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Heart transplantation has become a standard therapy option for advanced heart failure. The translation of heart transplantation from innovative experiments to long-term clinical success has married prescient insights with discipline and organization in the domains of surgical techniques, organ preservation, immunosuppression, organ donation and transplantation logistics, infection control, and long-term graft surveillance. This review explores the key milestones of the past 50 years of heart transplantation and discusses current challenges and promising innovations on the clinical horizon., (© 2018 American Heart Association, Inc.)

Many children who undergo heart transplantation will survive into adulthood. We sought to examine the QOL and capacity for achievement in long-term adult survivors of pediatric heart transplantation. Adults >18 yr of age who received transplants as children (≤18 yr old) and had survived for at least 10 yr post-transplant completed two self-report questionnaires: (i) Ferrans & Powers QLI, in which life satisfaction is reported as an overall score and in four subscale domains and is then indexed from 0 (very dissatisfied) to 1 (very satisfied); and (ii) a "Metrics of Life Achievement" questionnaire regarding income, education, relationships, housing status, and access to health care. A total of 20 subjects completed the survey. The overall mean QLI score was 0.77 ± 0.16. Subjects were most satisfied in the family domain (0.84 ± 0.21) and least satisfied in the psychological/spiritual domain (0.7 ± 0.28). Satisfaction in the domains of health/functioning and socioeconomic were intermediate at 0.78 and 0.76, respectively. Most respondents had graduated from high school, reported a median annual income >$50 000/yr, and lived independently. Adult survivors of pediatric heart transplant report a good QOL and demonstrate the ability to obtain an education, work, and live independently., (© 2014 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Recent advances in the management of heart transplant recipients have resulted in improved survival, particularly in the early post-transplant period. Although graft rejection, infection, malignancy, and allograft vasculopathy remain important challenges to the long-term management of heart transplant recipients, active research in these fields continues to advance our understanding and improve outcomes. This review will provide an overview of modern heart transplantation, summarize our current understanding of best practices for the management of heart transplant recipients, and describe recent advances in the field and areas of active research., (Copyright © 2014 Elsevier Inc. All rights reserved.)

Background: We evaluated the potential effects of granulocyte colony-simulating factor (G- CSF) on the incidence of rejection and allograft vasculopathy in heart transplant recipients., Methods: Of 247 patients undergoing heart transplantation from 2000 to 2007, 52 (21%) developed leukopenia (white blood cell [WBC] <2.5 × 10(9) cells/L) in the absence of active infection, rejection, or malignancy. In 24 (46%) patients a clinical decision was made to treat the leukopenia with G-CSF (G-CSF group), and 28 (54%) Patients received no G-CSF (non-GCSF group). Patients followed up for 1 year after the period of leukopenia were assessed for allograft vasculopathy and acute rejection incidence., Results: At baseline, the G-CSF group and the non-GCSF group did not differ in age, gender, race, heart failure etiology, creatinine, left ventricular ejection fraction (LVEF) or immunosupressive regimen. During 1-year follow-up there were no deaths in the G-CSF group, and 1 death in the non-GCSF group (P = .34). The incidence of rejection or progressive allograft vasculopathy was lower in the G-CSF group when compared with the non-GCSF group (2 [8%] vs 15 [53%]; P < .01). Multivariate analysis identified both prior rejection episodes and G-CSF therapy as factors associated with the combined end-point of rejection or progressive allograft vasculopathy (odds ratio [OR] = 7.89 [1.67-37.2] and OR = 0.09 [0.02-0.52], respectively)., Conclusions: G-CSF therapy appears to be associated with a decreased incidence of acute rejection episodes or allograft vasculopathy in heart transplant recipients, suggesting a potential immunomodulatory effect of G-CSF., (Copyright © 2013 Elsevier Inc. All rights reserved.)

Background: Microvascular dysfunction is emerging as a strong predictor of outcome in heart transplant recipients. At this time, the determinants and consequences of early microvascular dysfunction are not well established. The objective of the study was to determine the risk factors and functional correlates associated with early microvascular dysfunction in heart transplant recipients., Methods and Results: Sixty-three heart transplant recipients who had coronary physiology assessment, right heart catheterization, and echocardiography performed at the time of their first annual evaluation were included in the study. Microvascular dysfunction was assessed using the recently described index of microcirculatory resistance. The presence of microvascular dysfunction, predefined by an index of microcirculatory resistance >20, was observed in 46% of patients at 1 year. A history of acute rejection and undersized donor hearts were associated with microvascular dysfunction at 1 year, with odds ratio of 4.0 (1.3-12.8) and 3.6 (1.2-11.1), respectively. Patients with microvascular dysfunction had lower cardiac index (3.1±0.7 versus 3.5±0.7 L/min per m(2); P=0.02) and mild graft dysfunction measured by echocardiography-derived left and right myocardial performance indices ([0.54±0.09 versus 0.43±0.09; P<0.01] and [0.47±0.14 versus 0.32±0.05; P<0.01], respectively). Microvascular dysfunction was also associated with a higher likelihood of death, graft failure, or allograft vasculopathy at 5 years after transplant (hazard ratio, 2.52 [95% CI, 1.04-5.91])., Conclusions: A history of acute rejection during the first year and smaller donor hearts were identified as risk factors for early microvascular dysfunction. Microvascular dysfunction assessed using index of microcirculatory resistances at 1 year was also associated with worse graft function and possibly worse clinical outcomes.

