Prognostic Value of High-Sensitivity Troponin-T to Identify Patients at Risk of Left Ventricular Graft Dysfunction After Heart Transplantation.

Primary graft dysfunction after heart transplantation (HTx) has a very high mortality rate, especially if the left ventricle (PGD-LV) is involved. Early diagnosis is important to select the appropriate therapy to improve prognosis. The value of high-sensitivity troponin T (HS-TNT) measurement obtained at patient arrival at the intensive care unit was analyzed in 71 HTx patients. Mild or moderate PGD-LV was defined by hemodynamic compromise with one of the following criteria: left ventricular ejection fraction <40%, hemodynamic compromise with right atrial pressure >15 mm Hg, pulmonary capillary wedge pressure >20 mm Hg, cardiac index <2.0 L/min/m2, hypotension (mean arterial pressure <70 mm Hg), and need for high-dose inotropes (inotrope score >10) or newly placed intra-aortic balloon pump. The mean recipient age was 54 ± 12 years (73% men), and donor age was 47 ± 11 years. Ischemic time was 200 ± 51 minutes, and coronary bypass time was 122 ± 31 minutes. Nine (13%) HTx patients were diagnosed with PGD-LV post-HTx, 8 with biventricular dysfunction. Four patients died, 2 with PGD-LV (22%) and 2 without PGD (4%). Mean HS-TNT before HTx was 158 ± 565 ng/L, and post-HT was 1621 ± 1269 ng/L. The area under the curve (receiver-operator characteristic) of HS-TNT to detect patients at risk of PGD-LV was 0.860 (P < .003). A cutoff value of HS-TNT >2000 ng/L had a sensitivity of 75% and specificity of 87% to identify patients at risk of PGD-LV. Multivariate analysis identified HS-TNT >2000 ng/L (P < .02) and coronary bypass-time (P < .01) as independent predictors of PGD-LV. HS-TNT >2000 ng/L at intensive care admission after HT and prolonged coronary bypass time were the most powerful predictors of PGD-LV. HS-TNT may be helpful for early detection of HTx patients at risk of PGD-LV.

De Novo Anti-HLA Antibodies After Heart Transplantation Are Associated With Adverse Events in the Long-term Follow-up of Cardiac Transplant Recipients.

BACKGROUND AND OBJECTIVES: Long-term morbidity and mortality after heart transplantation (HTx) remain very high. Several reports have suggested that anti-HLA antibodies (anti-HLA-AB) detected after HTx might be associated with poor survival, but the implication of isolated anti-HLA-AB is still under debate. The aim of the study was to analyze the incidence of de novo anti-HLA-AB and whether they are associated with adverse events after HTx. METHODS: This retrospective study analyzed the presence of anti-HLA-AB assessed by fluorimetry (Luminex) and quantified by a single-antigen bead assay in 119 HTx patients. Mortality, graft dysfunction, antibody-mediated rejection (AMR), and cardiac allograft vasculopathy (CAV) were recorded. Cardiovascular mortality of patients with and without anti-HLA-AB was compared according Kaplan-Meier curves. Cox regression analyses were performed to identify predictors for global mortality and for a combined endpoint (cardiovascular mortality, AMR, and CAV). Mean age of recipients and donors was 49 ± 15 and 38 ± 14 years, 70% were men, 29% were urgent transplants, and mean ischemic time was 195 ± 56 minutes. RESULTS: Anti-HLA-AB were detected in 23 patients (19%). These patients had higher rates of AMR (39% vs 1%; P < .05) and cardiovascular mortality (17% vs 2%; P < .05). By multivariate analysis, anti-HLA-AB were the only predictor of the combined endpoint (hazard ratio 3.1; confidence interval 1.3 to 7.5; P = .01). Kaplan-Meier curves showed the worse cardiovascular survival of patients with anti-HLA-AB (72% vs 97%; P = .003). CONCLUSIONS: Presence of anti-HLA-AB identifies a group of HTx patients with worse prognosis. Better understanding of the immunologic relevance of anti-HLA-AB is expected to improve long-term survival after HTx.

Role of Vascular Disease in the Evolution of Heart Transplant Patients.

