprostheses and bileaflet mechanical prostheses in patients who underwent aortic valve replacement between 50 and 70 years old.MethodsIn this retrospective study, patients received either St Jude bileaflet valves or Carpentier–Edwards bioprostheses. Operations were performed between January 1991 and December 2000, and groups were matched one-to-one according to age, sex, need for coronary artery bypass grafting, and valve size.ResultsFour hundred forty patients were matched, and follow-up was 92% complete, with median durations of 9.1 years for patients who received mechanical valves and 6.2 years for patients who received bioprostheses. The 5- and 10-year unadjusted survivals were 87% and 68% for mechanical valves and 72% and 50% for bioprostheses, respectively (P < .01). Freedoms from reoperation at 10 years were 98% for mechanical valves and 91% for bioprostheses (P = .06). Rates of late stroke or other embolic events and of endocarditis were similar between groups. Hemorrhagic complications necessitating hospitalization occurred in 15% of patients with mechanical valves and 7% of patients with bioprostheses (P = .01). Notably, 19% of patients with bioprostheses were receiving warfarin sodium at last follow-up. After adjustment for unmatched variables, including diabetes, renal failure, lung disease, New York Heart Association functional class, ejection fraction, and stroke, the use of a mechanical valve was protective against late mortality (hazard ratio 0.46, P < .01).ConclusionIn this study, patients aged 50 to 70 years who underwent aortic valve replacement with mechanical valves had a survival advantage relative to matched patients who received bioprostheses. These findings question recommendations of bioprostheses for younger patients and suggest that a randomized trial may be warranted.

Introduction Endomyocardial biopsy is the standard means of establishing cardiac allograft rejection diagnosis. The efficacy of this procedure in xenotransplantation has not been determined. In this study we compare the histology of right ventricular endomyocardial biopsy specimens with the corresponding full cross sections of explanted right ventricle (RV). We also compare RV with the related left ventricle (LV) cross sections. Methods Heterotopic CD46 pig-to-baboon cardiac xenotransplants (n = 64) were studied. RV endomyocardial biopsy specimens were taken at cardiac explant by using a standard bioptome (n = 24) or by sharp dissection (n = 40). Hematoxylin and eosin stained sections of RV and LV cross-section and RV endomyocardial biopsy specimens were compared in a blinded fashion. Characteristics of delayed xenograft rejection and a global assessment of ischemia were scored from 0 to 4 according to the percentage of myocardium involved (0, 0%; 1, 1%–25%; 2, 26%–50%; 3, 51%–75%; and 4, 76%–100%). Results Median graft survival was 30 days (range, 3–137 days). Linear regression analysis of histology scores demonstrated that specimens from both bioptome and sharp dissection equally represented the histology of the RV cross section. Global ischemic injury was strongly correlated between RV and RV endomyocardial biopsy ( R 2 = 0.84) and between RV and LV cross sections ( R 2 = 0.84). Individual characteristics of delayed xenograft rejection showed no significant variation between RV and RV endomyocardial biopsy or between RV and LV ( p Conclusions These results indicate that delayed xenograft rejection is a widespread process involving both right and left ventricles similarly. This study shows that histologic assessment of RV endomyocardial biopsy specimens is an effective method for the monitoring of delayed xenograft rejection after cardiac xenotransplantation.

Objective Although radiofrequency ablation is increasingly used to create the atrial lesions of the Cox maze procedure, its effectiveness in ablating atrial fibrillation compared with the standard cut-and-sew method is not known. We compare the freedom from atrial fibrillation in patients undergoing both methods with identical lesion sets. Methods Radiofrequency ablation was used to create full Cox maze lesions in 56 patients between January 2002 and February 2005; these patients were matched with those who underwent the standard cut-and-sew method. Matched variables were gender (33 male, 23 female, both), age (67.5 vs 67.2 years), New York Heart Association class (mean 2.28 vs 1.96), atrial fibrillation type (37 paroxysmal, 19 continuous, both), and concomitant mitral valve surgery (37 in both). Hypertension, preoperative left atrial size, and preoperative duration of atrial fibrillation were similar between groups. Results When compared with matched controls, fewer patients undergoing radiofrequency ablation were free from atrial fibrillation at dismissal (63% vs 88%; P = .0039) and at last follow-up (62% vs 92%; P = .016). According to logistic regression for matched pairs, patients undergoing radiofrequency ablation were 4.5 times more likely to be in atrial fibrillation at dismissal (95% confidence intervals [CI], 1.8, 10.9) and 5 times more likely to be in atrial fibrillation at follow-up (95% CI, 1.4, 17.3). No other covariate was associated with atrial fibrillation status at hospital dismissal or follow-up. Conclusion Creating Cox maze lesions with radiofrequency ablation is associated with less freedom from atrial fibrillation both early and late postoperatively. Because transmurality can be assured, the standard cut-and-sew Cox maze procedure remains the gold standard for the surgical treatment of atrial fibrillation.

OBJECTIVE: Infection is a major cause of mortality in the first year following single lung transplantation and is a distinct risk factor for the development of obliterative bronchiolitis. However, little is known about changes in pulmonary vascular activity in the setting of infection, which might affect and limit function of the graft. Therefore, the aim of this study was to determine how acute infection altered pulmonary arterial reactivity in single lung allografts. Such information could help to develop better diagnostic and therapeutic targets to improve outcome when grafts become infected. METHODS: Following single lung transplantation, dogs were immunosuppressed with methylprednisolone acetate, cyclosporine and azathioprine. On postoperative day 5, infection was induced in one group of dogs by endobronchial inoculation of antibiotic resistant Eschericia coli (infection group, n=5); in the second group, the same amount of culture media without bacteria was flushed into the bronchus (control group, n=4). All animals were medicated under the same drug protocol. On postoperative day 8, lungs were removed, reviewed for histological assessment, pulmonary arteries were isolated, cut into rings and suspended for pharmacological characterization in organ chambers. RESULTS: With acute infections, contractions to phenylephrine and angiotensin-1, but not endothelin-1, were reduced in pulmonary arteries with but not without endothelium. Inhibition of nitric oxide synthase with N(G)-monomethyl-L-arginine, monoacetate salt (L-NMMA) restored these contractions. Endothelium-dependent relaxations to adenosine diphosphate and calcium ionophore, which stimulate release of endothelium-derived nitric oxide by a receptor and non-receptor mediated process, respectively, were not different between groups. Relaxations to nitric oxide also were not different between groups. CONCLUSION: These results suggest that acute infection selectively reduces contractions of pulmonary arteries in part through receptor-mediated release of nitric oxide from the endothelium. Inhibiting nitric oxide during episodes of acute infection may help to improve graft perfusion during episodes of acute infection.

