What is the best biomarker for diagnosis of rejection in heart transplantation?

INTRODUCTION: Acute cellular rejection is a major cause of graft loss in heart transplantation (HT). Endomyocardial biopsy remains the gold standard for its diagnosis, but it is an invasive procedure not without risk. A proinflammatory state exists in rejection that could be assessed by determining plasma levels of inflammatory biomarkers. OBJECTIVE: To analyze the utility of various inflammatory markers, which is most important and what values best classify patients to diagnose rejection. MATERIALS AND METHODS: A prospective study in 123 consecutive cardiac transplant recipients was conducted from January 2002 to December 2006. Fibrinogen protein (Fgp) and function (Fgf), C-reactive protein (CRP), tumor necrosis factor-alpha (TNF-alpha), interleukin-6 (IL-6), and sialic acid (SA) determinations were performed at one, two, four, six, nine, and 12 months post-HT at the same time as biopsies. Coronary arteriography and intravascular ultrasound were performed on the first and last follow-up visits. Heart-lung transplants, retransplants, pediatric transplants, patients who died in the first month, and patients who refused consent were excluded. Also excluded were determinations that coincided with renal dysfunction, active infection, hemodynamic instability, or a non-evaluable biopsy. The final analysis included 79 patients and 294 determinations. The correlation between the levels of these biomarkers and the presence of rejection in the biopsy (> or = ISHLT grade 3) was studied. RESULTS: We did not find significant differences in the values of any of the markers analyzed on the six follow-up visits. Only CRP showed significant and sustained differences between the two groups (with and without rejection) from the second follow-up visit (month 2). The area under the curve showed significant differences in Fgp (0.614, p = 0.013), Fgf (0.585, p = 0.05), TNF-alpha (0.605, p = 0.02), SA (0.637, p = 0.002) and mainly CRP (0.765, p = 0.0001). CRP levels below 0.87 mg/dL ruled out rejection with a specificity of 90%. CONCLUSIONS: Among the inflammatory markers analyzed, CRP was the most useful parameter for non-invasive screening of acute cellular rejection in the first year post-HT.

Effect of clinical trials on survival after heart transplantation.

UNLABELLED: The application of clinical trials (CTs) to daily practice is based on the assumption that the patients included in these trials are similar to those seen on a daily basis. We performed a retrospective study to evaluate patient survival depending on whether they were included in a CT. We studied 217 patients who underwent heart transplantation (HT) between January 2000 and September 2006. We excluded patients who received combination transplants, those who underwent repeat HT, and pediatric patients who underwent HT. In total, 54 patients were included in a CT and 163 were not (NCT). The statistical tests included the t test, the chi(2) test and the Kaplan-Meier method. RESULTS: Patients in the NCT group were in worse condition at HT, with a greater percentage of inotropic treatments pre-HT (36% vs 17%; P = .005), emergency transplants procedures (30% vs 13%; P = .01), and worse functional status pre-HT (P = .03). The NCT group exhibited lower survival (80.37% vs 87.04%; P = 0.13, log-rank test). There were no significant differences in the other analyzed variables. CONCLUSIONS: Patients included in CTs tend to have better long-term survival rates, for several reasons: patients in the CT group were more stable at HT (selection bias), and the close follow-up of patients in CTs makes it more likely that any complication will be detected and treated early (follow-up bias).

Analysis of heart rate turbulence in advanced heart failure and heart transplantation patients.

OBJECTIVE: The objective of this study was to describe heart rate turbulence (HRT) in advanced heart failure (HF) patients and in a group of patients who underwent heart transplantation (HT). MATERIALS AND METHODS: We performed 24-hour Holter recordings in 20 patients with advanced HF referred to our hospital for HT, including 16 males of overall mean age of 44 +/- 13 years and with a mean ejection fraction (EF) 21 +/- 7%. An additional set of recordings was obtained in a second group of 27 patients who had already undergone HT, including of 21 males of overall mean age of 47 +/- 14 years. We recorded the number of premature ventricular contractions (PVCs), mean heart rate (MHR), and 2 parameters of HRT-turbulence onset (TO) and turbulence slope (TS). RESULTS: Patients with HT showed a low density of premature ventricular complexes, in contrast to patients in the advanced HF group. For this reason, HRT could only be analyzed in 15 of the patients with advanced HF (66%) and in 10 of the patients who underwent HT (37%). MHR was 77 +/- 10 bpm in the advanced HF group and 90 +/- 10 bpm in the HT group. In both groups, TO and TS showed highly attenuated values. CONCLUSIONS: Patients with advanced HF showed a high number of PVCs with attenuated HRT parameters, reflecting increased circulating catecholamine levels and decreased response of the autonomic nervous system. Patients who underwent HT showed elevated MHRs, a small number of PVCs, and attenuated HRT values, as corresponds to a denervated heart.

Effect of circulatory assistance on premature death and long-term prognosis.

BACKGROUND: Patients undergoing urgent heart transplantation (HT) have a poorer prognosis and more long-term complications. The objective of this study was to compare the preoperative course in patients undergoing urgent HT according to the need for preoperative intra-aortic balloon counterpulsation (IABP). MATERIALS AND METHODS: We studied 102 consecutive patients including 23 patients with IABP who underwent urgent HT between January 2000 and September 2006. We excluded patients who received combination transplants, those who underwent repeat HT, and pediatric patients who underwent HT. The statistical methods used were the t test for quantitative variables and the chi(2) test for qualitative variables. A logistic regression model was constructed to assess the possible relationship between IABP and other variables on premature death within 30 days after HT. RESULTS: Mean (SD) patient-age was 50 (10) years. No significant differences were observed in baseline characteristics between the IABP and the non-IAPB groups. The IABP patient group had higher rates of acute graft failure (45.5% vs 35.4%; P = .46) and premature death (18.8% vs 14.8%; P = .67) and shorter long-term survival (40.6 [34.9] vs 54.5 [43.7] mo; P = .30). Multivariate analysis demonstrated no association between the need for IABP and increased frequency of premature death. CONCLUSIONS: Use of IABP is not associated with premature or late death. We recommend use of IABP in patients with acute decompensated heart failure to stabilize them before HT.

