Heart transplantation with and without prior sternotomy: analysis of the United Network for Organ Sharing database.

INTRODUCTION: Patients with history of prior sternotomy may have poorer outcomes after heart transplantation. Quantitation of risk from prior sternotomy has not been well established. The United Network for Organ Sharing (UNOS) database was analyzed to assess early and late survival and predictors of outcome in adult heart transplant recipients with and without prior sternotomy. METHODS: Of 11,266 adults with first heart-only transplantation from 1997 to 2011, recipients were divided into 2 groups: those without prior sternotomy (first sternotomy group; n = 6006 or 53.3%) and those with at least 1 prior sternotomy (redo sternotomy group; n = 5260 or 46.7%). A multivariable Cox model was used to identify predictors of mortality. RESULTS: Survival was lower in the redo group at 60 days (92.6% vs 95.9%; hazard ratio [HR] 1.83, 95% confidence interval [CI]: 1.56-2.15; P < .001). Conditional 5-year survival in 60-day survivors was similar in the 2 groups (HR = 1.01, 95% CI 0.90-1.12, P = .90). During the first 60 days post-transplant, the redo group had more cardiac reoperations (12.3% vs 8.8%, P = .0008), a higher frequency of dialysis (8.9% vs 5.2%, P < .0001), a greater percentage of drug-treated infections (23.2% vs 19%, P = .003), and a higher percentage of strokes (2.5% vs 1.4%, P = .0001). A multivariable Cox proportional hazards model identified prior sternotomy as a significant independent predictor of mortality, in addition to age, female gender, congenital cardiomyopathy, need for ventilation, mechanical circulatory support, dialysis prior to transplant, pretransplant serum bilirubin (≥ 3 mg/dL), and preoperative serum creatinine (≥ 2 mg/dL). CONCLUSIONS: Prior sternotomy is associated with an excess 3.3% mortality and higher morbidity within the first 60 days after heart transplantation, as measured by frequency of dialysis, drug-treated infections, and strokes. Conditional 5-year survival after 60 days is unaffected by prior sternotomy. These findings should be taken into account for risk assessment of patients undergoing heart transplantation.

Antithymocyte globulin induction therapy adjusted for immunologic risk after heart transplantation.

INTRODUCTION: The efficacy of antithymocyte globulin (ATG) induction in the therapy of immunologically low- and high-risk patients after heart transplantation is not known. METHODS: All patients who received ATG induction from January 2000 through January 2010 were divided into two groups based on the risk of rejection. A higher-risk group (age younger than 60 years, multiparous females, African Americans, panel-reactive antibody >10%, or positive cross-match) received ATG (1.5 mg/kg) for 7 days (ATG7), and the remaining lower-risk group received ATG for 5 days (ATG5), all followed by calcineurin inhibitor, mycophenolate, and prednisone. Endomyocardial biopsies were performed based a standard protocol for up to 3 years after heart transplantation, and for suspected rejection. RESULTS: Of 253 heart transplant recipients, 87 received ATG5 and 166 ATG7. Absolute lymphocyte count <200 per microliter was achieved within 10 days in 88% of ATG5 and 86% of ATG7. Baseline creatinine was 1.3 ± 0.8 pre-transplantation, 1.8 ± 0.9 post-transplantation, and 1.0 ± 0.4 mg/dL at discharge (mean ± standard deviation [SD]; P < .001, compared with pre-transplantation). Of 3667 biopsies, 33 (0.90%) had ≥3A/2R cellular rejection (CR). Of 3599 biopsies, 16 (0.44%) had definite antibody-mediated rejection (AMR). At 5 years, freedom from ≥3A/2R CR (94% ± 2.8% vs 83% ± 7.7%; P = .31) and freedom from AMR (95% ± 2.4% vs 90% ± 6.4%; P = .98) were similar between ATG5 and ATG7, respectively. Survival for ATG5 and ATG7 was comparable at one year (94% ± 2.5% vs 93% ± 2.0%), and at 8 years (61% ± 6.9% and 61% ± 4.7%; P = .88). At 5 years, ATG5 and ATG7 were similar in freedom from cytomegalovirus (CMV) infection (92.3% vs 94.3%; P = not significant [NS]), freedom from pneumonia (83.8% vs 82.1%; P = NS), and in rate of malignancy (excluding skin cancer; 8.0% vs 6.0%; P = NS). CONCLUSIONS: ATG induction therapy (prospectively dose-adjusted for immunologic risk) in low- and high-risk patients results in excellent and equivalent short- and long-term survival rates, with a low incidence of CR and AMR. The use of ATG does not increase rates of CMV infection with appropriate prophylaxis. ATG may benefit renal function by delaying calcineurin inhibitor exposure, and may have a role in the prevention of AMR.

Aortic valve replacement or heart transplantation in patients with aortic stenosis and severe left ventricular dysfunction.