Successful thromboendarterectomy for chronic thromboembolic pulmonary hypertension promptly improves right ventricular (RV) function by decreasing RV volume and increasing ejection fraction (EF). Single photon emission computed tomography (SPECT) equilibrium radionuclide angiocardiography (ERNA) has been validated as a measure of RV and left ventricular (LV) volume and EF.Nine patients with chronic thromboembolic pulmonary hypertension underwent electron beam computed tomography (EBCT) and SPECT ERNA cardiac studies before and after thromboendarterectomy. EBCT and SPECT ERNA measures of RV and LV volume and EF were compared. Before thromboendarterectomy, EBCT and SPECT ERNA RV and LV volumes and RV EF were similar. LV EF was within the normal range with both methods but was slightly greater (P = .004) when measured by EBCT (mean +/- SD, 0.61 +/- 0.08) compared with SPECT ERNA (0.54 +/- 0.10). Thromboendarterectomy measured by EBCT and SPECT ERNA produced marked similar and significant decreases in RV end-systolic (-72 +/- 59 mL vs -58 +/- 25 mL) and end-diastolic (-75 +/- 85 mL vs -76 +/- 32 mL) volumes and similar slight increases in RV EF (0.12 +/- 0.07 vs 0.05 +/- 0.06). Slight decreases in mean LV end-systolic (-19 +/- 23 mL vs -5 +/- 13 mL, P = .05) and end-diastolic (-32 +/- 53 mL vs -9 +/- 31 mL, P = .21) volumes occurred, with little change in mean LV EF (0.05 +/- 0.07 vs 0.00 +/- 0.10).SPECT ERNA is an accurate method for measuring RV and LV volume and EF before and after thromboendarterectomy.

Atrial rhythm disturbances, in particular atrial fibrillation (AF) and flutter (AFL), are common in the denervated transplanted heart. However, there is a relative paucity of data in the prevalence, mechanism of arrhythmia, and long-term significance.(1) Determine the prevalence of AF and AFL in heart transplant patients, (2) define the echo/Doppler features associated with arrhythmia, and (3) evaluate the impact of arrhythmia on long-term survival.All patients who received an orthotopic heart transplant at the Mayo Clinic, Rochester, Minnesota, between 1988 and 2000 were included. Analysis of serial electrocardiograms and Holter monitor records provided evidence of AF or AFL development. Variables including general patient demographics, histology-proven rejection numbers and grades, results of serial coronary angiography, endomyocardial biopsy specimens, and echocardiographic studies performed at 6 weeks and 3 years after transplant were obtained to determine variables predictive of arrhythmia development.There were 167 heart transplant recipients, of which 16 (9.5%) developed AF and another 25 (15.0%) developed AFL over 6.5 +/- 3.4 years. Patients who developed AF or AFL had lower left ventricular (LV) ejection fractions (56.6% +/- 1.6% vs 62.5% +/- 1.5%, p0.05), higher LV end-systolic dimensions (LVESD) (33.6 +/- 1.12 mm vs 29.7 +/- 0.97 mm, p0.01), higher right atrial volume indexes (43.2 +/- 12.3 ml vs 35 +/- 5.3 ml, p0.03), lower mitral deceleration time (145 +/- 8 msec vs 160 +/- 12 msec, p0.05), and lower late mitral annulus tissue a' velocities (0.06 +/- 0.005 cm/sec vs 0.08 +/- 0.01 cm/sec, p0.02) compared with an age- and gender-matched Sinus Rhythm Group. Grade 3 rejection was a time-dependent covariate predictor of AFL risk (hazard ratio [HR], 2.95; 95% confidence interval [CI], 1.3-6.6, p0.008) but not AF (HR, 2.264; 95% CI, 0.72-7.1; p = 0.10). Thirty-nine of 167 patients died: 13 in the arrhythmia group and 26 in the normal sinus rhythm group. Development of atrial dysrhythmia adversely affected the outcome in the first 5 years (p0.001) compared with normal sinus rhythm. Predictors of long-term mortality included AF/AFL (HR, 2.88; 95% CI, 1.38-5.96; p0.004), age at transplant (HR, 1.04; 95% CI, 1.00-1.07, p0.03), coronary artery disease (HR, 2.655; 95% CI, 1.25-5.64; p = 0.01), pre-transplant cardiac amyloidosis (HR, 5.02; 95% CI 2.37-10.62; p0.001), right atrial volume index (HR, 1.03; 95% CI, 1.00-10.7; p = 0.03), mitral deceleration time160 msec (p0.01), and LVESD30 mm (p0.04).Development of AF/AFL post-heart transplantation is not uncommon and is associated with decreased long-term survival. Cumulative effects of repeated moderate-to-severe (grade 3 or more) rejections that result in increased cardiac fibrosis are associated with the development of AFL, but not AF. Similarly advanced restrictive diastolic dysfunction caused by fibrosis from repeated moderate-to-severe (grade 3 or more) rejections was predominant in the patients with arrhythmia and was a marker of poor long-term outcome.

Background Cardiac allograft vasculopathy (CAV) is considered a major cause of morbidity and mortality in transplant recipients and may reflect immune-mediated endothelial injury in response to the donor heart. Elevated troponin levels in the donor serum might provide a marker for this phenomenon; therefore, we evaluated the relationship of donor troponin levels to the development of CAV. Methods A retrospective analysis of troponin levels was undertaken from cardiac donor patients, and transplant recipients were monitored for the development of vasculopathy by angiography (N = 171). Results Angiographically significant CAV developed in 6% of transplantation patients and troponin levels were inversely related to the severity of CAV. Conclusions Elevated donor troponin levels are not associated with the development of CAV but rather with a significantly reduced long-term risk of developing CAV, suggesting a possible protective effect of donor released protein.