Although not a definitive treatment, percutaneous coronary intervention offers a palliative benefit to patients with cardiac allograft vasculopathy. Given the superior outcomes with drug-eluting stents (DESs) over bare metal stents (BMSs) in native coronary artery disease, similar improvements might be expected in transplant patients; however, the results have been mixed. Consecutive cardiac transplantation recipients at a single center receiving a stent for de novo cardiac allograft vasculopathy from 1997 to 2009 were retrospectively analyzed according to receipt of a DES versus a BMS. The angiographic and clinical outcomes were subsequently evaluated at 1 year. The baseline clinical and procedural characteristics were similar among those receiving DESs (n = 18) and BMSs (n = 16). Quantitative coronary angiography revealed no difference in the reference diameter, lesion length, or pre-/postprocedural minimal luminal diameter. At the 12-month angiographic follow-up visit, the mean lumen loss was significantly lower in the DES group than in the BMS group (0.19 ± 0.73 mm vs 0.76 ± 0.97 mm, p = 0.02). The DES group also had a lower rate of in-stent restenosis (12.5% vs 33%, p = 0.18), as well as a significantly lower rate of target lesion revascularization (0% vs 19%, p = 0.03). At 1 year, DESs were associated with a lower composite rate of cardiac death and nonfatal myocardial infarction (12% vs 38%, p = 0.04). In conclusion, DESs are safe and effective in the suppression of neointimal hyperplasia after percutaneous coronary intervention for cardiac allograft vasculopathy, resulting in significantly lower rates of late lumen loss and target lesion revascularization, as well as a reduced combined rate of cardiac death and nonfatal myocardial infarction., (Copyright © 2011 Elsevier Inc. All rights reserved.)

Background: During the past 25 years, advances in immunosuppression and the use of selective anti-microbial prophylaxis have progressively reduced the risk of infection after heart transplantation. This study presents a historical perspective of the changing trends of infectious disease after heart transplantation., Methods: Infectious complications in 4 representative eras of immunosuppression and anti-microbial prophylaxis were analyzed: (1) 38 in the pre-cyclosporine era (1978-1980), (2) 72 in the early cyclosporine era (1982-1984), where maintenance immunosuppression included high-dose cyclosporine and corticosteroid therapy; (3) 395 in the cyclosporine era (1988-1997), where maintenance immunosuppression included cyclosporine, azathioprine, and lower corticosteroid doses; and (4) 167 in the more recent era (2002-2005), where maintenance immunosuppression included cyclosporine and mycophenolate mofetil., Results: The overall incidence of infections decreased in the 4 cohorts from 3.35 episodes/patient to 2.03, 1.35, and 0.60 in the more recent cohorts (p < 0.001). Gram-positive bacteria are emerging as the predominant cause of bacterial infections (28.6%, 31.4%, 51.0%, 67.6%, p = 0.001). Cytomegalovirus infections have significantly decreased in incidence and occur later after transplantation (88 +/- 77 days, pre-cyclosporine era; 304 +/- 238 days, recent cohort; p < 0.001). Fungal infections also decreased, from an incidence of 0.29/patient in the pre-cyclosporine era to 0.08 in the most recent era. A major decrease in Pneumocystis jiroveci and Nocardia infections has also occurred., Conclusions: The overall incidence and mortality associated with infections continues to decrease in heart transplantation and coincides with advances in immunosuppression, the use of selective anti-microbial prophylaxis, and more effective treatment regimens.

It has been 40 years since the first human-to-human heart transplant performed in South Africa by Christiaan Barnard in December 1967. This achievement did not come as a surprise to the medical community but was the result of many years of early pioneering experimental work by Alexis Carrel, Frank Mann, Norman Shumway, and Richard Lower. Since then, refinement of donor and recipient selection methods, better donor heart management, and advances in immunosuppression have significantly improved survival. In this article, we hope to give a perspective on the changing face of heart transplantation. Topics that will be covered in this review include the changing patient population as well as recent advances in transplantation immunology, organ preservation, allograft vasculopathy, and immune tolerance.

Background: Rapamycin has been shown to reduce anatomical evidence of cardiac allograft vasculopathy, but its effect on coronary artery physiology is unknown., Methods: Twenty-seven patients without angiographic evidence of coronary artery disease underwent measurement of fractional flow reserve (FFR), coronary flow reserve (CFR), and the index of microcirculatory resistance (IMR) within 8 weeks and then 1 year after transplantation using a pressure sensor/thermistor-tipped guidewire. Measurements were compared between consecutive patients who were on rapamycin for at least 3 months during the first year after transplantation (rapamycin group, n = 9) and a comparable group on mycophenolate mofetil (MMF) instead (MMF group, n = 18)., Results: At baseline, there was no significant difference in FFR, CFR, or IMR between the 2 groups. At 1 year, FFR declined significantly in the MMF group (0.87 +/- 0.06 to 0.82 +/- 0.06, P = .009) but did not change in the rapamycin group (0.91 +/- 0.05 to 0.89 +/- 0.04, P = .33). Coronary flow reserve and IMR did not change significantly in the MMF group (3.1 +/- 1.7 to 3.2 +/- 1.0, P = .76; and 27.5 +/- 18.1 to 19.1 +/- 7.6, P = .10, respectively) but improved significantly in the rapamycin group (2.3 +/- 0.8 to 3.8 +/- 1.4, P < .03; and 27.0 +/- 11.5 to 17.6 +/- 7.5, P < .03, respectively). Multivariate regression analysis revealed that rapamycin therapy was an independent predictor of CFR and FFR at 1 year after transplantation., Conclusion: Early after cardiac transplantation, rapamycin therapy is associated with improved coronary artery physiology involving both the epicardial vessel and the microvasculature.