INTRODUCTION: The decision to perform aortic valve replacement (AVR) or heart transplantation (HTx) for aortic stenosis (AS) with severe left ventricular dysfunction is difficult and may be affected by prior myocardial infarction (MI) and coronary artery disease (CAD). METHODS: Patients who underwent AVR from 1988 to 2001 with left ventricular ejection fraction (LVEF) <30% and severe AS (aortic valve area [AVA] < 1.0 cm(2); n = 51) were assessed for operative mortality, late survival, and predictors of outcome, and were compared with HTx. Subsequently, 131 patients with LVEF ≤ 35% who underwent AVR for critical AS (AVA < 0.8 cm(2)) were evaluated. RESULTS: In the first 51 patients, 3-year survival was 100% ± 0% with no CAD, and 45% ± 10% with CAD (P < .05); 3-year survival was 88% ± 12% with no bypass, 73% ± 12% with one to two grafts, and 18% ± 11% with three grafts (P < .01). Survival with HTx was 78% at 3 years. In the subsequent analysis of 131 patients, 90-day survivors were followed for a mean 4.6 ± 3.5 years. Advanced age (P = .001) was the only predictor of long-term mortality. LVEF improved from 28.5% ± 5.2% before AVR to 45.4% ± 13.2% at 1-month postoperatively (P < .0001). New York Heart Association (NYHA) class III/IV decreased from 94.2% pre-AVR to 12.8% at 1 year (P < .0001). Predictors of LVEF recovery were no previous MI (P = .007) and higher AS gradient (P = .03). CONCLUSIONS: In severe AS and LVEF <30% with no concomitant CAD or with CAD requiring one to two bypass grafts, AVR has a survival equal to or exceeding that of HTx. In patients with CAD requiring more than two bypass grafts, survival is significantly reduced, and HTx can be considered.

Heart transplantation in patients aged 70 years and older: a two-decade experience.

OBJECTIVE: Advanced age has been viewed as a contraindication to orthotopic heart transplantation (OHT). We analyzed the outcome of OHT in patients who were aged 70 years or older and compared the results with those in younger patients during a two-decade period. METHODS: A total of 519 patients underwent first-time single-organ OHT at our institution from 1988 to 2009. Patients were divided into three groups by age: ≥70-years old (group 1, n=37), 60 to 69-years old (group 2, n=206), and ≤60-years old (group 3, n=276). Primary endpoints were 30-days, and 1-, 5-, and 10-years survival. Secondary outcomes included re-operation for bleeding, postoperative need for dialysis, and length of postoperative intubation. RESULTS: There was no significant difference in survival between the greater than or equal to 70-year-old group and the two younger age groups for the first 10 years after OHT. Survival rates at 30 days, and 1-, 5-, and 10-years, and median survival in group 1 recipients were 100%, 94.6%, 83.2%, 51.7%, and 10.9 years (CI 7.1-11.0), respectively; in group 2 those numbers were 97.6%, 92.7%, 73.8%, 47.7%, and 9.1 years (CI 6.7-10.9), respectively; and in group 3 those numbers were 96.4%, 92.0%, 74.7%, 57.1%, and 12.2 years (CI 10.7-15.4; P=NS), respectively. There was no significant difference in secondary outcomes of re-operation for bleeding, postoperative need for dialysis, and prolonged intubation among the three age groups. CONCLUSIONS: Patients who are aged 70 years and older can undergo heart transplantation with similar morbidity and mortality when compared with younger recipients. Advanced heart failure patients who are aged 70 years and older should not be excluded from transplant consideration based solely on an age criterion. Stringent patient selection, however, is necessary.

Survival and allograft rejection rates after combined heart and kidney transplantation in comparison with heart transplantation alone.

BACKGROUND: The role of solid multiorgan transplantation remains to be determined. We compared our experience with combined heart-kidney transplantation (HKT) and heart transplant alone (HT), and assessed patient survival rates and freedom from allograft rejection in these two patient groups. METHODS: We reviewed the clinical outcomes of patients undergoing HKT (n=30) or HT (n=440) between June 1992 and March 2009. Baseline patient characteristics, perioperative factors, incidence of rejection, and survival were examined. RESULTS: There were no significant differences between the two groups for age, gender, etiology of heart disease, functional class, preoperative left ventricular ejection fraction, end-diastolic diameter, cardiac output, or transplant waitlist status. Patients with HKT had a higher serum creatinine level (P<.001) and a greater incidence of hypertension (P=.04). No differences were found in cardiac allograft ischemic times, including cardiopulmonary bypass or cross-clamp times. Kidney allograft ischemic time was 14.6±9 hours (mean±SD; range, 4 hours to 49 hours). Kaplan-Meier survival estimates were similar for the HKT and HT groups at 30 days (93%±4.6% versus 98%±0.7%), 1 year (87%±6.2% versus 93%±1.2%), 5 years (68%±9.0% versus 76%±2.1%), and 10 years (51%±11% versus 53%±3.0%; P=.54 for all comparisons). Follow-up serum creatinine levels were similar after HKT and HT at 30 days (1.6±1.8 mg/dL versus 1.1±0.4 mg/dL), 1 year (1.4±0.6 mg/dL versus 1.5±0.6 mg/dL), and 5 years (1.8±1.8 mg/dL versus 1.8±1.2 mg/dL; P>.05 for all comparisons). CONCLUSIONS: HKT offers excellent survival and similar renal function when compared with HT alone. Patients with end-stage cardiac and renal failure can be considered for HKT.