Background Cardiac papillary fibroelastoma is a rare benign tumor that can cause thromboembolism. We have found no large surgical series describing its treatment and outcome. Methods A retrospective review of all patients treated surgically for this tumor from 1985 to 2002. Results There were 88 patients with a mean age of 62 ± 16 years. Sixty-two (71%) were male. Cardiac papillary fibroelastoma was a primary indication for surgery in 47 (group 1, 53%) and an incidental finding in 41 (group 2, 47%). The common clinical symptoms were neurologic (group 1) and cardiac (group 2). Cardiac valves were predominantly involved (77%); the aortic valve was the most affected (52%). Other common sites were the left ventricular outflow tract (18%) and anterior mitral leaflet (11%). All heart valves were involved in one patient. Seventy-three patients (83%) had shave excision and 8 (9%) excision with valve repair. Of 5 (6%) valve replacements, 2 were for concurrent degenerative valve disease. Concomitant procedures included repair or replacement of another valve (32 %), CABG (28%), and septal myectomy (19%). Surgical mortality occurred in 1 patient (2.1%) in group 1 who had concomitant lung resection for bronchiolitis obliterans. There was no tumor recurrence, and no tumor-related late morbidity or mortality at a mean follow-up of 3 years. Conclusions Cardiac papillary fibroelastoma has a propensity to affect the anatomically contiguous structures of the aortic valve, left ventricular outflow tract, and anterior mitral leaflet. Surgical treatment by simple shave excision is low risk and can achieve good results.

Background The process by which cardiac myocytes die during xenograft rejection is incompletely understood. The presence of cardiac myocyte apoptosis in discordant xenotransplant models has been noted, yet no investigators have examined whether a relationship between myocyte apoptosis and rejection severity exists. Thus, we chose to further investigate this observation. Methods Eight explanted pig-to-baboon cardiac grafts with varying severities of rejection, as determined by hematoxylin and eosin histology, were examined for apoptosis by transmission electron microscopy (TEM) and TUNEL (terminal deoxynucleotide transferase-mediated digoxigenin-dUTP nick-end labeling) immunohistochemistry. In addition, Western blot analysis for the cleavage of the apoptosis regulatory proteins pro-caspase 8 and 3 was performed. Results Transmission electron microscopy revealed that a severely rejected graft displayed widespread condensation of nuclear chromatin, which is a characteristic morphologic feature of apoptosis. TUNEL staining verified this observation and allowed for the quantification of myocyte apoptosis in each graft. Subsequent linear regression analysis of the extent of myocyte apoptosis and rejection severity revealed a direct correlation ( R 2 = 0.757, p = 0.005). In addition, Western blot analysis demonstrated that myocyte apoptosis involves the cleavage of pro-caspase 8 and 3. Conclusions Myocyte death in rejecting pig-to-baboon cardiac xenografts occurs through an apoptotic pathway and directly correlates with the severity of graft rejection. Further studies aimed at elucidating the apoptotic stimulus are therefore warranted. Moreover, our data suggest that antiapoptotic strategies may be of benefit in the treatment of xenograft rejection.

Hypertrophic cardiomyopathy (HCM) is the most common inherited cardiomyopathy, and is the leading cause of sudden cardiac death in the young and a major cause of heart failure [1]. Numerous studies have shown that myocardial ischemia caused by an inability to increase myocardial blood flow (MBF) during stress contribute to the pathophysiology of HCM and are associated with adverse left ventricular (LV) remodelling and systolic dysfunction [1]. Numerous studies have shown that myocardial ischemia, which is caused by an inability to increase myocardial blood flow (MBF) during stress, contributes to the pathophysiology of HCM and is associated with adverse left ventricular (LV) remodelling and systolic dysfunction. In this regard the opening of the mitochondrial permeability transition pore (MPTP) at the onset of reperfusion is a critical determinant of cardiomyocyte death following myocardial ischaemiareperfusion injury (IRI) [2, 3]. Pharmacological inhibition of MPTP opening at the onset of reperfusion, using agents such as ciclosporin-A (CsA), has been reported to reduce myocardial infarct (MI) size in animal models of IRI [4]. Importantly, MPTP inhibition at the time of myocardial reperfusion has been demonstrated to protect human atrial cardiomyocytes and trabeculae, harvested from patients undergoing coronary artery bypass graft (CABG) surgery, against simulated IRI [5]. Furthermore, CsA has been reported to be reduce MI size in patients when administered at the time of myocardial reperfusion [6, 7]. MPTP inhibition can also be achieved by pharmacologically activating pro-survival kinases such as Akt and Erk1/2 using the HMG Co-A reductase inhibitor, atorvastatin [8]. Experimental animal studies have demonstrated a reduction in MI size with the administration of atorvastatin at reperfusion in both animal and human heart tissue models of simulated IRI [8, 9]. Whilst these cardioprotective mechanisms are known to operate in the setting of “normal” myocardium, little is understood about potential cardioprotective signaling pathways in HCM. The ability of pharmacological agents to inhibit MPTP opening as a strategy for limiting myocardial IRI, may provide a novel therapeutic intervention for patients with HCM. Therefore, in the current study, the overall objective was to demonstrate the MPTP to be a viable target for cardioprotection in patients with HCM.

Background The purpose of this study was to evaluate outcomes of mitral and tricuspid valve repair after mediastinal radiation therapy. Methods From 1976 to 2001, 22 patients (mean age 61 ± 14 years) underwent mitral (n = 14), tricuspid (n = 6), or both (n = 2) valve repairs 15 ± 9 years after mediastinal radiation therapy. Concomitant procedures included coronary artery bypass graft, 11 patients; valve replacement, 6 patients (4 aortic, 3 mitral, 1 tricuspid, and 1 pulmonary); and pericardiectomy, 4 patients. Results Total follow-up was 82.5 patient-years (mean 3.7 ± 3.3 years). Early mortality was 3 patients. There were 7 late deaths, 4 of which were of cardiovascular origin. Of the 19 early survivors, 2 required subsequent valve replacements, and 1 required cardiac transplantation 3.4 ± 2.8 years after valve repair. One patient died after reoperation. In 4 patients who did not undergo reoperation, echocardiographic examinations showed progressive deterioration of their repaired valve function. Overall survival, freedom from cardiac death, and freedom from valve reoperation or cardiac transplantation at 5 years for early survivors was 66%, 85%, and 88%, respectively. New York Heart Association functional class at follow-up was I or II in 8 of the 12 late survivors. Conclusions Functional status was good in two-thirds of late survivors. However, severe dysfunction of the repaired valve developed in 32% of early survivors and 16% required further surgery. Valve repair is technically feasible in selected patients after mediastinal radiation therapy; however, the limited durability of repairs after mediastinal radiation in this series suggests that valve replacement might be preferable.