Background: Sudden cardiac death (SCD) has been shown to be a significant cause of death after heart transplantation. QT dispersion (QTd) is associated with SCD in several high-risk populations. We hypothesized that QTd would predict mortality and SCD in heart transplantation patients., Methods: We examined the clinical charts and most recent electrocardiograms (ECGs) for patients who received heart transplants at Stanford University Medical Center during the period 1981-1995. QTd was measured with all 12 leads and the precordial leads. Analysis was performed by a single reader blinded to patient outcomes., Results: A total of 346 patients who had undergone transplantation had available ECGs and known outcomes; 155 of these patients died, and 42 of these deaths were attributed to SCD. The 12-lead mean QTd was not significantly different between outcome groups: patients who survived had a 12-lead mean QTd of 58 +/- 29 milliseconds and those who died had a 12-lead mean QTd of 61 +/- 32 milliseconds (P = .57). Patients who died from SCD had a 12-lead mean QTd of 57 +/- 31 milliseconds (P = .40), and those who died of other causes had a 12-lead mean QTd of 59 +/- 34 milliseconds (P = .36 vs those who died of SCD). Similarly, the precordial-lead mean QTd did not differ significantly between the different outcome groups., Conclusions: We found no correlation between QTd and SCD or mortality in heart transplant recipients. Until additional studies prove a positive association, QTd should not be used as a prognostic marker in these patients.

The ongoing shortage of donors for cardiac transplantation has led to a trend toward acceptance of donor hearts with some structural abnormalities including left ventricular hypertrophy. To evaluate the outcome in recipients of donor hearts with increased left ventricular wall thickness (LVWT), we retrospectively analyzed data for 157 cardiac donors and respective recipients from January 2001 to December 2004. There were 47 recipients of donor heart with increased LVWT >or=1.2 cm, which constituted the study group and 110 recipients of a donor heart with normal LVWT < 1.2 cm that formed the control group. At 3 +/- 1.5 years, recipient survival was lower (50% vs. 82%, p = 0.0053) and incidence of allograft vasculopathy was higher (50% vs. 22%, p = 0.05) in recipients of donor heart with LVWT > 1.4 cm as compared to LVWT 1.4 cm (p = 0.003), recipient preoperative ventricular assist device (VAD) support (p = 0.04) and bypass time > 150 min (p = 0.05) were predictors of reduced survival. Our results suggest careful consideration of donor hearts with echocardiographic evidence of increased LVWT in the absence of hypovolemia, because they may be associated with poorer outcomes; such hearts should potentially be reserved only for the most desperately ill recipients.

Cardiac allograft vasculopathy (CAV) is a progressive process involving the epicardial and microvascular coronary systems. The timing of the development of abnormalities in these 2 compartments and the correlation between changes in physiology and anatomy are undefined. The invasive evaluation of coronary artery anatomy and physiology with intravascular ultrasound, fractional flow reserve, coronary flow reserve, and the index of microcirculatory resistance (IMR) was performed in the left anterior descending coronary artery during 151 angiographic evaluations of asymptomatic heart transplant recipients from 0 to >5 years after heart transplantation (HT). There was no angiographic evidence of significant CAV, but during the first year after HT, fractional flow reserve decreased significantly (0.89 +/- 0.06 vs 0.85 +/- 0.07, p = 0.001), and percentage plaque volume derived by intravascular ultrasound increased significantly (15.6 +/- 7.7% to 22.5 +/- 12.3%, p = 0.0002), resulting in a significant inverse correlation between epicardial physiology and anatomy (r = -0.58, p <0.0001). The IMR was lower in these patients compared with those > or =2 years after HT (24.1 +/- 14.3 vs 29.4 +/- 18.8 units, p = 0.05), suggesting later spread of CAV to the microvasculature. As the IMR increased, fractional flow reserve increased (0.86 +/- 0.06 to 0.90 +/- 0.06, p = 0.0035 comparing recipients with IMRs < or =20 to those with IMRs > or =40), despite no difference in percentage plaque volume (21.0 +/- 11.2% vs 20.5 +/- 10.5%, p = NS). In conclusion, early after HT, anatomic and physiologic evidence of epicardial CAV was found. Later after HT, the physiologic effect of epicardial CAV may be less, because of increased microvascular dysfunction.

Background: Metabolic and immuno-inflammatory risk factors contribute to cardiac allograft vasculopathy (CAV) pathogenesis. Although systemic inflammation, as detected by C-reactive protein (CRP), predicts CAV development, the relationship between CRP and markers of metabolic abnormalities remains unexplored., Methods: CRP and the entire metabolic panel were evaluated in 98 consecutive heart transplant recipients at the time of annual coronary angiography, 5.8 years after transplant (range, 1-12 years). A ratio of triglycerides (TG) to high-density lipoproteins (HDL) of 3.0 or more was considered a marker of insulin resistance. CAV prevalence was defined by angiography, and subsequent prognosis was evaluated as incidence of major cardiac adverse events., Results: CRP was higher in the 34 patients with angiographic CAV than in those without CAV (1.10 +/- 0.20 vs 0.50 +/- 0.05 mg/dl, p < 0.001). Patients with insulin resistance had higher CRP concentrations (p = 0.023) and higher CAV prevalence (p = 0.005). High CRP and a TG/HDL of 3.0 or more were independently associated with an increased likelihood of CAV (odds ratio, > or = 3.9; p = 0.02) and predicted an increased risk of major cardiac adverse events. The combination of high CRP and a TG/HDL of 3.0 or more identified a subgroup of patients having a 4-fold increased risk for CAV and a 3-fold increased risk for major cardiac adverse events compared with patients with low CRP and normal values for metabolic indicators., Conclusions: Both CRP and insulin resistance, as estimated by TG/HDL, appear to be strong, synergic risk factors for CAV and for major cardiac adverse events. These findings support the hypothesis that in heart transplant recipients, systemic inflammation may be an important mediator of graft vascular injury associated with metabolic syndrome.