Amiodarone-induced QT prolongation in a newly transplanted heart associated with recurrent ventricular fibrillation.

Anti-arrhythmic drugs such as amiodarone have the potential to prolong QT intervals, which can result in torsades de point arrhythmia. It is unknown whether amiodarone, given to a recipient prior to cardiac transplantation, can cause arrhythmia in a newly transplanted donor heart. We report on a case of a 71-year-old male patient who had received intravenous and oral amiodarone prior to transplantation, which was associated with QT prolongation in the transplanted heart after re-exposure to the drug during subsequent episodes of ventricular fibrillation. An ICD was implanted, which has not been described that soon after cardiac transplantation. Amiodarone, given to a recipient, might cause QT prolongation in a donor heart after transplantation, possibly due to its long half-life and increased bioavailability caused by interaction with immunosuppressive drugs.

Twenty-year comparison of tissue and mechanical valve replacement.

OBJECTIVE: We sought to compare outcomes with tissue and St Jude Medical mechanical valves over a 20-year period. METHODS: Valve-related events and overall survival were analyzed in 2533 patients 18 years of age or older undergoing initial aortic, mitral, or combined aortic and mitral (double) valve replacement with a tissue valve (Hancock, Carpentier-Edwards porcine, or Carpentier-Edwards pericardial) or a St Jude Medical mechanical valve. Total follow-up was 13,390 patient-years. There were 666 St Jude Medical aortic valve replacements, 723 tissue aortic valve replacements, 513 St Jude Medical mitral valve replacements, 402 tissue mitral valve replacements, 161 St Jude Medical double valve replacements, and 68 tissue double valve replacements. The mean age was 68 +/- 13.3 years (St Jude Medical valve, 64.5 +/- 12.9; tissue valve, 72.0 +/- 12.6). RESULTS: There were no overall differences in survival between tissue and mechanical valves. Multivariable analysis indicated that the type of valve did not affect survival. Analysis by age less than 65 years or 65 years or older and presence or absence of coronary disease revealed similar long-term survival in all subgroups. The risk of hemorrhage was lower in patients receiving tissue aortic valve replacements but was not significantly different in patients receiving mitral valve or double valve replacements. Thromboembolism rates were similar for tissue and mechanical valve recipients. However, reoperation rates were significantly higher in patients receiving both aortic and mitral tissue valves. The reoperation hazard increased progressively with time both in patients receiving aortic and in those receiving mitral tissue valves. Overall valve complications were initially higher with mechanical aortic valves but not with mechanical mitral valves. However, valve complication rates later crossed over, with higher rates in tissue valve recipients after 7 years in patients undergoing mitral valve replacement and 10 years in those undergoing aortic valve replacement. CONCLUSIONS: Tissue and mechanical valve recipients have similar survival over 20 years of follow-up. The primary tradeoff is an increased risk of hemorrhage in patients receiving mechanical aortic valve replacements and an increased risk of late reoperation in all patients receiving tissue valve replacements. The risk of tissue valve reoperation increases progressively with time.

Radial artery harvesting for coronary bypass operations: neurologic complications and their potential mechanisms.

OBJECTIVES: We sought to determine the incidence of self-reported neurologic hand complications after radial artery harvest for coronary artery bypass grafting. METHODS: Between February 20, 1996, and December 31, 1999, 615 patients underwent coronary bypass operations with radial arteries. A scripted telephone interview was performed, collecting data on perceived thumb weakness and sensation abnormalities in the distribution of the radial nerve in 560 patients. The average time to follow-up interview was 14.5 +/- 9 months. RESULTS: Neurologic complications were reported in 30.1%, decreased thumb strength in 5.5%, and any sensation abnormality in 18.1% of patients. There was a high rate of symptom improvement over an average of 8.7 +/- 7.5 months, such that only 12.1% of patients reported symptoms without any improvement. Associations between thumb weakness and sensory abnormalities imply median nerve damage in some patients. There were statistically significant associations between neurologic complications and diabetes, peripheral vascular disease, elevated creatinine levels, smoking, and number and site of radial artery harvest. CONCLUSIONS: The overall rate of self-reported neurologic complications after radial artery harvest was higher than previously reported. These symptoms may be attributable to radial and median nerve injury caused by trauma and devascularization. These data have important implications not only in attempting to improve harvesting techniques but also in guiding informed consent before coronary artery bypass grafting.

Regression of hypertrophy after Carpentier-Edwards pericardial aortic valve replacement.