Background Advances in tissue prosthetic valve design and manufacturing have stimulated renewed interest in the use of biological valves in younger patients. This approach, however, risks reoperation. We therefore reviewed our recent experience with repeat mitral valve replacement to better define its contemporary risks. Methods Using a computerized database, we identified and compared 106 patients undergoing repeat mitral valve replacement with 562 control patients undergoing primary mitral valve replacement between January 1993 and December 2000 at our institution. Results There were no significant differences between repeat and primary surgery groups with respect to age (mean 66 ± 12 vs 64 ± 13 years), gender distribution (women 65% vs 64%), preoperative functional class, ejection fraction, or active endocarditis (6.6% vs 3.4%). The indication for reoperation in the repeat group was structural dysfunction in 49 patients (46%), paravalvular leak in 21 patients (20%), nonstructural dysfunction in 11 patients (10%), and progression of other native valve disease in 8 patients (8%). Prior prostheses were mechanical in 46 patients (43%). Mean time to reoperation was 11.5 ± 7.1 years. There were 5 deaths out of 106 patients in the repeat group (4.7%) and there were 23 deaths out of 562 patients in the control group (4.1%) ( p = NS). Multivariate analysis identified prior myocardial infarction ( p = 0.014, odds ratio 2.9) and nonelective surgical status ( p = 0.004, odds ratio 2.3) as significant predictors of operative mortality. Conclusions The risk of repeat mitral valve replacement was low suggesting that there should be less reluctance to recommend patients choose a bioprosthesis over a mechanical prosthesis. Given the expected durability of current designs, bioprosthetic use may be explored in younger patients without subjecting those individuals to excessive risk.

Background— Recent studies in animals suggest that circulating recipient endothelial precursors may participate in the biology of transplant vasculopathy. It is currently unknown whether a similar interaction between recipient endothelial cells and the vessel wall occurs in human subjects undergoing allogeneic cardiac transplantation. Methods and Results— Circulating endothelial cells and endothelial progenitor cells (EPCs) were quantified in 15 cardiac transplantation subjects with and without angiographic evidence of vasculopathy. In a separate series of experiments, the origin (donor or recipient) of transplant plaque endothelial cells was assessed in subjects who had undergone a gender-mismatched cardiac transplantation and had histological evidence of severe vasculopathy at the time of heart explantation. Circulating EPC outgrowth colonies in peripheral blood were significantly reduced in subjects with transplant vasculopathy compared with those without angiographic evidence of disease (EPC colony-forming units [CFU EPC ]: 4.5±1.9 versus 15.1±3.7, P Conclusions— These data suggest that the human cardiac transplant arteriopathy is associated with reduction in circulating endothelial precursors and with seeding of recipient-derived endothelial cells at the site of plaque development.

The exercise capacity of cardiac transplant recipients is reduced compared with normal controls. However, clinical variables predictive of post-transplant exercise capacity have not been well defined. The objective of the present study was to identify clinical features predictive of post-transplant exercise capacity.Ninety-five cardiac transplant recipients underwent cardiopulmonary testing at 1 year after transplant. The exercise parameters were compared with both pre-transplant values and normal subjects. The relationships between exercise parameters and clinical characteristics were analyzed.Mean peak oxygen consumption (VO(2)) and exercise test duration at 1-year post-transplant improved significantly from 16.4 to 19.9 ml/kg/min and 5.5 to 7.6 minutes, respectively (p0.001), but were significantly lower than for normal controls (peak VO(2) 34.0 ml/kg/min; exercise duration 11.2 minutes; p0.001). Age- and gender-adjusted VO(2) was 54% of predicted. Pre-operative body weight correlated strongly with post-transplant weight (r = 0.80, p0.001). Significant recipient predictors of 1-year post-transplant peak VO(2) identified by multivariate regression analysis were age, male gender, body mass index, exercise peak heart rate and duration of post-operative intensive care. Donor variables did not contribute significantly to post-transplant peak VO(2).Peak VO(2) improved after cardiac transplantation but remained significantly impaired compared with normal subjects. In estimating the impact of cardiac transplantation on exercise capacity the most important pre-transplant factors to consider are age, gender and height and weight (or, alternatively, body mass index).

Introducing recombinant genes into donor hearts may offer a therapeutic intervention that could potentially attenuate the complications of heart transplantation, including rejection, infection and accelerated atherosclerosis. In the cardiovascular system, reduced bioactivity of endothelial nitric oxide is a feature of atherosclerosis and vascular injury. Nitric oxide is an arterial vasodilator that also inhibits proliferation of vascular smooth muscle cells and platelet aggregation. Experiments were designed to determine the distribution of adenoviral-mediated transfer of recombinant endothelial nitric oxide synthase gene (eNOS) and the effect of recombinant gene expression on the function of transplanted hearts. Adenoviral vectors for (a) bovine eNOS (AdeNOS) or (b) beta-galactosidase (AdLacZ; control) were infused into two groups (n = 12, per group) of explanted rat hearts. The transduced hearts were then implanted heterotopically into the abdomen of syngeneic recipient rats. After four days, the hearts were excised and examined for distribution and function of the recombinant genes. Polymerase chain reaction (PCR) verified the presence of the recombinant eNOS gene in eNOS-transduced but not in beta-galactosidase-transduced hearts; reverse transcriptase-PCR identified mRNA for eNOS in AdeNOS-transduced hearts. NOS activity (conversion of tritiated L-arginine to citrulline) was greater in homogenates of AdeNOS-compared to AdLacZ-transduced hearts. Positive immunoreactivity for eNOS was present in cardiomyocytes predominantly in eNOS-transduced hearts. Myocardial contractility and coronary blood flow, as determined using a Langendorff preparation, were not different between hearts transduced with AdeNOS or AdLacZ. These results suggest that, up to four days post transplantation, adenoviral-mediated transfer of eNOS into transplanted hearts is possible. However, expression of the recombinant protein did not result in measurable changes in myocardial contractility or coronary perfusion.