BACKGROUND: The clinical profile of heart transplantation (HT) recipients has changed in recent years. Nowadays, we have to deal with a higher number of co-morbidities, including peripheral vascular disease (PVD). Previous studies suggest an increase in post-HT morbidity and mortality associated with PVD, especially when it is symptomatic. Our study aims were to analyze the prognostic implications of the presence of PVD before transplantation and to determine the factors associated with its development after it. METHODS: HT patients (n = 217) who survived the first year after surgery were included in the study. Mean follow-up was 9 ± 5 years. RESULTS: There were no statistically significant differences in mortality rates between patients with PVD (before or after HT) and those without. One third of patients with PVD required surgery in the post-HT monitoring, either revascularization or amputation. Furthermore, the prevalence of PVD was doubled. Dyslipidemia before HT (odds ratio [OR]: 2.9, 95% confidence interval [CI]: 1.3-6.4; P < .01) and older recipient age (OR: 1.05, 95% CI: 1.01-1.09; P < .05) were independently associated with development of PVD by means of multivariate analysis. CONCLUSIONS: The presence of PVD must be evaluated individually in candidates for heart transplantation despite being a relative contraindication to it at the present time.

Cost-Effectiveness of Highly Sensitive Cardiac Troponin T to Rule Out Acute Rejection After Heart Transplantation.

BACKGROUND: Endomyocardial biopsy (EMB) remains the gold standard for detecting acute rejection (AR) after heart transplantation (HTx). Non-invasive detection of AR thus far remains a challenge. Several studies have demonstrated that highly sensitive cardiac troponin T (hs-cTnT) concentrations have a low positive predictive value for diagnosing AR. Nevertheless, hs-cTnT proved to be useful for ruling out AR after HTx. An hs-cTnT concentration <17 ng/L, a value close to that used for rule-in or rule-out myocardial infarction, was associated with a 100% negative predictive value of AR. However, the cost-effectiveness of a strategy with the use of hs-cTnT for ruling out AR in HTx patients remains to be proven. METHODS: The cost-effectiveness of hs-cTnT determination for ruling out AR was assessed, comparing the costs of hs-cTnT measurements in 305 blood samples obtained at the time of EMB. Eighteen samples were excluded because the EMB was not assessable. RESULTS: Hs-cTnT determination cost 16.00€ per sample, whereas EMB cost 1752.00€ per biopsy; cost estimations included direct and indirect (30%) charges. Thirty-nine (13.6%) of the 287 blood samples presented hs-cTnT concentrations <17 ng/L; in none of them was an AR >2R degree found in the EMB. The cost of the assessment in the 287 blood samples and biopsies was of 4592.00€ for hs-cTnT and 502,824.00€ for EMB. Hs-cTnT systematic measurement would have avoided 39 EMB, with a saving of 68,328.00€, which represents the 13.5% of the total budget expended in these cases. CONCLUSIONS: The use of hs-cTnT values to rule out the need of EMB for AR diagnosis after HTx appears to be a cost-effective procedure.

Health-related quality of life, social support, and caregiver burden between six and 120 months after heart transplantation: a Spanish multicenter cross-sectional study.

A multicenter cross-sectional study was conducted to determine the current heart transplant (HTx) outcomes in Spain. Clinical and functional status, health-related quality of life (HRQoL), social support, and caregiver burden were analyzed in 303 adult transplant recipients (77.9% males) living with one functioning graft. Mean age at time of HTx (SD) was 56.4 (11.4) years, and the reason for transplantation in all patients was congestive heart failure. All patients had received a first heart transplant 6 (± 1), 12 (± 2), 36 (± 6), 60 (± 10), or 120 (± 20) months previously. Participants completed the Kansas City Cardiomyopathy Questionnaire (KCCQ), the EQ-5D, the Duke-UNC Functional Social Support Questionnaire, and the Zarit Caregiver Burden Scale. Reasonable HRQoL, social support, and caregiver burden levels were found at all time points, although a slight decrease in HRQoL was recorded at 120 months (p ≤ 0.033). Multivariate regression analyses showed that complications, comorbidities, and hospitalizations were associated with HRQoL (EQ-5D: 48.4% of explained variance, F4,164 = 38.46, p < 0.001; KCCQ overall summary score: 45.0%, F3,198 = 54.073, p < 0.001). Patient functional capabilities and complications affected caregiver burden (p < 0.05). In conclusion, HTx patients reported reasonable levels of HRQoL with low caregiver burden. Clinical variables related to these outcomes included functional status, complications, and number of admissions.

RAndomized Comparison of raDIal vs. femorAL Access for Routine Catheterization of Heart Transplant Patients (RADIAL-heart transplant study).