BACKGROUND: The purpose of this study was to determine whether significant regression of left ventricular hypertrophy is seen after implantation of small sizes (19 to 23 mm) of the Carpentier-Edwards (CE) pericardial valve, a stented pericardial valve. METHODS: Echocardiograms and electrocardiograms (ECGs) were performed at least 1 year after surgery (mean 18 months) in patients with 19-, 21-, and 23-mm CE pericardial aortic valves and compared with preoperative echocardiograms and ECGs. RESULTS: A total of 41 patients, mean age 79 +/- 9 years (range 46 to 93 years), were studied, including 7 19-mm, 22 21-mm, and 12 23-mm patients. The mean postoperative gradient was 22 +/- 7 mm Hg for 19-mm valves, 18 +/- 5 mm Hg for 21-mm valves, and 16 +/- 4 mm Hg for 23-mm valves. The postoperative valve areas were 1.1 +/- 0.3 cm2 for the 19-mm, 1.3 +/- 0.3 cm2 for the 21-mm, and 1.5 +/- 0.4 cm2 for the 23-mm valves. Left ventricular end diastolic diameter, end systolic diameter, septal thickness, and posterior wall thickness all decreased significantly (p <0.05) postoperatively. The proportion of patients with significant left ventricular hypertrophy on ECG decreased from 63% to 47% (p = 0.001). Left ventricular mass decreased significantly by echocardiography from 265 g preoperatively to 208 g postoperatively (p = 0.004). Left ventricular mass decreased for each valve size, and the greatest absolute reduction in mass occurred in the 19-mm valve recipients. CONCLUSIONS: Implantation of the 19-, 21-, and 23-mm CE pericardial valves results in significant reductions in left ventricular mass. These findings suggest that stented pericardial valves can be used in the small aortic root without the need for aortic root enlargement procedures.

Relation between cellular repolarization characteristics and critical mass for human ventricular fibrillation.

INTRODUCTION: The critical mass for human ventricular fibrillation (VF) and its electrical determinants are unclear. The goal of this study was to evaluate the relationship between repolarization characteristics and critical mass for VF in diseased human cardiac tissues. METHODS AND RESULTS: Eight native hearts from transplant recipients were studied. The right ventricle was immediately excised, then perfused (n = 6) or superfused (n = 2) with Tyrode's solution at 36 degrees C. The action potential duration (APD) restitution curve was determined by an S1-S2 method. Programmed stimulation and burst pacing were used to induce VF. In 3 of 8 tissues, 10 microM cromakalim, an ATP-sensitive potassium channel opener, was added to the perfusate and the stimulation protocol repeated. Results show that, at baseline, VF did not occur either spontaneously or during rewarming, and it could not be induced by aggressive electrical stimulation in any tissue. The mean APD at 90% depolarization (APD90) at a cycle length of 600 msec was 227+/-49 msec, and the mean slope of the APD restitution curve was 0.22+/-0.08. Among the six tissues perfused, five were not treated with any antiarrhythmic agent. The weight of these five heart samples averaged 111+/-23 g (range 85 to 138). However, after cromakalim infusion, sustained VF (> 30 min in duration) was consistently induced. As compared with baseline in the same tissues, cromakalim shortened the APD90 from 243+/-32 msec to 55+/-18 msec (P < 0.001) and increased the maximum slope of the APD restitution curve from 0.24+/-0.11 to 1.43+/-0.10 (P < 0.01). CONCLUSION: At baseline, the critical mass for VF in diseased human hearts in vitro is > 111 g. However, the critical mass for VF can vary, as it can be reduced by shortening APD and increasing the slope of the APD restitution curve.

Lung allograft dysfunction correlates with gamma-interferon gene expression in bronchoalveolar lavage.

BACKGROUND: Preceding episodes of acute cellular rejection (ACR) may predispose lung allografts to the subsequent development of irreversible dysfunction or bronchiolitis obliterans syndrome (BOS). Other histologic patterns such as bronchiolitis obliterans with organizing pneumonia (BOOP), organizing pneumonia, lymphocytic bronchiolitis and diffuse alveolar damage (DAD) may also adversely affect allograft function. We have previously reported the predominant expression of Th1 cytokines (IL-2 and interferon gamma) in rejecting and Th2 (IL-10) in a tolerant model of rat lung transplantation. Here we correlate the "Th1/Th2 paradigm" in clinical lung transplantation with histologic findings and assess the effect on serial spirometric function. METHODS: We examined the mRNA expression of IL-2, interferon gamma, IL-10 and ICAM-1 in 53 bronchoalveolar lavage (BAL) specimens from 23 lung transplant (LT) recipients utilizing qualitative "nested" reverse transcriptase polymerase chain reaction (RT-PCR). We also measured IgG1 and IgG2 levels in 44 BAL specimens by ELISA. The mRNA expression for cytokines, ICAM-1 and the IgG2/IgG1 ratios were correlated with the presence or absence of ACR and alternate "histologic patterns". Serial spirometry were analyzed for the 2-3 month interval before bronchoscopic (FOB) assessment to derive "baseline" forced expiratory volume-one second (FEV1) values. The change in FEV1 coincident with (deltaFEV1 pre) and for the 2-3 month interval subsequent to (deltaFEV1 post) FOB were expressed relative to "baseline" spirometric indexes. RESULTS: Detection of mRNA for interferon gamma and ICAM-1 correlated significantly with ACR, whereas IL-2 and IL-10 expression did not correlate. IL-10 was virtually "ubiquitous" in most BAL samples irrespective of the presence or absence of ACR. The highest correlation was observed with interferon gamma for acute cellular rejection whereupon the sensitivity was 77.7%, specificity 87.7%, positive predictive value 73.6% and negative predictive value 88.2%, although for ICAM-1 these values were 75%, 65.7%, 50.0% and 85.0%, respectively. Nevertheless, 4 of 5 episodes of respiratory tract infection (bacterial, CMV, Aspergillus spp.) were similarly associated with cytokine mRNA. The ratios of IgG2 to IgG1, a reflection of Th1/Th2 influence, were not statistically different when analyzed for the presence or absence of ACR (0.91+/-0.53 vs. 1.02+/-0.70, respectively; p = NS). By analysis of FEV1 trends, expression of interferon gamma was associated with a greater and persistent decrement (deltaFEV1 pre: -0.265+/-0.78 liters, and post: -0.236+/-0.1161; mean +/- SE) than ACR in the absence of interferon gamma expression (+0.158 +/- +0.065 and +0.236+/-0.007 liters, respectively) (Student-Newman-Keuls, p<.05). CONCLUSION: Our findings suggest that interferon gamma mRNA expression and ICAM-1 may be valuable in both the diagnosis and prognosis for lung allograft ACR. IL-10, a Th2 cytokine, was locally expressed both in the presence and absence of ACR. Expression of mRNA for interferon y in BAL and, to a lesser extent ICAM-1, were associated with increased lung allograft dysfunction. Whether BAL cytokine "immunosurveillance" would complement or possibly supplant a specific "histologic pattern" and thereby direct different therapies after lung transplantation, may be potentially rewarding areas of further investigation.