Evolution of right cardiac pressures during the first year after heart transplantation.

INTRODUCTION: Preoperative pulmonary hypertension is an adverse prognostic factor for early morbidity-mortality after heart transplantation (HT). The persistence of hypertension is likewise associated with a poorer patient prognosis. The present study investigated the evolution of right cardiac pressures in the first year after HT with respect to the background cardiac disease. METHODS: This study of 60 consecutive patients subjected to HT analyzed the baseline clinical characteristics and mean right atrial and right ventricle systolic and diastolic pressures in a pre-HT study and during biopsies performed in the first 2 weeks as well as at 1, 3, 6, 9, and 12 months after transplantation. The study excluded retransplantations, heart and lung transplantations, and pediatric patients, as well as patients not subjected to biopsy because of early mortality. RESULTS: The mean patient age was 50 years (83% males); 31.7% were diabetics, and 33% showed hypertension. The background heart disease was of ischemic origin in 35% of cases, and consisted of dilated myocardiopathy in 33%, with a mean left ventricle ejection fraction (LVEF) of 23% and a mean pulmonary artery systolic pressure of 50.1 mm Hg. During the postoperative course, an important decrease versus baseline was observed in right heart pressures as soon as 2 weeks post-HT, with a drop in right ventricle (RV) systolic pressure from 50.3 +/- 13.7 to 42.5 +/- 10.4 mm Hg (P = .013), and a drop in RV diastolic pressure from 17.4 +/- 5.8 to 14.2 +/- 4.1 mm Hg (P = .007). This decreased tendency continued to a more moderate extent to the third month, after which the pressures stabilized. The same behavior was observed in patients with diseases of ischemic origin and in those with dilated myocardiopathy. CONCLUSIONS: In our series, right cardiac pressures showed an important decrease in the first days after HT, with stabilization by the third month--though without returning to normal values and without modifications in the first year after transplantation. No differences in this evolutive trend were seen according to the type of background heart disease.

Diagnostic usefulness of inflammatory markers in acute cellular rejection after heart transplantation.

BACKGROUND: Acute cellular rejection (ACR) affects early morbidity and mortality after heart transplantation. The diagnostic technique of choice is endomyocardial biopsy. Our aim was to evaluate the diagnostic usefulness of inflammatory markers as a noninvasive method to monitor cellular rejection. MATERIAL AND METHODS: We prospectively analyzed 73 cardiac transplant patients by determining the serum levels of protein fibrinogen (fgpro), functional fibrinogen (fgfun), C-reactive protein (CRP), and sialic acid (SA) coinciding with an endomyocardial biopsy (5.1 revisions/patient). The statistical methods were chi(2), Student's t-test, and ROC curves. RESULTS: Of the 373 controls, significant rejection was detected in 19%. Analysis of the relationship between ACR and the markers showed significantly elevated levels of fgpro (345 +/- 90 versus 307 +/- 74 mg/dL; P = .03), fgfun (361 +/- 101 versus 318 +/- 89 mg/dL; P = .04), and SA (74 +/- 22 versus 66 +/- 15 mg/dL; P = .02), but not CRP (19 +/- 29 versus 10 +/- 21 mg/dL; P = .07). SA displayed a better diagnostic utility (area under the curve 0.7; P < .01), 35% sensitivity, 85% specificity, and 82% negative predictive value for a cutoff point of 80 mg/dL. CONCLUSIONS: Among the inflammatory markers increased in ACR, SA was the most useful noninvasive tool for screening.

Do cardiovascular risk factors influence cardiac allograft vasculopathy?

BACKGROUND: Cardiac allograft vasculopathy (CAV) is the leading cause of heart transplant failure after the first year. The etiological factors involved are currently a controversial matter. Intravascular ultrasound (IVUS) is considered the diagnostic procedure of choice. We assessed the relationship of cardiovascular risk factors with CAV. MATERIALS: We analyzed prospectively 22 patients. We conducted a first study with coronary angiography and IVUS at 36 +/- 3 days and a second at 598 +/- 49 days. We performed an average of 5.6 clinical revisions per patient, assessing the effect of the classic cardiovascular risk factors, the cause of heart failure, and the age of the patient and donor. The statistics used were chi(2), Fisher exact test, and Student t test. RESULTS: CAV was found in 10 subjects (45.5%). Univariate analysis showed statistically significant differences in the assessment of the presence of diabetes and dyslipidemia posttransplantation, but not pretransplantation. Among the patients with CAV there was a higher percentage of diabetics (32.8% vs 12%, P < .01). The patients with CAV also had higher levels of total cholesterol (211 +/- 40 mg/dL vs 195 +/- 35 mg/dL, P = .02), triglycerides (172 +/- 108 mg/dL vs 136 +/- 66 mg/dL, P = .03), low-density lipoprotein (133 +/- 35 mg/dL vs 117 +/- 30 mg/dL, P = .01), and lower high-density lipoprotein levels (46 +/- 15 mg/dL vs 52 +/- 12 mg/dL, P = .03). CONCLUSIONS: Only the diabetes and dyslipidemia present in the posttransplantation period were associated with CAV, which highlights the fact that it is a condition that both shares and has different features with atherosclerosis and probably requires a different diagnostic-therapeutic approach.