OBJECTIVE: The transfer of recombinant genes to donor organs may allow for novel therapeutic approaches to the challenges of acute and chronic rejection. Adenoviral vectors are capable of efficient gene transfer, but use of these vectors during donor organ preservation may be less efficient due to the low temperature. This study was designed to examine the effect of temperature on the efficiency of adenovirus-mediated gene transfer. METHODS: Gene transfer to human endothelial cells, porcine vascular smooth muscle cells and cultured rat thoracic aortas was examined. Incubation with an adenoviral vector encoding for E. coli beta-galactosidase was performed for 1 h at three different temperatures: 4 degrees C, 10 degrees C and 37 degrees C. Transgene expression was assessed by histochemical staining for beta-galactosidase in transduced cells and by evaluation of beta-galactosidase activity in organ cultures. RESULTS: Both in human endothelial cells and vascular smooth muscle cells the percentage of positively staining cells following transduction at 37 degrees C was significantly greater than at 4 degrees C and at 10 degrees C (30.55 +/- 7.26% vs. 14.29 +/- 3.79% and 12.43 +/- 2.47%, respectively for endothelial cells, P < 0.01 vs. 4 degrees C and 10 degrees C; and 28.25 +/- 4.52% vs. 17.91 +/- 3.76% and 16.63 +/- 3.92%, respectively for smooth muscle cells, P < 0.05 vs. 4 degrees C, P < 0.01 vs. 10 degrees C). Beta-galactosidase activity was significantly greater in aortas transduced at 37 degrees C than in vessels transduced at 4 degrees C and 10 degrees C (289,700 +/- 113,300 vs. 149,600 +/- 54,390 and 108,800 +/- 23,140 relative chemiluminesce units/mg of total protein, respectively; P < 0.05 vs. 4 degrees C, P < 0.001 vs. 10 degrees C). CONCLUSIONS: The present study demonstrates that the efficiency of adenovirus-mediated gene transfer is significantly reduced at lower temperatures. The need for cold preservation of donor organs may render efficient adenovirus-mediated gene transfer more difficult in the transplantation setting.

Objective: Shortage of donor organs for children has led to the use of living related adult lung lobar transplants. It is not known how these lobes or the recipient remaining lung grow after such transplants. The purpose of the present study was to assess lung growth in rat lungs up to 6 months after adult lobe transplantation into a juvenile recipient. Methods: Right cardiac lung lobes from adult male Lewis rats were transplanted into the left hemithorax of juvenile (6-week-old) male Lewis rats after left pneumonectomy. Animals with appropriate controls were put to death 14 days and 6 months after transplantation. The lungs were fixed inflated and studied by means of quantitative morphometric techniques. Results: By 6 months after transplantation both the recipient right lung and the transplanted cardiac lobe were significantly larger than normal ( p = 0.005; p = 0.001). In the recipient right lung this increase was due to an increase in the number of alveoli ( p = 0.004) and in the transplanted cardiac lobe to an increase in size of the alveoli ( p = 0.008). Conclusions: An adult lobe transplanted into a young recipient is still viable and has normal architecture after 6 months, and growth of the recipients' own lung continues. The outlook for comparable transplants in children is promising, although the human condition can be complicated by rejection, infection, and treatment strategies. (J Thorac Cardiovasc Surg 1998;115:644-51)

Background —The physiological stress suffered by patients with heart failure results in an increased production of cortisol and a shift in the leukocyte differential toward a decreased percentage of lymphocytes (%L). The purpose of this study was to determine the prognostic significance of a low %L in advanced heart failure. Methods and Results —Patients evaluated in our cardiac transplantation clinic between April 1988 and July 1995 were retrospectively reviewed (n=263). Fifty-two patients were excluded because they had recent trauma, infection, surgery, myocardial infarction, corticosteroid use, or history of malignancy. In the remaining 211 patients, we used Cox proportional hazards analysis to examine the association between survival and transplant-free survival with baseline variables. Univariate analysis showed a significant association between time to death and %L ( P =.004), New York Heart Association (NYHA) class ( P =.002), and maximal oxygen uptake ( P =.05). Univariate analysis of the end point of survival free from transplantation yielded similar results. One- and 4-year survival rates for patients with a low %L (P P Conclusions The relative lymphocyte concentration is an inexpensive, readily available, simple prognostic marker in patients with symptomatic heart failure who do not have recent trauma, infection, surgery, myocardial infarction, corticosteroid use, or history of malignancy. It could be incorporated into clinical models to predict patient outcome and to aid in the selection of patients for cardiac transplantation.

Experiments were designed to determine whether normal fluctuations in sex steroid hormones alter gene transcription for endothelial nitric oxide synthase (NOS) and preproendothelin-1 (prepro-ET-1). Aortic endothelial cells were removed from adult, gonadally intact male and female or ovariectomized Yorkshire pigs. Endothelial cells were prepared for Northern blot analysis, Western blot analysis or enzyme activity. Nitric oxide products (NOx) and endothelin-1 (ET-1) in plasma were measured by chemiluminescence and radioimmunoassay, respectively. Northern blot analysis identified single bands corresponding to endothelial NOS and prepro-ET-1. Quantification of the blots showed an increase in expression of mRNA for both endothelial NOS and prepro-ET-1 in ovariectomized pigs compared with gonadally intact male and female pigs. There were no differences in amount of endothelial NOS protein identified by Western blot analysis among groups. On the contrary, plasma concentrations of NOx were significantly decreased in ovariectomized pigs, and there were no differences either in the concentrations of ET-1 in the plasma or extracts from the coronary arteries. These results suggest that expression of endothelial NOS and prepro-ET-1 may be regulated at transcriptional level by ovarian hormones. In addition, the ovarian hormones may regulate production of these endothelium-derived factors at the posttranscriptional level.