Correlation of acute and chronic defibrillation threshold with upper limit of vulnerability determined in normal sinus rhythm.

BACKGROUND: The upper limit of vulnerability (ULV) is the stimulus strength above which ventricular fibrillation cannot be induced, even when the stimulus occurs during the vulnerable period of the cardiac cycle. Determination of ULV using T-wave shocks during ventricular pacing has been shown to closely correlate with the defibrillation threshold (DFT) at ICD implantation. However, there are no data correlating ULV determined in sinus rhythm at ICD implantation, with DFT determined at implantation or during long-term follow-up. This is of clinical importance since ULV may be used to estimate DFT during ICD implantation, both during ventricular pacing or sinus rhythm. METHODS AND RESULTS: Twenty-one patients receiving a transvenous ICD system were studied prospectively. There were 16 males and 5 females, mean age 68 +/- 15 years, with mean ejection fraction 37.4 +/- 17.4%. All had structural heart disease. The ULV was defined as the lowest energy that did not induce ventricular fibrillation with shocks at 0, 20 and 40ms before the peak of the T-wave, using a step-down protocol. The initial energy tested was 15J and the lowest energy 2J. DFT was determined following a similar step-down protocol. The DFT was defined as the lowest energy that successfully defibrillated the ventricles. The linear correlation coefficient between ULV and DFT was r = 0.73 (p < 0.001). At implant, mean ULV was 9.2 +/- 5J, not statistically different from mean DFT 9.4 +/- 4J. ULV plus 5J successfully defibrillated 19 of 21 patients. During long-term follow-up of 10.1 +/- 1.8 months in eight patients, DFT was 8.8 +/- 5.8J, not significantly different than the DFT of 7.5 +/- 4.1J or ULV of 8.0 +/- 5.3 at implant. CONCLUSION: 1) When determined during normal sinus rhythm the ULV significantly correlates with DFT. 2) ULV testing might be used in lieu of standard DFT testing to confirm adequate lead placement thus minimizing or eliminating VF inductions, particularly in hemodynamically unstable patients. 3) Since ULV + 5J has a high probability of successful defibrillation in most patients, programming ICD first shock energy for VF at ULV + 5J may result in lower first shock energies compared to the standard methods of programming first shock energy at twice DFT. CONDENSED ABSTRACT: The purpose of this study was to determine if the upper limit of vulnerability (ULV) determined during normal sinus rhythm correlates with the defibrillation threshold (DFT), as has been previously shown when determined during ventricular pacing. The linear correlation coefficient between the ULV and DFT was r = 0.73 (p < 0.001). Mean ULV at implant was 9.2 +/- 5J, not statistically different from mean DFT of 0.4 +/- 4J. During long-term follow-up of 10.1 +/- 1.8 months in 8 patients, DFT was 8.75 +/- 8J, not significantly different than the DFT of 7.5 +/- 4.1J or ULV of 8.0 +/- 5.3 at implant. Shocks energies of ULV + 5J successfully defibrillated 19 of 21 patients at implant and 8 of 8 at follow-up. This study indicates that the ULV determined in normal sinus rhythm closely correlates with the DFT, and that ULV + 5J defibrillated most patients. ULV testing could be used to predict DFT and reduce or eliminate the need for DFT testing and VF induction. Programming ICD first shock energy for VF to ULV + 5J will result in lower energy than that used with standard DFT testing.

A stable prostacyclin analog, beraprost sodium, attenuates platelet accumulation and preservation-reperfusion injury of isografts in a rat model of lung transplantation.