Although a transradial approach (TRA) is considered feasible in many clinical situations, no data are available in patients undergoing orthotopic heart transplantation (OHT). Our goal was to randomly compare TRA versus a transfemoral approach (TFA) in this clinical setting. This single-center, prospective, randomized trial was conducted from January to November 2006, and all OHT patients scheduled for a control coronary angiography were randomized to receive TRA or TFA. The primary endpoint was the amount of contrast used during the procedure. The participating interventional cardiologists were intermediate-volume radial operators, and this was their initial experience of TRA in OHT patients. The analysis was performed according to the intention-to-treat principle. Overall, 49 patients (mean age, 55 ± 13 years; 74% male) were included in the trial: 26 patients were assigned to TRA, and 23 were assigned to TFA. A higher amount of contrast (147 mL [range, 113-175 mL] vs 105 mL [range, 86-127 mL]; P = .009), a longer fluoroscopy time (9.2 minutes [range, 6-12 minutes] vs 3.5 minutes [range, 3-5 minutes]; P < .001), a trend toward increased number of catheters used for left ostium cannulation, and a higher crossover rate (19% vs 0%; P = .03) were associated with TRA compared with TFA. Furthermore, patients treated with TRA exhibit a shorter hospital stay (6 [range 4-8]) compared with the other group (26 [range 24-28]) (P < .001). There were no significant differences between the 2 groups regarding total procedural time, and no vascular complications were reported in either group. For these operators with their first experience of TRA in OHT patients, TFA seemed to be more efficient.

Correlation of immunological markers with graft vasculopathy development in heart transplantation.

This study examined the imbalance between T effector cells (Th1 defined as CD3+ interferonγ+) and T regulatory cells (Treg defined as CD4+CD25(high)FoxP3+) as a valuable albeit limited marker of cardiac allograft vasculopathy (CAV) after heart transplantation (HTx). CAV remains, with neoplasms, the most important cause of death in patients surviving the first year after HTx. It is an immune-mediated pathology, although nonimmune factors may also play a role. The process included concentric fibrous intima hyperplasia that narrows the entire length of the affected arteries. Coronary angiography is the usual method of diagnosis. Because a transplanted heart is a denervated organ, CAV is not diagnosed until the disease reaches an advanced stage, in which case transplantation is the only option for treatment. Although the host's immune response against an allogeneic graft is the major cause of endothelial dysfunction, the objective of this study was to detect anti-allogeneic responses on peripheral blood, seeking to identify signs of CAV before classical methods to predict outcomes in HTx recipients. CD3, CD4, CD8, CD19, CD56, Th1, and the Treg mononuclear cell populations were studied in 37 de novo and 20 long-term (more than 3 years) HTx patients as well as 20 healthy volunteers using flow cytometry. A progressive increase in CD8 and Th1 percentages and decrease in the CD4 population were detected during follow-up. Although Th1 changes also reflect processes not related to CAV receiver operating characteristics analysis of Th1/Treg ratio showed an area under the curve of 0.976, with an estimated sensitivity of 100% and specificity of 90%. The positive prediction value was 58.8% and the negative prediction value, 100%. These results prove that the Th1/Treg ratio was an important marker to following host immune response after HTx. The results confirm the need to test other T lymphocyte subsets.

Assessment of immunological markers as mediators of graft vasculopathy development in heart transplantation.

Heart transplantation (HT) remains the treatment of choice for patients with end-stage heart failure. Cardiac allograft vasculopathy (CAV), a diffuse form of coronary atherosclerosis, is the major cause of death after the first year of HT. CAV is thought to be multifactorial in origin. Although nonimmune factors may play a role in CAV development, it is primarily an immune-mediated disease. CAV is diagnosed by routine annual coronary angiography, and usually when diagnosed, the disease is advanced. There is a need to develop noninvasive surrogate markers for early detection. For this purpose, careful immune monitoring and graft histologic assessment are mandatory. The main objective of this study was the assessment of immunologic markers as mediators of CAV development in HT. Flow cytometry was performed to assess peripheral blood mononuclear cell populations forming CD3, CD4, CD8, CD19, CD56, Th1 (CD3+IFNγ+) or Treg (CD4+CD25(high)FoxP3+) markers among 20 de novo HT recipients. The control group included 13 patients who were more than 2 years post-HT (four with and nine without CAV) as well as 20 healthy subjects. CAV-related events over 2 years' follow-up correlated with the Th1/Treg ratio. An increased Th1 lymphocyte percentage was detected over the follow-up. Patients with medium and high Th1/Treg ratios showed higher acute rejection scores as well as greater incidences of CAV. These results indicated that the Th1/Treg ratio may represent a valuable marker to monitor allospecific T-cell responses in peripheral blood. Changes in the Th1/Treg ratio may help in the early detection of patients at risk for CAV. More studies with longer follow-up are needed to confirm these preliminary results.