This study compares the effect of lung preservation using flush perfusion of Euro-Collins or University of Wisconsin solution on the pulmonary vascular function of endothelium-dependent and endothelium-independent relaxations.Rings of canine intrapulmonary arteries were studied after 6 hours of cold ischemia in Euro-Collins or University of Wisconsin preservation solution. Endothelium-dependent and endothelium-independent relaxations were induced in organ chamber experiments. To also study pulmonary resistance vessels, endothelium-dependent relaxations were induced in in vitro perfused intact rabbit lungs.In the organ chamber experiments, a moderate but significant (p0.05) reduction in endothelium-dependent relaxations were found in the perfused and stored vessels. In perfused rabbit lungs, a decrease in the endothelial response occurred immediately after perfusion with Euro-Collins solution. However, a recovery and overshooting response was found after preservation with either solution and 6 hours of cold ischemia. A significant increase in the sensitivity of smooth muscle cells to nitric oxide was shown in both preparations.Both crystalloid perfusion fluids cause a decrease in endothelial function during the perfusion procedure. In contrast, endothelial function is well preserved during the ischemic time. University of Wisconsin solution induced a higher sensitivity of the vascular smooth muscle to the endothelium-derived relaxing factor nitric oxide. A reduction in pulmonary vascular resistance after University of Wisconsin preservation may be of importance in subsequent clinical lung transplantation.

The use of paracorporeal mechanical biventricular support devices either as a bridge to transplantation or while awaiting recovery of the failing heart has been well described in the literature. The majority of these reports detail conditions specific to the adult population. We describe use of the Thoratec ventricular assist device (Thoratec Corp, Pleasanton, CA) in the smallest known cardiomyopathy patient to date to be successfully supported with an emergent biventricular device before subsequent cardiac transplantation. The operative technique, pump settings, and modifications utilized to optimize peripheral perfusion are detailed.

Circulating leukocytes activated during rejection of organ allografts could potentially have generalized effects on systemic blood vessels of the transplant recipient. Experiments were designed, therefore, to determine the function of the endothelium and smooth muscle of arteries from nontransplanted organs in dogs who received single lung transplants. Dogs underwent single lung allotransplantation and were immunosuppressed for 5 days. Immunosuppression was then withheld for 3 days, allowing rejection to occur. Dogs were studied at this time (rejecting) or following treatment for rejection for an additional 6-8 days (treated). Arteries from unoperated, untreated dogs also were studied to provide baseline responses of healthy tissue. Rings cut from left circumflex coronary, nonoperated native pulmonary, and renal arteries were suspended in organ chambers for measurement of isometric force. Endothelium-dependent relaxations to the calcium ionophore A23187 were not affected by rejection in any of the arteries. Contractions to angiotensin I were reduced significantly only in native pulmonary arteries. Contractions to KCI and endothelin-1 increased in renal arteries with endothelium during rejection. These contractions in renal arteries were reduced following treatment of rejection. None of the responses of the coronary arteries were affected significantly by rejection of the lung allograft. These results demonstrate that contractions of arteries in the transplant recipient's native organs are altered during rejection of lung allografts. The effects are organ specific, may include production of endothelium-derived contractile factors in renal arteries, and can be partially reversed by treatment of rejection.

PURPOSE Experiments were designed to determine whether or not leukocytes activated by acute pulmonary rejection cause contractions of isolated pulmonary arteries. METHODS AND RESULTS Separate suspensions of (a) polymorphonuclear cells (> 95%) and (b) mononuclear cells (85% lymphocytes/10% monocytes/5% polymorphonuclear cells), respectively, were obtained from the arterial blood of four groups of adult male mongrel dogs: unoperated dogs (controls), dogs with single-lung autotransplants, dogs with rejecting single-lung allotransplants, and unoperated dogs treated with the same immunosuppressants as allotransplanted dogs. These suspensions were added to rings of control intralobar pulmonary arteries suspended in organ chambers for measurement of isometric force. The endothelium was removed mechanically from selected rings. No significant change in basal tension of pulmonary arterial rings occurred by adding suspensions of polymorphonuclear cells from any of the four groups of dogs. Significant cell-number-dependent increases in tension occurred with suspensions of mononuclear cells from unoperated dogs, autotransplanted dogs, and unoperated, medicated dogs. These increases in tension were less in rings with compared to those without endothelium. Addition of a synthetic analogue of L-arginine abolished this difference. Suspensions of mononuclear cells from rejecting allotransplanted dogs caused significantly greater contractions in rings with endothelium than those observed with suspended cells from either unoperated, autotransplanted dogs or unoperated, medicated dogs. Addition of superoxide dismutase plus catalase or an antagonist of endothelin-A receptors (BQ-123) reduced contractions in rings with endothelium but not in those without endothelium to suspensions of mononuclear cells from rejecting allotransplanted dogs. CONCLUSIONS The results of this study suggest that mononuclear cells cause contraction of pulmonary arteries, which can be partially inhibited by endothelium-derived nitric oxide. However, if the mononuclear cells are activated by acute pulmonary rejection, contractions are no longer inhibited by the endothelium. Under conditions of rejection, contractions are mediated in part by oxygen radicals and endothelin(s).

Ischemia of the donor airway remains a significant cause of morbidity after single-lung transplantation; serious manifestations may occur early (anastomotic dehiscence) or late (stricture). Direct, immediate revascularization of the donor bronchial arteries, using the recipient internal thoracic artery, was performed in 10 consecutive recipients of single-lung transplants for whom we procured the organs. Mean recipient age was 52.6 years (range, 43 to 59 years); 6 were male and 4 female. Recipient diagnoses were emphysema (6), obliterative bronchiolitis (2), pulmonary fibrosis (1), and primary pulmonary hypertension (1). Bronchial artery revascularization initially prolonged the ischemic time by only 15 to 20 minutes; this improved with experience. There was one early death and two late deaths in the series. Internal thoracic arteriography was performed 7 to 10 days postoperatively in all 9 surviving patients. There was excellent perfusion of the donor bronchial arteries in 7 of these 9 patients. Bronchoscopy was performed when clinically indicated. No patient had early or late airway healing complications at a median follow-up of 13 months (range, 6 to 16 months). We conclude that direct, immediate bronchial artery revascularization is feasible on a routine basis for single-lung transplantation, and airway healing has been excellent.