Pulmonary infection with Nocardia is an uncommon but serious infection found in immunocompromised patients. We describe a rapidly progressive pulmonary nocardiosis in a heart transplant patient. We then review the common clinical features of Nocardia infection in transplant recipients, outlining the challenges in its diagnosis and management. We also review the differences between Pneumocystis jiroveci prophylaxis regimens with respect to concomitant prophylaxis of Nocardia and other opportunistic infections.

Right bundle branch block (RBBB) is the most common electrocardiographic abnormality in heart transplant recipients, but the cause remains unknown, data regarding the prognosis are conflicting, and all previous studies have been limited to <100 patients. This was a study of patients who underwent heart transplantation at Stanford University Medical Center from 1981 to 1995 with known outcomes and >or=2 available electrocardiograms (ECGs). Outcomes were assessed in those with and without conduction disturbances recorded from the ECGs closest to the time of transplantation and the most recent ECGs. Of the 322 heart transplant recipients studied, 141 (44%) died over a mean follow-up of 9 +/- 3.5 years, and 40 (13%) died of sudden cardiac death. In the first ECG obtained, a mean of 1.8 +/- 2.4 years after transplantation, 44 patients (14%) had incomplete RBBB and 26 (8%) had RBBB; in the second ECG, obtained a mean of 5.6 +/- 3.7 years after transplantation, 59 patients (18%) had incomplete RBBB and 63 (20%) had RBBB. Increasing time from transplantation was associated with a greater likelihood for RBBB on the first and second ECGs (p = 0.001 and p <0.0001, respectively). QRS duration, incomplete RBBB, RBBB, or the development of RBBB was not associated with mortality or sudden cardiac death. In conclusion, although RBBB was the most common electrocardiographic abnormality in our study, the prevalence was lower than previously reported. The cause of RBBB appears to be largely related to events that occur well after transplantation, and the prognosis is benign.

Cardiac allograft vasculopathy is a leading cause of death during long-term follow-up of heart transplant recipients. We report 2 cases of cardiac allograft vasculopathy associated with giant coronary aneurysms. To our knowledge, these are the first reported cases of spontaneous giant coronary aneurysms in heart transplant recipients.

Background: Investigating changes in coronary physiology that occur after cardiac transplantation has been challenging. Simultaneous and independent assessment of the epicardial artery by measuring fractional flow reserve (FFR) and of the microvasculature by calculating the index of microvascular resistance (IMR) with a single coronary pressure wire may be useful., Methods: Twenty-five asymptomatic patients with normal coronary angiograms underwent FFR, thermodilution-derived IMR and coronary flow reserve (CFR) and intravascular ultrasound (IVUS) evaluation soon after cardiac transplantation and 1 year later., Results: FFR significantly worsened (0.90 +/- 0.05 at baseline to 0.85 +/- 0.06 at 1 year, p = 0.004). FFR correlated strongly with percent plaque volume as measured by IVUS (r = -0.58, p < 0.0001). IMR improved significantly (29.2 +/- 15.9 at baseline to 19.3 +/- 7.6 units at 1 year, p = 0.007). CFR increased, but not significantly (2.6 +/- 1.4 at baseline to 3.2 +/- 1.2 at 1 year, p = not significant). Diabetes and donor heart ischemic time independently predicted baseline IMR. Treatment with rapamycin independently predicted FFR at 1 year., Conclusions: New coronary physiologic measures, FFR and IMR, show that epicardial artery physiology worsens and correlates with anatomic changes, whereas microvascular physiology improves during the first year after cardiac transplantation. CFR, the traditional method for evaluating coronary circulatory physiology, did not identify these changes.

Sirolimus was introduced in de novo immunosuppression at Stanford University in view of its favorable effects on reduced rejection and cardiac allograft vasculopathy. After an apparent increase in the incidence of post-surgical wound complications as well as symptomatic pleural and pericardial effusions, we reverted to a mycophenolate mofetil (MMF)-based regimen. This retrospective study compared the outcome in heart transplant recipients on sirolimus (48 patients) with those on MMF (46 patients) in de novo immunosuppressive regimen. The incidence of any post-surgical wound complication (52% vs. 28%, p=0.019) and deep surgical wound complication (35% vs. 13%, p=0.012) was significantly higher in patients on sirolimus than on MMF. More patients on sirolimus also had symptomatic pleural (p=0.035) and large pericardial effusions (p=0.033) requiring intervention. Logistic regression analysis showed sirolimus (p=0.027) and longer cardiac bypass time (OR=1.011; p=0.048) as risk factors for any wound complication. Sirolimus in de novo immunosuppression after cardiac transplantation was associated with a significant increase in the incidence of post-surgical wound healing complications as well as symptomatic pleural and pericardial effusions.

We report the case of a 36-year-old woman with a diagnosis of idiopathic dilated cardiomyopathy who underwent cardiac transplantation. The results of her initial iron studies were normal, but hemochromatosis was suspected after microscopy of the explanted heart revealed iron deposition. By 6 months post-transplantation, iron deposition was detected in her surveillance endomyocardial biopsy specimens and studies then confirmed the existence of non-HFE hemochromatosis. The patient has been stable on treatment with regular phlebotomies and a low vitamin C diet.