BACKGROUND: Recent studies have shown that the extent of platelet accumulation in the vasculature of transplanted organs correlates with the degree of preservation-reperfusion injury. In this study, we examined the effect of a stable prostacyclin analog, beraprost sodium, which possesses potent antiplatelet activity, on parameters of platelet accumulation and preservation-reperfusion injury of isografts in a rat model of lung transplantation. METHODS: The heart-lung blocks of donor rats were flushed with and preserved in modified Euro-Collins solution at 4 degrees C for 6 hr or 24 hr. The left lung was transplanted into recipient rats and reperfused for 1 hr. Lung injury was evaluated by the pulmonary blood flow ratios to the lung isografts, the weight gain of the isografts, and histological examination. Small portions of the lung isografts were excised and stained with an antibody specific for rat platelets. A scoring system was developed to semiquantitate the intensity of antibody staining (score 0-4). The recipient rats received oral administration of beraprost sodium (0.3 mg/kg) before lung transplantation. Control animals received no beraprost sodium. RESULTS: In the 6-hr preservation study, administration of beraprost sodium significantly reduced the score for platelet accumulation (1.8+/-0.4 vs. 3.3+/-0.5, P<0.01). This observation was accompanied by a significantly decreased degree of preservation-reperfusion injury as evidenced by an increased blood flow ratio (13.7+/-2.6% vs. 4.5+/-3.6%, P<0.01) and a reduced weight gain (0.7+/-0.2 g vs. 1.1+/-0.2 g, P<0.01). Histological examination revealed severe capillary congestion in three of six cases in the control group, while no capillary congestion was observed in the beraprost group. In the 24-hr preservation study, no differences were seen in platelet accumulation scores or parameters of lung injury. CONCLUSION: Beraprost sodium, an antiplatelet agent, reduces platelet accumulation and preservation-reperfusion injury of lung transplants at 6 hr in this rat isograft model.

Mycophenolate mofetil versus azathioprine immunosuppressive regimens after lung transplantation: preliminary experience.

BACKGROUND: Mycophenolate mofetil reduces episodes of biopsy-proven acute cellular rejection or treatment failure in the first year after kidney transplantation; however, limited data exist regarding the efficacy after lung transplantation. METHODS: In a 2-center, nonrandomized concurrent cohort study (level III evidence), we analyzed the incidence of biopsy-proven acute cellular rejection (International Society for Heart and Lung Transplantation grade > or=A2) and decrement in pulmonary function during the first 12 months after successful lung transplantation. All patients received induction immunosuppression with antithymocyte globulin (< or=5 days' duration), cyclosporine and prednisone, in addition to either mycophenolate mofetil (2.0 g/d) [n=11] or azathioprine (1 to 2 mg/kg per day) [n=11]. RESULTS: During the first 12 months after lung transplantation, the mycophenolate mofetil group experienced significantly fewer episodes of acute cellular rejection than the azathioprine group (0.26+/-0.34 vs 0.72+/-0.43 episodes/100 patient-days [mean+/-SD], p < 0.01; 95% CI for the difference=0.126 to 0.813). The change in forced expiratory volume -1 second [deltaFEV1] (liters) between the 3rd and 12th months after lung transplantation was analyzed for the two treatment groups. For this interval, deltaFEV1 for the mycophenolate mofetil group was +0.158+/-0.497 L vs -0.281+/-0.406 L for the azathioprine group (p < 0.05; 95% CI for difference=+0.0356 to 0.843). During the first year, there was 1 death in each group attributed to bronchiolitis obliterans syndrome with concurrent pneumonia. There were no differences in incidence of cytomegalovirus or bacterial infections between the treatment groups; however, a higher prevalence of aspergillus sp airway colonization in bronchoalveolar lavage fluid was observed for the mycophenolate mofetil group (p < .05). The prevalence of bronchiolitis obliterans syndrome at 12 months was 36% for the azathioprine group vs 18% for the mycophenolate mofetil group (p=NS). CONCLUSIONS: Our preliminary experience with mycophenolate mofetil after lung transplantation suggests a decreased incidence of biopsy-proven acute cellular rejection. Furthermore, less decline in FEV1 after 12 months may suggest a reduced incidence or delayed onset for development of bronchiolitis obliterans syndrome. Prospective randomized trials with low beta error (level I evidence) should be performed to assess the efficacy of mycophenolate mofetil vis-à-vis acute allograft rejection and bronchiolitis obliterans syndrome.

Characteristics of wave fronts during ventricular fibrillation in human hearts with dilated cardiomyopathy: role of increased fibrosis in the generation of reentry.