BACKGROUND Although recent investigations report the elevation of plasma endothelin (ET) in congestive heart failure (CHF), it remains unclear if this elevation is that of the biologically active peptide ET-1 or of its precursor big-ET. Furthermore, it is unclear if such elevation is associated with increased myocardial ET and if the molecular form from cardiac tissue is altered ET. Last, it remains to be established whether circulating ET is increased at the earliest stage of CHF in patients with asymptomatic left ventricular dysfunction and correlates with the magnitude of ventricular dysfunction. METHODS AND RESULTS The present study was designed to investigate concentrations and molecular forms of ET in plasma and cardiac tissue in healthy subjects and CHF patients with New York Heart Association (NYHA) class I through IV using cardiac radionuclide angiogram, cardiac myocardial biopsy, radioimmunoassay, gel permeation chromatography (GPC), and immunohistochemical staining (IHCS). Plasma ET was increased only in patients with moderate (NYHA class III) or severe (NYHA class IV) CHF compared with healthy subjects and individuals with asymptomatic (NYHA class I) or mild (NYHA class II) CHF. The elevation of circulating ET in CHF showed a negative correlation with left ventricular ejection fraction and cardiac index and a positive correlation with functional class and left ventricular end-diastolic volume index. GPC demonstrated that immunoreactive plasma ET was ET-1 in healthy subjects and both mature ET-1 and its precursor big-ET in severe CHF patients, with big-ET the predominant molecular form. Cardiac tissue concentrations and IHCS revealed ET presence in healthy atrial and ventricular tissue, which were not different in severe CHF. GPC revealed that the molecular form of cardiac ET was ET-1 in both healthy and CHF hearts. CONCLUSIONS The present study establishes for the first time that the elevation of plasma ET in severe human CHF represents principally elevation of big-ET. Second, ET is present in healthy and failing myocardia, and its activity by both immunohistochemistry and radioimmunoassay is not changed in CHF. Furthermore, the elevated plasma ET is characteristic of severe CHF and not asymptomatic or mild CHF. In addition, the degree of plasma elevation of ET correlates with the magnitude of alterations in cardiac hemodynamics and functional class. The present study confirms and extends previous investigations of ET in human CHF and establishes the evolution of circulating and local cardiac ET in the spectrum of human CHF.

The effects of pulmonary denervation and rejection on contractions of bronchial smooth muscle and epithelial modulation of these contractions were studied in dogs after denervation in right lung autotransplantation (n = 6) and acute rejection after right lung allotransplantation (n = 8). Immunosuppression was withdrawn from the latter group after 5 days; rejection developed after 3 additional days. A significant (p < 0.05) increase in mean peak airway pressure occurred with rejection of allotransplanted lungs. Rings cut from third-order bronchi of transplanted and contralateral unoperated (native) lungs in each animal were suspended in organ chambers for the measurement of isometric force. In some rings, the epithelium was removed mechanically. Acetylcholine (cholinergic neurotransmitter), serotonin (platelet-product), histamine (mast cell product), and endothelin-1 (endothelium-derived contracting factor) caused concentration-dependent contractions in all rings. In bronchi from native lungs, rings with epithelium contracted less than those without epithelium. This difference was lost after autotransplantation. The smooth muscle and epithelium were affected differently by autotransplantation. Contractions of rings without epithelium decreased in response to acetylcholine and endothelin-1, whereas contractions of rings with epithelium increased in response to histamine and 5-hydroxytryptamine (p < 0.05). During acute rejection, contractions were the same as those after autotransplantation. Bronchial content of endothelin increased fourfold with rejection. Relaxations to isoproterenol and prostaglandin E2 were similar in both groups. In conclusion, denervation reduced the ability of the smooth muscle to contract. The degree of acute pulmonary rejection seen in this study did not further affect bronchial contractions. Modulation of contractions by the bronchial epithelium was lost with both denervation and rejection.

BACKGROUND Atrial natriuretic peptide (ANP), brain natriuretic peptide (BNP), and C-type natriuretic peptide (CNP) are a family of structurally related peptides that participate in the integrated control of renal and cardiovascular function. Previous studies suggest a functional role for these hormonal peptides in cardiorenal regulation in congestive heart failure (CHF). METHODS AND RESULTS The present studies were performed in normal subjects (n = 6) and in patients with mild (New York Heart Association [NYHA] class I to II, n = 20) and severe (NYHA class III to IV, n = 20) CHF by use of radioimmunoassay and immunohistochemical staining (IHCS). Plasma ANP was significantly increased in both mild and severe CHF compared with normal subjects. In contrast, plasma BNP was only moderately increased in the severe CHF group, and plasma CNP concentration was unchanged in CHF compared with normal subjects. Atrial tissue concentrations of the natriuretic peptides did not parallel circulating concentrations. ANP predominated in normal atrial tissue, but BNP predominated in CHF. In ventricular tissue, IHCS staining was present for all three peptides in normal ventricular myocardium and was markedly enhanced in CHF. CONCLUSIONS These studies support a differential regulation of ANP, BNP, and CNP circulating concentrations and tissue activity in human CHF.

To determine factors that influence survival and recovery of ventricular function in patients undergoing aortic valve replacement in the current surgical era, baseline risk factors related to outcome were analyzed in 1,012 consecutive patients undergoing aortic valve replacement between 1983 and 1990. Forty-two percent of patients underwent concomitant coronary bypass. Observed survival probabilities (expressed as 30-day/5-year) were 0.97/0.81 overall, 0.99/0.89 for patients aged less than 70 years, and 0.95/0.74 for patients aged 70 years or greater. Advanced age (p < 0.0001), decreased ejection fraction (p < 0.0001), extent of coronary disease (p < 0.006), smaller prosthetic valve (p < 0.03), and advanced New York Heart Association class (p < 0.04) were incremental risk factors for mortality. In patients with preoperative ventricular dysfunction (ejection fraction < or = 0.45), ejection fraction measured 1.4 years after aortic valve replacement improved in 72% and the mean increment in ejection fraction was 0.175 (95% confidence interval, 0.154 to 0.195). The increment in ejection fraction was greater in female patients than in male patients (p < 0.02) and greater in patients without than with coronary disease (p < 0.02). Female sex (p < 0.02) and lesser extent of coronary disease (p < 0.05) were independent predictors of change in ejection fraction. In all patients, early improvement in ejection fraction conveyed an independent subsequent survival benefit (p < 0.0001). The results of aortic valve replacement in the current era are excellent, and the majority of patients with ventricular dysfunction demonstrate significant improvement. Early improvement in ejection fraction, influenced by coexistent coronary artery disease and sex-associated factors, importantly affects subsequent survival.