Background: Orthotopic heart transplantation is considered an effective treatment for patients with refractory heart failure. The long-term survival of orthotopic heart transplantation recipients has increased over the last several decades, but many long-term survivors of orthotopic heart transplantation develop graft atherosclerosis and associated left ventricular dysfunction. The risk of sudden cardiac death in long-term survivors of orthotopic heart transplantation with these complications is believed to be high. There are no data on the usefulness of implantable cardioverter-defibrillators (ICDs) in this population; therefore, we report our early experience with ICD placement in such patients., Objectives: The purpose of this study was to examine the use of ICDs in adults who are long-term survivors of heart transplantation., Methods: We retrospectively reviewed all adult patients who underwent orthotopic heart transplantation at Stanford University Hospital (Stanford, CA, USA) from 1980 to 2004. All patients who received an ICD after transplant were included in this study. We reviewed demographic data, medical history, ejection fraction, presence of graft atherosclerosis, indication for ICD placement, and any device therapy delivered., Results: Of the 925 patients who had orthotopic heart transplantation during this time period, 493 patients were alive at the beginning of the year 2000. Of these patients, 10 ( approximately 2%) had subsequent placement of an ICD. All 10 patients were male. The average age at orthotopic heart transplantation was 37.8 years. The average age at ICD placement was 50.5 years. The average time from orthotopic heart transplantation to ICD placement was 14.6 years. The average ejection fraction at the time of implant was 46.5%. Five of the 10 patients had a low ejection fraction (within this subgroup, the average ejection fraction was 31%, range 15%-45%) and graft atherosclerosis. ICDs were placed because of symptomatic episodes of ventricular tachycardia (3 patients), low ejection fraction and severe graft atherosclerosis without symptoms (3 patients), and after thorough evaluation for otherwise unexplained syncope (4 patients). The average follow-up after device implantation was 13 months. Complications related to ICD placement were an infected ICD system requiring explant in one patient and a lead fracture in another patient. Three patients had subsequent appropriate shocks for ventricular arrhythmias, and one patient underwent a second orthotopic heart transplantation. One patient died of malignancy., Conclusion: Use of the ICD in long-term survivors of orthotopic heart transplantation should be considered in appropriately selected patients. Further data are needed regarding ICD use in this population.

Endomyocardial biopsy is the mainstay for monitoring cardiac allograft rejection. A noninvasive strategy--peripheral blood gene expression profiling of circulating leukocytes--is an alternative with proven benefits, but unclear economic implications. Financial data were obtained from five cardiac transplant centers. An economic evaluation was conducted to compare the costs of outpatient biopsy with those of a noninvasive approach to monitoring cardiac allograft rejection. Hospital outpatient biopsy costs averaged 3297 US dollars, excluding reimbursement for professional fees. Costs to Medicare and private payers averaged 3581 US dollars and 4140 US dollars, respectively. A noninvasive monitoring test can reduce biopsy utilization. The savings to health care payers in the United States can be conservatively estimated at approximately 12.0 million US dollars annually. Molecular testing using gene expression profiling of peripheral circulating leukocytes is a new technology that offers physicians a noninvasive, less expensive alternative to endomyocardial biopsy for monitoring allograft rejection in cardiac transplant patients.

Objectives: The possible effect of plasma hemoglobin A(1c) (HbA(1c)) on the development of transplant coronary artery disease (TxCAD) was investigated., Background: Glucose intolerance is implicated as a risk factor for TxCAD. However, a relationship between HbA(1c) and TxCAD has not been demonstrated., Methods: Plasma HbA(1c) was measured in 151 adult patients undergoing routine annual coronary angiography at a mean period of 4.1 years after heart transplantation. Intracoronary ultrasound (ICUS) was also performed in 42 patients. Transplant CAD was graded by angiography as none, mild (stenosis in any vessel < or =30%), moderate (31% to 69%), or severe (> or =70%) and was defined by ICUS as a mean intimal thickness (MIT) > or =0.3 mm in any coronary artery segment. The association between TxCAD and established risk factors was examined., Results: Plasma HbA(1c) increased with the angiographic grade of TxCAD (5.6%, 5.8%, 6.4%, and 6.2% for none, mild, moderate, and severe disease, respectively; p < 0.05 for none vs. moderate or severe) and correlated with disease severity (r = 0.24, p < 0.05). The HbA(1c) level was higher in patients with MIT > or =0.3 mm than in those with MIT <0.3 mm (6.4% vs. 5.7%, p < 0.05). Multivariate logistic regression analysis identified HbA(1c) as an independent predictor of TxCAD, as detected by angiography or ICUS (odds ratios 1.9 and 2.4, 95% confidence intervals 1.5 to 6.3 [p = 0.010] and 1.3 to 4.2 [p < 0.005], respectively)., Conclusions: Persistent glucose intolerance, as reflected by plasma HbA(1c), is associated with the occurrence of TxCAD and may play an important role in its pathogenesis.

Background: Truly long term survival post heart transplantation has become increasingly frequent over the past two decades., Methods: We analyzed multiple clinical outcomes in the cohort of 140 patients in the Stanford database who underwent heart transplantation after the introduction of cyclosporine-based immunosuppression in 1980 and survived >10 years after transplantation., Results: We found generally excellent functional status in these patients, but a high incidence of hypertension, renal dysfunction, and graft CAD as well as malignancy., Conclusion: With continued improvement in post-transplant survival rates, providing complex care for such long-term recipients as these will assume increasing clinical importance in the everyday practice of transplant medicine and these data highlight the problems to be anticipated.

Background: It has been suggested that the modality of brain death and time from brain death until harvest impact survival and rejection after heart transplantation., Methods: Donor files from 475 adult heart-transplant recipients were examined. From these files, a total management time (time from incident leading to brain death until aortic cross clamp) was determined, and the cause of brain death was noted. Recipient characteristics, details of postoperative course, as well as survival were obtained from the Stanford University Medical Center Heart Transplantation Database., Results: Two hundred and thirty (48.4%) donors sustained traumatic injuries, 112 (23.6%) suffered a subarachnoid hemorrhage, and 102 (21.4%) died of a gunshot wound to the head. The modality of brain death did not influence medium and long-term survival. A management time longer than 72 hours was associated with poorer outcome of the heart-transplant recipients. There were significantly more treated rejection episodes in recipients whose donor sustained traumatic injuries., Conclusion: Modality of brain death does not impact survival but appears to influence rejection. Increased management time is associated with adverse survival trends in heart-transplant recipients.