The prognosis of noncutaneous, nonlymphomatous malignancy after heart transplantation: data from the Spanish Post-Heart Transplant Tumour Registry.

INTRODUCTION: Malignancy is a major complication in the management of solid organ transplant patients. Skin cancers show a better prognosis than other neoplasms, but not all others are equal: Ideally, patient management must take into account the natural history of each type of cancer in relation to the transplanted organs. We sought to determine the prognosis of various groups of noncutaneous nonlymphomatous (NCNL) cancers after heart transplantation (HT). METHODS: We retrospectively analyzed the records of the Spanish Post-Heart-Transplant Tumour Registry, which collects data on posttransplant tumors in all patients who have undergone HT in Spain since 1984. Data were included in the study up to December 2008. We considered only the first NCNL post-HT tumors. RESULTS: Of 4359 patients, 375 developed an NCNL cancer. The most frequent were cancers of the lung (n=97; 25.9%); gastrointestinal tract (n=52; 13.9%); prostate gland (n=47; 12.5%; 14.0% of men), bladder (n=32; 8.5%), liver (n=14; 3.7%), and pharynx (n=14; 3.7%), as well as Kaposi's sarcoma (n=11; 2.9%). The corresponding Kaplan-Meier survival curves differed significantly (P<.0001; log-rank test), with respective survival rates of 47%, 72%, 91%, 73%, 36%, 64%, and 73% at 1 year versus 26%, 62%, 89%, 56%, 21%, 64%, and 73% at 2 years; and 15%, 51%, 77%, 42%, 21%, 64%, and 52% at 5 years post-diagnosis, respectively. CONCLUSION: Mortality among HT patients with post-HT NCNL solid organ cancers was highest for cancers of the liver or lung (79%-85% at 5 years), and lowest for prostate cancer (23%).

Steroid use in heart transplant patients in Spain in the current era: a multicenter survey.

OBJECTIVE: Steroid withdrawal (SW) from maintenance therapy in heart transplant patients is still a controversial subject. We designed a questionnaire to ascertain the attitudes and procedures of a number of Spanish heart transplant units (16) regarding the use/withdrawal of steroids as part of the immunosuppressive maintenance therapy. MATERIALS AND METHODS: We sent an 11-item questionnaire to the clinical director in charge of each unit. The questionnaire was completed and returned by 14 units. RESULTS: In 21.5% of the centers SW was performed in all patients, while 78.5% of the centers only performed SW in selected patients. In 57% of units SW was performed at 12 months posttransplantation and between 6 and 12 months in the rest. Fewer than 20% of patients were steroid-free in 46% of units while in 23% of units this proportion was >50%. In 11 units, the minimum prednisone dose administered was

Malignancy after heart transplantation: incidence, prognosis and risk factors.

The Spanish Post-Heart-Transplant Tumour Registry comprises data on neoplasia following heart transplantation (HT) for all Spanish HT patients (1984-2003). This retrospective analysis of 3393 patients investigated the incidence and prognosis of neoplasia, and the influence of antiviral prophylaxis. About 50% of post-HT neoplasias were cutaneous, and 10% lymphomas. The cumulative incidence of skin cancers and other nonlymphoma cancers increased with age at HT and with time post-HT (from respectively 5.2 and 8.9 per 1000 person-years in the first year to 14.8 and 12.6 after 10 years), and was greater among men than women. None of these trends held for lymphomas. Induction therapy other than with IL2R-blockers generally increased the risk of neoplasia except when acyclovir was administered prophylactically during the first 3 months post-HT; prophylactic acyclovir halved the risk of lymphoma, regardless of other therapies. Institution of MMF during the first 3 months post-HT reduced the incidence of skin cancer independently of the effects of sex, age group, pre-HT smoking, use of tacrolimus in the first 3 months, induction treatment and antiviral treatment. Five-year survival rates after first tumor diagnosis were 74% for skin cancer, 20% for lymphoma and 32% for other tumors.

Burden of myocardial damage in cardiac allograft rejection: scintigraphic evidence of myocardial injury and histologic evidence of myocyte necrosis and apoptosis.