OBJECTIVES: We sought to evaluate the characteristics of wave fronts during ventricular fibrillation (VF) in human hearts with dilated cardiomyopathy (DCM) and to determine the role of increased fibrosis in the generation of reentry during VF. BACKGROUND: The role of increased fibrosis in reentry formation during human VF is unclear. METHODS: Five hearts from transplant recipients with DCM were supported by Langendorff perfusion and were mapped during VF. A plaque electrode array with 477 bipolar electrodes (1.6-mm resolution) was used for epicardial mapping. In heart no. 5, we also used 440 transmural bipolar recordings. Each mapped area was analyzed histologically. RESULTS: Fifteen runs of VF (8 s/run) recorded from the epicardium were analyzed, and 55 episodes of reentry were observed. The life span of reentry was short (one to four cycles), and the mean cycle length was 172 +/- 24 ms. In heart no. 5, transmural scroll waves were demonstrated. The most common mode of initiation of reentry was epicardial breakthrough, followed by a line of conduction block parallel to the epicardial fiber orientation (34 [62%] of 55 episodes). In the areas with lines of block, histologic examination showed significant fibrosis separating the epicardial muscle fibers and bundles along the longitudinal axis of fiber orientation. The mean percent fibrous tissue in these areas (n = 20) was significantly higher than that in the areas without block (n = 28) (24 +/- 7.5% vs. 10 +/- 3.8%, p < 0.0001). CONCLUSIONS: In human hearts with DCM, epicardial reentrant wave fronts and transmural scroll waves were present during VF. Increased fibrosis provides a site for conduction block, leading to the continuous generation of reentry.

Effect of shock waveform on relationship between upper limit of vulnerability and defibrillation threshold.

INTRODUCTION: The upper limit of vulnerability (ULV) correlates with the defibrillation threshold (DFT). The ULV can be determined with a single episode of ventricular fibrillation and is more reproducible than the single-point DFT. The critical-point hypothesis of defibrillation predicts that the relation between the ULV and the DFT is independent of shock waveform. The principal goal of this study was to test this prediction. METHODS AND RESULTS: We studied 45 patients at implants of pectoral cardioverter defibrillators. In the monophasic-biphasic group (n = 15), DFT and ULV were determined for monophasic and biphasic pulses from a 120-microF capacitor. In the 60- to 110-microF group (n = 30), DFT and ULV were compared for a clinically used 110-microF waveform and a novel 60-microF waveform with 70% phase 1 tilt and 7-msec phase 2 duration. In the monophasic-biphasic group, all measures of ULV and DFT were greater for monophasic than biphasic waveforms (P < 0.0001). In the 60- to 110-microF group, the current and voltage at the ULV and DFT were higher for the 60-microF waveform (P < 0.0001), but stored energy was lower (ULV 17%, P < 0.0001; DFT 19%, P = 0.03). There was a close correlation between ULV and DFT for both the monophasic-biphasic group (monophasic r2 = 0.75, P < 0.001; biphasic r2 = 0.82, P < 0.001) and the 60- to 110-microF group (60 microF r2 = 0.81 P < 0.001; 110 microF r2 = 0.75, P < 0.001). The ratio of ULV to DFT was not significantly different for monophasic versus biphasic pulses (1.17 +/- 0.12 vs 1.14 +/- 0.19, P = 0.19) or 60-microF versus 110-microF pulses (1.15 +/- 0.16 vs 1.11 +/- 0.14, P = 0.82). The slopes of the ULV versus DFT regression lines also were not significantly different (monophasic vs biphasic pulses, P = 0.46; 60-microF vs 110-microF pulses, P = 0.99). The sample sizes required to detect the observed differences between experimental conditions (P < 0.05) were 4 for ULV versus 6 for DFT in the monophasic-biphasic group (95% power) and 11 for ULV versus 31 for DFT in the 60- to 110-microF group (75% power). CONCLUSION: The relation between ULV and DFT is independent of shock waveform. Fewer patients are required to detect a moderate difference in efficacy of defibrillation waveforms by ULV than by DFT. A small-capacitor biphasic waveform with a long second phase defibrillates with lower stored energy than a clinically used waveform.

A 20-year experience with the Hancock porcine xenograft in the elderly.

BACKGROUND: The availability of 20 years of follow-up data on the Hancock porcine valve (Medtronic Inc, Irvine, CA) allows determination of long-term actual and actuarial failure rates in the elderly. METHODS: We analyzed outcomes after mitral or aortic valve replacement with the Hancock porcine valve in 491 consecutive patients, comparing actual and actuarial valve failure rates in the elderly (age 65 or older) with those in younger patients. RESULTS: The average age of aortic valve replacement recipients was 68+/-14 years (N = 243) and of mitral valve replacement recipients, 64+/-12 years (N = 248). Average follow-up was 7.0 years (1,673 patient-years) for aortic valve replacement and 7.3 years (1,781 patient years) for mitral valve replacement recipients. The median time to reoperation or structural failure was 15.9 years for aortic valve replacement patients and 14.3 years for mitral valve replacement patients. However, few elderly patients survived to 15 years (22% of the elderly aortic valve replacement and 13% of the older mitral valve replacement patients). The 15-year actual reoperation rate was therefore only 10% in the elderly aortic valve replacement compared to 30% in the younger aortic valve replacement patients. For mitral valve replacement, the 15-year actual reoperation rate was 11% in the elderly and 36% in the younger patients. The lifetime reoperation risk (the maximum potential number of patients who might ever undergo reoperation during their lifetime) is the sum of actual survival and actual reoperation rates. The lifetime reoperation risk was 20% or less for elderly aortic valve replacement patients and 18% or less for elderly mitral valve replacement patients. CONCLUSION: These data suggest that about 1 in 10 elderly patients (65 years or older) receiving a Hancock valve will require reoperation within 15 years and less than one in five will ever require reoperation in their lifetimes.