Background: Long-term survival after heart transplantation is common in the cyclosporine era. However, there are few data documenting pre-transplant/peri-operative factors predictive of truly long-term survival (>10 years). The purpose of this study is to identify factors associated with 10-year survival after heart transplantation., Methods: Our study population included 197 adults who survived >6 months and died <10 years after heart transplant (medium-term group) and 140 adults who survived >10 years after heart transplant (long-term group) between December 1980 and May 2001. A comparison was done between the two groups and we used multivariate analysis to identify which factors predicted 10-year survival., Results: The long-term group had younger recipient and donor age, lower recipient body mass index at transplant, shorter waiting time and lower percentages of ischemic etiology/male recipient/non-white recipient. Kaplan-Meier plots of freedom from graft coronary artery disease and malignancy showed later onset patterns in the long-term group compared with the medium-term group. Multivariate analysis showed that white recipient, younger recipient and lower recipient body mass index at heart transplant were factors significantly associated with 10-year survival., Conclusions: Several pre-transplant/peri-operative factors were associated with survival beyond 10 years after heart transplantation. Stratified/tailored strategies based on these factors may be helpful to attain longer-term survival of recipients with higher risks.

Background: The utility of measuring fractional flow reserve (FFR) to assess cardiac transplant arteriopathy has not been evaluated. Measuring coronary flow reserve (CFR) as well as FFR could add information about the microcirculation, but until recently, this has required two coronary wires. We evaluated a new method for simultaneously measuring FFR and CFR with a single wire to investigate transplant arteriopathy., Methods and Results: In 53 cases of asymptomatic cardiac transplant recipients without angiographically significant coronary disease, FFR and thermodilution-derived CFR (CFRthermo) were measured simultaneously with the same coronary pressure wire in the left anterior descending artery and compared with volumetric intravascular ultrasound (IVUS) imaging. The average FFR was 0.88+/-0.07; in 75% of cases, the FFR was less than the normal threshold of 0.94; and in 15% of cases, the FFR was < or =0.80, the upper boundary of the gray zone of the ischemic threshold. There was a significant inverse correlation between FFR and IVUS-derived measures of plaque burden, including percent plaque volume (r=0.55, P<0.0001). The average CFRthermo was 2.5+/-1.2; in 47% of cases, CFRthermo was < or =2.0. In 14%, the FFR was normal (> or =0.94) and the CFR was abnormal (<2.0), suggesting predominant microcirculatory dysfunction., Conclusions: FFR correlates with IVUS findings and is abnormal in a significant proportion of asymptomatic cardiac transplant patients with normal angiograms. Simultaneous measurement of CFR with the same pressure wire, with the use of a novel coronary thermodilution technique, is feasible and adds information to the physiological evaluation of these patients.

Background: Tacrolimus is a potent calcineurin inhibitor that was introduced to heart transplantation in the early 1990s. The side-effect profile of tacrolimus is more favorable than that of cyclosporine and some reports have suggested an advantage of tacrolimus in the treatment of rejection. The present study was undertaken to determine whether a late conversion to tacrolimus affords these benefits to heart transplant recipients., Methods: Charts from 109 patients who underwent conversion from cyclosporine to tacrolimus for recurrent rejection or adverse effects were retrospectively reviewed., Results: During the year after conversion to tacrolimus, there was a significant decrease in treated rejection episodes. Conversion to tacrolimus rapidly resulted in an improved lipid profile. Two years after conversion blood pressure was significantly reduced. Apart from rejection, these benefits were found mainly among individuals converted to tacrolimus within 1 year of heart transplantation., Conclusions: Conversion from cyclosporine to tacrolimus is safe and results in a more favorable risk factor profile. However, most of the benefits are seen in individuals converted within 1 year of transplantation.

Background: Advanced age has been traditionally considered a relative contraindication for heart transplantation. Older patients are now considered as potential candidates for heart transplantation. The objective of this study was to evaluate the long-term results of heart transplantation in patients older than 60 years., Methods: Between 1986 and 2001, 81 patients aged between 60 and 70 years (mean, 63 +/- 2 years) underwent heart transplantation. These patients were compared with 403 adult recipients younger than 60 years (mean, 47 +/- 11 years) who underwent transplantation during the same period., Results: Thirty-day mortality was 6% (5/81) and 6% (25/403) in the older and younger patients, respectively (P = NS). Actuarial survival at 1, 5, and 10 years was 88% +/- 4% versus 83% +/- 2%, 75% +/- 5% versus 69% +/- 2%, and 50% +/- 9% versus 51% +/- 3% in the older and younger patients, respectively (P = NS). Older patients had significantly fewer rejection episodes (P =.003). Freedom from allograft coronary artery disease at 1, 5, and 10 years was 98% +/- 2% versus 92% +/- 2%, 85% +/- 6% versus 76% +/- 3%, and 81% +/- 7% versus 68% +/- 3% (P =.1). The incidences of infectious complication, cytomegalovirus infection, and posttransplant lymphoproliferative disorder were similar between the 2 groups, but older recipients were more likely to have a nonposttransplant lymphoproliferative disorder cancer (P =.002). Age at transplantation was not identified as an independent risk factor for early and late death., Conclusion: Heart transplantation in selected patients aged 60 years and older results in survival comparable with that of younger patients. Older patients have a lower risk of rejection but an increased risk of development of a nonposttransplant lymphoproliferative disorder cancer. Advanced age per se should not be considered as an exclusion criterion for transplantation.