BACKGROUND: Because myocardial damage determines morbidity and outcomes in heart transplant rejection, assessment of total burden of myocardial damage is highly desirable. In addition to myocyte necrosis, programmed cell death, or apoptosis, has recently been shown to contribute to cardiac allograft rejection. In the present study, we noninvasively determined myocardial damage by antimyosin scintigraphy and compared it with necrotic and apoptotic myocardial damage in endomyocardial biopsy (EMB) specimens. METHODS AND RESULTS: Forty scintigraphic and histologic studies were simultaneously performed. Of these, 19 patients had no EMB evidence of allograft rejection (group I, International Society of Heart and Lung Transplantation [ISHLT] grade 0/4), 12 had mild rejection (group II, ISHLT grades 1A and 1B), and 9 had evidence of moderate allograft rejection (group III, ISHLT grades 2, 3A, and 3B). None of the biopsies demonstrated severe allograft rejection (ISHLT grade 4/4). The severity of global myocyte damage in 40 patients was assessed by antimyosin scintigraphy. Endomyocardial biopsies were performed in these patients within 48 hours of imaging study; biopsy specimens were characterized for presence of myocyte necrosis and apoptosis. Evidence of myocyte necrosis was observed in 9 (23%) of 40 EMB specimens. Nineteen EMB specimens of group I had no inflammation and no myocyte necrosis, 12 of group II specimens showed interstitial mononuclear cell infiltration (only) but no myocyte necrosis, and all 9 of group III specimens had evidence of cellular infiltration and myocyte damage. Myocyte necrosis was assessed by hematoxylin-eosin and trichrome staining of EMB specimens. On the other hand, apoptosis of myocytes, as assessed by TUNEL staining of DNA fragments, was seen in 22 (55%) of the 40 biopsy specimens: 47%, 58%, and 67% in groups I, II and III, respectively. Abnormal antimyosin scan findings, indicating presence of myocardial damage, were observed in 9 of the 19 patients in group I and in all patients in groups II and III. Although positive antimyosin scan results in group III patients are concordant with the presence of histologic myocardial necrosis, myocardial uptake of antimyosin antibodies in groups I and II (no apparent myocyte damage at light microscopic examination) could reflect either sampling error of the biopsy or ongoing apoptotic myocyte damage. CONCLUSIONS: Apoptosis of myocytes is frequently observed during cardiac allograft rejection. The presence of apoptotic myocytes in the absence of histologic rejection activity in patients with antimyosin uptake suggests that apoptosis could be an additional mechanism of transplant-associated myocardial damage.

Efficacy of augmented immunosuppressive therapy for early vasculopathy in heart transplantation.

OBJECTIVES: The present study was undertaken to prospectively and comparatively evaluate the role of serial myocardial perfusion imaging and coronary angiography for the detection of early vasculopathy in a large patient population and also to determine the short- and long-term efficacy of augmented immunosuppressive therapy in the potential reversal of the early vasculopathy. BACKGROUND: Allograft vasculopathy is the commonest cause of death after the first year of heart transplantation. Anecdotal studies have reported the efficacy of augmented immunosuppressive therapy after early detection of vascular involvement. However, no prospective study has evaluated the feasibility of early detection and treatment of allograft vasculopathy. METHODS: In 76 cardiac allograft recipients, 230 coronary angiographic and 376 scintigraphic studies were performed in a follow-up period of 8 years. Angiography was performed at 1 month and every year after transplantation, and thallium-201 scintigraphy at 1, 3, 6 and 12 months after transplantation and twice a year thereafter. Prospective follow-up of 76 patients showed that 18 developed either angiographic or scintigraphic evidence of coronary vasculopathy. All episodes were treated with 3-day methylprednisolone pulse and antithymocyte globulin. RESULTS: Twenty-two episodes of vasculopathy were diagnosed and treated in these 18 patients. Of these 22 episodes, two were detected only by angiography, seven by both angiography and scintigraphy, four by scintigraphy and histologic evidence of vasculitis and nine episodes only by thallium-201 scintigraphy studies. Angiographic and/or scintigraphic resolution was observed in 15 of the 22 episodes (68%) with augmented immunosuppression. The likelihood of regression was higher when treatment was instituted within the first year of transplantation (92%) than after the first year (40%) (p = 0.033). Eighty percent of patients who responded to follow-up. CONCLUSIONS: The present study suggests that early detection of allograft coronary vasculopathy is feasible with surveillance myocardial perfusion or coronary angiographic studies. When identified early after transplantation, immunosuppressive treatment may result in regression of coronary disease.