Transbronchial biopsy has become the procedure of choice for the diagnosis of acute lung rejection after transplantation, but the sensitivity of the technique in this setting remains unknown. In this study, 14 mongrel dogs underwent left lung transplantation, after which triple-drug immunosuppression was given for 5 days and then all immunosuppression was stopped. All animals had clear chest radiographs at this time. Transbronchial biopsy was performed in nine lung regions (two to six pieces of lung tissue were obtained per region, with a mean of 4.3 pieces per region) before the animals were killed 2 to 4 days later, at which time varying degrees of rejection had occurred. Rejection was graded histologically on a scale of 0 to 3 (0 = no rejection, 1 = mild rejection, 2 = moderate rejection, 3 = severe rejection) in each piece of lung tissue obtained at transbronchial biopsy. After the dogs were put to death, the true state of lung rejection was determined by histologic examination of the entire lung. We calculated the sensitivity of transbronchial biopsy with 95% confidence intervals. Five pieces of lung tissue were needed to yield a sensitivity of 92% (82%, 100%) to identify mild rejection in the entire lung with transbronchial biopsy. Three pieces of lung tissue were needed to yield a sensitivity of 92% (84%, 100%) to identify the presence of moderate to severe rejection in the entire lung (that is, rejection that requires pulse therapy) on transbronchial biopsy. These results indicate that three to five pieces of lung tissue that are suitable for diagnostic purposes obtained at transbronchial biopsy are adequate for the diagnosis of acute pulmonary rejection after lung transplantation.

Experiments were designed to determine the viability of endothelial cells and their responses to products released by aggregating platelets following single flush perfusion of the coronary arteries with cardioplegic solutions used for cardiac transplantation. Porcine coronary arteries were perfused with crystalloid (Plegisol) or blood cardioplegic solutions; nonperfused hearts placed in 0.9% saline were used as controls. Immediately following perfusion and after 5-hour storage of the hearts in the same cardioplegic solution, rings were cut from the right coronary arteries and suspended in organ chambers for the measurement of isometric force. In some rings the endothelium was removed deliberately. The left circumflex coronary arteries were flushed with collagenase and the harvested endothelial cells were plated for cell culture. Left anterior descending coronary arteries were perfusion fixed with glutaraldehyde for scanning electron microscopy. In the organ chamber experiments, aggregating platelets and adenosine diphosphate caused relaxations in rings with endothelium. These relaxations were reduced immediately following crystalloid cardioplegia and were restored following 5-hour storage. Serotonin caused contractions in all rings. Rings without endothelium were more sensitive than rings with endothelium to the amine; this difference was augmented following 5-hour storage of the heart. Significantly fewer foci of endothelial cells grew in culture following 5-hour storage of the hearts in crystalloid cardioplegic solution compared to control (p < 0.05). There were no anatomical differences identified among groups by scanning electron microscopy. These results suggest that crystalloid cardioplegia alters the responses of coronary arteries to substances released by aggregating platelets and reduces the ability of endothelial cells to replicate. Such changes may contribute to altered vascular resistance following reperfusion of transplanted hearts and potentially to later structural changes in the coronary arteries.

Background— Diffuse myocardial fibrosis is a final end point in most cardiac diseases. It is missed by the cardiovascular magnetic resonance (CMR) late gadolinium enhancement technique. Currently, quantifying diffuse myocardial fibrosis requires invasive biopsy, with inherent risk and sampling error. We have developed a robust and noninvasive technique, equilibrium contrast CMR (EQ–CMR) to quantify diffuse fibrosis and have validated it against the current gold standard of surgical myocardial biopsy. Methods and Results— The 3 principles of EQ–CMR are a bolus of extracellular gadolinium contrast followed by continuous infusion to achieve equilibrium; a blood sample to measure blood volume of distribution (1−hematocrit); and CMR to measure pre- and postequilibrium T1 (with heart rate correction). The myocardial volume of distribution is calculated, reflecting diffuse myocardial fibrosis. Clinical validation occurred in patients undergoing aortic valve replacement for aortic stenosis or myectomy in hypertrophic cardiomyopathy (n=18 and n=8, respectively). Surgical biopsies were analyzed for picrosirius red fibrosis quantification on histology. The mean histological fibrosis was 20.5±11% in aortic stenosis and 17.1±7.4% in hypertrophic cardiomyopathy. EQ–CMR correlated strongly with biopsy histological fibrosis: aortic stenosis, r 2 =0.86, Kendall Tau coefficient (T)=0.71, P r 2 =0.62, T=0.52, P =0.08; combined r 2 =0.80, T=0.67, P Conclusions— We have developed and validated a new technique, EQ–CMR, to measure diffuse myocardial fibrosis as an add-on to a standard CMR scan, which allows for the noninvasive quantification of the diffuse fibrosis burden in myocardial diseases.

Equilibrium acquisition was optimized in 16 individuals and achieved by a combination of loading bolus and slow continuous infusion. The T1 measurement technique and heart rate correction was validated in phantoms against T1 relaxometry and then against blood [Gd-DTPA]. Clinical validation was in patients undergoing AVR for AS or myectomy in HCM (n = 18 and 8 respectively). The surgical biopsies were analyzed using fully automated image analysis (macros in ImageJ) for picro-sirius red fibrosis quantification on histology. The scan protocol is outlined in Figure 1. from 13th Annual SCMR Scientific Sessions Phoenix, AZ, USA. 21-24 January 2010