Objectives: We sought to document whether a physiologic change in gender has any effect on coronary arterial size., Background: The coronary arteries are smaller in women, even after correction for body surface area (BSA). These differences may contribute to adverse clinical outcomes after coronary artery bypass graft surgery and myocardial infarction in women. In male and female transsexuals, pharmacologic doses of estrogens and androgens significantly influence vascular diameter. Thus, gender differences in the coronary vasculature may be a reflection of the hormonal environment., Methods: In 86 patients who had undergone orthotopic heart transplantation, serial intravascular ultrasound studies of the proximal left anterior descending coronary artery (LAD) were analyzed. Changes in vessel area (VA) over the first or second post-transplant year were recorded, and comparisons were made between donor hearts that were transplanted in a patient of the same gender and those that were transplanted in a patient of the opposite gender., Results: Vessel area of the proximal LAD increased over time in all patient groups. In hearts transplanted within the same gender and in male donor hearts transplanted to female recipients, the change was small and not significant. However, in hearts transplanted from female donors to male recipients, there was a substantial and highly significant increase in LAD VA (median 16.13 to 17.88 mm(2); p = 0.01). This increase was not explained by confounding due to changes in BSA or left ventricular wall thickness., Conclusions: This pattern of arterial remodeling early after heart transplantation supports a link between host gender and coronary arterial size.

Background: When used in conjunction with steroids and cyclosporin, mycophenolate mofetil (MMF) has been shown to significantly reduce mortality and incidence of rejection in the first year after heart transplantation. It also appears that in this early post-transplantation period, the monitoring of immunosuppressive therapies may be warranted. The current study was undertaken to determine if such monitoring is still useful more than 1 yr after heart transplantation., Methods: Twenty-six patients who had survived the first year after orthotopic heart transplantation and had been on MMF therapy for more than 3 months were prospectively followed. At the time of their routine endomyocardial biopsy blood samples were taken to monitor immunosuppressive therapy. Most patients had two samples taken, on average 109 d apart., Results: There were 22 episodes of asymptomatic rejection documented on a total of 48 biopsies. Of these, only two were of ISHLT (International Society for Heart and Lung Transplantation) grade 3A the remainder being of ISHLT grades 1 or 2. There was no relation between immunosuppressive regimen (tacrolimus and MMF or cyclosporin and MMF) and rejection. There was no relation between monitored immunosuppressive levels and rejection. Patients with the combination of MMF and tacrolimus had significantly higher plasma mycophenolic acid levels despite significantly lower daily MMF dose., Conclusion: There does not appear to be a benefit in continued monitoring of plasma mycophenolic acid levels beyond the first year of heart transplantation. There were significant differences in plasma mycophenolic acid levels depending on the type of calcineurin inhibitor concomitantly used.

Background: Hyperhomocysteinemia is an independent risk factor for coronary disease and elevated plasma homocysteine levels have been documented in heart transplant recipients. The aim of this study was to test the hypothesis that homocysteine levels are associated with presence or absence of transplant coronary artery disease., Methods: Forty-three non-smoking adults were recruited, all of whom had received a heart transplant between 2 and 7 yr previously. All 43 had blood drawn for fasting homocysteine level on the day of presentation. All patients had undergone diagnostic coronary angiography within the past 6 months., Results: For all patients, the average fasting plasma homocysteine level was 17.0+/-SD 6.6 micromol/L with a range from 6.0 to 36.9 micromol/L. Twenty-six patients (60%) had fasting plasma homocysteine levels above 15.0 micromol/L. On the basis of arteriography, patients were categorized as those with angiographically normal (n=22) or abnormal (n=21) coronary arteries. There was no difference in the mean plasma homocysteine level comparing patients with angiographically normal (17.2+/-SD 7.0 micromol/L) to those with abnormal (16.8+/-SD 6.2 micromol/L) coronary arteries. Plasma homocysteine levels increased with increasing plasma creatinine levels (r=0.63, p<0.0001) and with decreasing vitamin B6 levels (r=-0.56, p<0.0001)., Conclusions: Mild hyperhomocysteinemia is a consistent finding among heart transplant recipients. This finding was not associated with transplant coronary artery disease in our patients. The combination of renal dysfunction and vitamin B6 deficiency may explain the unusual prevalence of hyperhomocysteinemia in heart transplant recipients.

Background: Tricuspid regurgitation (TR) is common after heart transplantation. However, the incidence of severe TR and the incidence of symptoms after echocardiographic diagnosis of severe TR have not been documented. The purpose of this study is to determine the incidence of severe TR and its clinical significance in the heart transplant population., Methods: We reviewed echocardiograms (echo) of all heart transplant patients coming for regular echocardiographic follow-up between 1990 and 1995. We reviewed the charts of all patients who had echo diagnosis of severe TR., Results: A total of 336 patients had echo follow-up during this time period. The number of months post-heart transplant to last echo was 54 +/- 50 (range, 1 to 265 months). Ninety patients had moderate TR and 23 patients had severe TR. Mean time from heart transplantation to diagnosis of severe TR was 43 +/- 38 months (range, 1 to 132). Using Cutler-Ederer analysis, at 5 years, 92.2% of surviving patients were free from severe TR. At 10 years, 85.8% of surviving patients were free from severe TR. Of the 23 patients with severe TR, 17 had charts available for review. The mean number of prior endomyocardial biopsies was 28 +/- 21 (range, 3 to 88). These patients were followed for 35 +/- 18 months after diagnosis. During this period, they developed significant heart failure and peripheral edema. Six patients eventually underwent tricuspid valve replacement., Conclusions: Moderate to severe TR commonly occurs following heart transplantation. Severe TR is associated with significant morbidity.