Application of models of defibrillation to human defibrillation data: implications for optimizing implantable defibrillator capacitance.

BACKGROUND: Theoretical models predict that optimal capacitance for implantable cardioverter-defibrillators (ICDs) is proportional to the time-dependent parameter of the strength-duration relationship. The hyperbolic model gives this relationship for average current in terms of the chronaxie (t(c)). The exponential model gives the relationship for leading-edge current in terms of the membrane time constant (tau(m)). We hypothesized that these models predict results of clinical studies of ICD capacitance if human time constants are used. METHODS AND RESULTS: We studied 12 patients with epicardial ICDs and 15 patients with transvenous ICDs. Defibrillation threshold (DFT) was determined for 120-microF monophasic capacitive-discharge pulses at pulse widths of 1.5, 3.0, 7.5, and 15 ms. To compare the predictions of the average-current versus leading-edge-current methods, we derived a new exponential average-current model. We then calculated individual patient time parameters for each model. Model predictions were validated by retrospective comparison with clinical crossover studies of small-capacitor and standard-capacitor waveforms. All three models provided a good fit to the data (r2=.88 to .97, P<.001). Time constants were lower for transvenous pathways (53+/-7 omega) than epicardial pathways (36+/-6 omega) (t(c), P<.001; average-current tau(m), P=.002; leading-edge-current tau(m), P<.06). For epicardial pathways, optimal capacitance was greater for either average-current model than for the leading-edge-current model (P<.001). For transvenous pathways, optimal capacitance differed for all three models (P<.001). All models provided a good correlation with the effect of capacitance on DFT in previous clinical studies: r2=.75 to .84, P<.003. For 90-microF, 120-microF, and 150-microF capacitors, predicted stored-energy DFTs were 3% to 8%, 8% to 16%, and 14% to 26% above that for the optimal capacitance. CONCLUSIONS: Model predictions based on measured human cardiac-muscle time parameter have a good correlation with clinical studies of ICD capacitance. Most of the predicted reduction in DFT can be achieved with approximately 90-microF capacitors.

FK 506 'rescue' immunosuppression for obliterative bronchiolitis after lung transplantation.

PRELIMINARY EXPERIENCE: In a consecutive case series (level V evidence) involving 10 recipients of unilateral lung transplantation (LT) with bronchiolitis obliterans, in conjunction with Fujisawa protocol 93-0-003, the physiologic responses to FK 506 (tacrolimus) "rescue" immunosuppression were assessed. Recipients were 22+/-18 months post-LT and demonstrated progressive allograft dysfunction that was refractory to pulsed-dose methylprednisolone therapy. All recipients received induction immunosuppression with Minnesota antilymphocyte globulin (10 to 15 mg/kg/d) for 5 to 10 days, cyclosporine (CsA) (whole-blood Abbott TDX fluorescence polarization immunoassay (Abbott Inc, Abbott Park, IL)=600 to 800 ng/mL), azathioprine (2 mg/kg/d), and prednisone (tapered to 0.2 mg/kg/d). The "rescue" regimen consisted of oral FK 506 adjusted to maintain a whole-blood Abbott IMX microparticle enzyme immunoassay (Abbott Inc, Abbott Park, IL) of 10 to 15 ng/mL with an initial increase in prednisone (1.0 mg/kg/d) during conversion that was subsequently tapered to 0.2 mg/kg/d. Spirometry was performed monthly in accordance with accepted American Thoracic Society criteria. Recipients were classified in accordance with the International Society for Heart and Lung Transplantation (ISHLT) "Working Formulation for Standardization of Nomenclature and for Clinical Staging of Chronic Dysfunction in Lung Allografts" as stages Ib (n=2), IIb (n=4), and IIIb (n=4) upon entry to the protocol. The deltaFEV1/month relationships during CsA- and FK 506-based regimens were analyzed by linear regression and compared by signed rank test (p<0.05). RESULTS: The deltaFEV1/month slopes were -0.0687+/-0.0221 and +0.0300+/-0.033 L/mo (mean+/-SEM) for CsA and FK 506, respectively (p=0.037). Although no significant spirometric improvement was noted in most recipients, no further decline in FEV1 occurred after conversion to FK 506. Recipients with less severe chronic dysfunction (ie, obliterative bronchiolitis [OB] stages Ib and IIb) stabilized their spirometric indexes at higher levels. Two recipients with OB stage IIIb died of hypercapnic respiratory failure at 6 and 8 months after conversion. CONCLUSIONS: The deltaFEV1/mo slopes stabilized after FK 506 conversion. Earlier conversion may be beneficial in stabilizing FEV1 at a higher plateau. Significant economic impact may be anticipated with FK 506 compared to alternative cytolytic strategies for OB. However, multicenter prospective controlled investigations are necessary to further address the potential role of FK 506 after LT (level I evidence). Furthermore, the ISHLT "Staging of OB Syndrome" may have significant clinical implications vis-à-vis prognosis and potential therapies.