The number of patients who are potentially eligible for heart transplantation is increasing steadily in the face of a plateaued or stable donor supply. Therefore, development of fair, sensible, and consistently and widely applied criteria for transplant recipient selection is a crucial medical and societal issue. This article examines the evolution of these criteria and advocates a flexible approach to their continued evolution.

Transplant recipients have a higher incidence of cancer compared with the general population. This increased risk is related to the intensity and chronicity of immunosuppression that these patients receive. The common types and presentations of posttransplant tumors are reviewed and discussed. Regular surveillance is of paramount importance in detecting such tumors. Treatment invariably includes attempts to reduce immunosuppression.

Background: Coronary artery disease occurs in an accelerated fashion in the donor heart after heart transplantation (TxCAD), but the cause is poorly understood. The risk of developing TxCAD is increased by cytomegalovirus (CMV) infection and decreased by use of calcium blockers. Our group observed that prophylactic administration of ganciclovir early after heart transplantation inhibited CMV illness, and we now propose to determine whether this therapy also prevents TxCAD., Methods and Results: One hundred forty-nine consecutive patients (131 men and 18 women aged 48+/-13 years) were randomized to receive either ganciclovir or placebo during the initial 28 days after heart transplantation. Immunosuppression consisted of muromonab-CD3 (OKT-3) prophylaxis and maintenance with cyclosporine, prednisone, and azathioprine. Mean follow-up time was 4.7+/-1.3 years. In a post hoc analysis of this trial designed to assess efficacy of ganciclovir for prevention of CMV disease, we compared the actuarial incidence of TxCAD, defined by annual angiography as the presence of any stenosis. Because calcium blockers have been shown to prevent TxCAD, we analyzed the results by stratifying patients according to use of calcium blockers. TxCAD could not be evaluated in 28 patients because of early death or limited follow-up. Among the evaluable patients, actuarial incidence of TxCAD at follow-up (mean, 4.7 years) in ganciclovir-treated patients (n=62) compared with placebo (n=59) was 43+/-8% versus 60+/-10% (P<0.1). By Cox multivariate analysis, independent predictors of TxCAD were donor age >40 years (relative risk, 2.7; CI, 1.3 to 5.5; P<0.01) and no ganciclovir (relative risk, 2.1; CI, 1.1 to 5.3; P=0.04). Stratification on the basis of calcium blocker use revealed differences in TxCAD incidence when ganciclovir and placebo were compared: no calcium blockers (n=53), 32+/-11% (n=28) for ganciclovir versus 62+/-16% (n=25) for placebo (P<0.03); calcium blockers (n=68), 50+/-14% (n=33) for ganciclovir versus 45+/-12% (n=35) for placebo (P=NS)., Conclusions: TxCAD incidence appears to be lower in patients treated with ganciclovir who are not treated with calcium blockers. Given the limitations imposed by post hoc analysis, a randomized clinical trial is required to address this issue.

Background: The experience with 30 years of cardiac transplantation at Stanford University Medical Center was reviewed. A total of 954 transplants were performed in 885 patients. Patients were divided into 3 groups based on immunosuppression received: group I, no cyclosporine (INN: ciclosporin) (n = 201) (January 1968-November 1980); group II, cyclosporine (n = 248) (December 1980-June 1987); and group III, cyclosporine + OKT3 (n = 436) (July 1987-March 1998)., Results: The 1-, 5-, and 10-year actuarial survivals were 68%, 41%, and 24% (group I); 80%, 57%, and 37% (group II); and 85%, 68%, and 46% (group III) (I vs II, P <.01; I vs III, P <.005; and II vs III, P <.005). The 1-, 5-, and 10-year actuarial death rates from rejection were 8%, 12%, and 14% (group I); 5%, 7%, and 7% (group II); and 2%, 5%, and 5% (group III) (I vs II, P = not significant; I vs III, P <.005; and II vs III, P <.005). The 1-, 5-, and 10-year actuarial death rates from infection were 25%, 43%, and 50% (group I); 8%, 17%, and 29% (group II); and 6%, 11%, and 16% (group III) (I vs II, P <.005; I vs III, P <.005; and II vs III, P <.05). The 1-, 5-, and 10-year actuarial death rates from graft coronary artery disease were 0%, 5%, and 13% (group I); 0%, 12%, and 19% (group II); and 1%, 6%, and 9% (group III) (I vs II, P <.01; I vs III, P <.005; and II vs III, P = not significant). There have been 69 retransplants in 67 patients with 1-, 5-, and 10-year actuarial survivals of 49%, 27%, and 15%, respectively., Conclusions: The evolution of 3 decades of experience with cardiac transplantation has resulted in improved overall survival. The incidence of rejection and of death from infection and graft coronary artery disease have decreased over time, primarily as a result of improvements in immunosuppression and in the prevention and treatment of infection. Continued advances in perioperative management and the development of more specific, less toxic immunosuppressive agents could further refine this initial experience and improve the survival and quality of life of patients after cardiac transplantation.

Cardiac transplantation, first introduced 30 years ago, has become a widely used and increasingly important procedure for treatment of truly end-stage heart disease. Current use is limited strictly by donor supply, making selection of appropriate recipients an important ethical and societal issue. Survival rates after transplantation rose in the 1980s with the use of cyclosporine and have remained relatively consistent since then, although recipients older than 65 years or younger than 1 year have lower survival rates than recipients of other ages. Although immunosuppressive drugs have helped establish cardiac transplantation as a successful procedure, risks of opportunistic infection and rejection, as well as coronary arteriopathy, have led to development of new immunosuppressive agents currently under study. Future alternatives to the current technology of cardiac allotransplantation may include xenotransplantation and/or nonbiological replacement of the heart with mechanical devices.