Evaluation of the Graft Mechanical Function Using Speckle-Tracking Echocardiography During the First Year After Orthotropic Heart Transplantation.

BACKGROUND Recent advances in ultrasound strain imaging facilitate more precise monitoring of subtle myocardial changes and thus may allow for more appropriate assessment of myocardium after orthotopic heart transplantation (OHT). This study aimed to explore longitudinal left ventricular (LV) and right ventricular (RV) function by speckle-tracking echocardiography (STE) during a 12-month follow-up period in relation to acute cellular rejection (ACR) degree ≥2R and the response to intense immunosuppressive therapy with intravenous steroids. MATERIAL AND METHODS Forty-five adult heart transplant recipients were prospectively assessed at a single center from January 2016 until June 2017. Echocardiography was performed serially at baseline and together with routine biopsies at 2 weeks and 1, 2, 3, 6, 9, and 12 months after OHT. Changes in graft function were evaluated using STE before and during ACR and in the resolving period of ACR. RESULTS A total of 220 pairs of biopsy specimens and strain recordings were analyzed. Moderate ACR was seen in 30 biopsies (13.6%). In the serial assessment, longitudinal strain parameters of the LV (global and 4-, 2-, 3-chamber longitudinal strain) and RV (global and free wall longitudinal strain) were decreased at baseline and improved significantly (P<0.001) within 12 months after OHT. The degree of improvement was not influenced by ACR. There were no significant differences in circumferential, radial, or longitudinal strain rate, or mechanical dyssynchrony. Reduced LV and RV longitudinal strain was related to ACR degree 2R and increased significantly (P<0.0005) during 3 days of intravenous methylprednisolone therapy. CONCLUSIONS Using the STE technique, we have documented an acute improvement in mechanical myocardial function following ACR steroid therapy and a progressive recovery of LV and RV longitudinal function during the first year after OHT.

Persistent mild lesions in coronary angiography predict poor long-term survival of heart transplant recipients.

BACKGROUND: Even though coronary angiography (CAG) underestimates coronary allograft vasculopathy (CAV) development, especially in the distal parts of arteries, it remains a frame of reference for International Society for Heart and Lung Transplantation (ISHLT) CAV classification. A retrospective analysis was performed to assess the prognostic value of CAG findings. METHODS: Among 310 orthotopic heart transplantation (OHT) recipients with at least 2 CAGs at 2-year intervals, we identified 197 (146 men and 41 women; 55 ± 13 years) without lesions (Group 0), 27 (15 men and 12 women; 58 ± 8 years) in whom mild changes remained in consecutive CAGs (Group 1), 28 (24 men and 4 women; 58 ± 10 years) in whom mild lesions decreased in consecutive CAGs (Group 1REG), and 58 (53 men and 5 women; 56 ± 10 years) in whom the stenosis criteria of ISHLT CAV 2 or 3 were covered (Group 2). We compared survival and other clinical variables among the groups. RESULTS: The average follow-up was 10 ± 4 years. Forty-one (21%) deaths occurred in Group 0, 15 (56%) in Group 1 (p = 0.002), 9(31%) in Group 1REG (p = NS), and 26 (46%) in Group 2 (p = 0.004, chi-square test). Time free from all-cause death was significantly shorter in Group 1 (T1/2 = 8 years) than in Group 0 (T1/2 = 15.5 years; p = 0.00072, log-rank test). Time free from cardiovascular death was significantly shorter in Groups 1 and 2, as was time free from CAV-related death in Groups 1, 1REG, and 2. Multivariate analysis, using a Cox proportional hazards model, revealed that Group 1 inclusion criterion of CAG findings is an independent predictor of all-cause death, cardiovascular death, and CAV-related death. CONCLUSIONS: Persistent mild coronary lesions, observed in consecutive CAG, predicted shorter survival of OHT recipients.

Advanced glycation end products and lipofuscin deposits share the same location in cardiocytes of the failing heart.

BACKGROUND: Disturbed glucose metabolism, particularly in diabetes type 2 (DM2), may result in advanced glycation end product (AGE) formation. One of the possible targets for this reaction is lipofuscin (LF), an intracytoplasmic garbage presumed to be a marker of physiologic and preterm aging of cells. The study was performed to seek for a relationship between AGE and LF in cardiocytes of the failing hearts. MATERIAL AND METHODS: Archived tissue samples from 136 hearts explanted before transplantation (in 14 pts. with ischemic cardiomyopathy (CM) and DM2; 8 pts. with dilated CM and DM2; 67 non-diabetic pts. with ischemic CM; 47 non-diabetic pts. with dilated CM), 14 autopsy cases with DM2, and 20 heart donors (control group) were involved in the study. Immunohistochemical localization of AGE was applied. The coexistence of lipofuscin and AGE was studied by LF autofluorescence in AGE-positive slides. RESULTS: LF granules inside AGE deposits were present in all studied groups with varying frequencies, but the differences were non-significant. LF granules joined significantly with dispersed patterns of AGE i.e. diffuse and mixed, whereas coincidence of LF and AGE forming granular pattern was rare. CONCLUSIONS: We demonstrate that LF may belong to the components of the AGE deposits. The frequency of this phenomenon is dependent on the AGE dispersion grade, but neither on diabetes nor cardiomyopathy presence.

Concordance among pathologists in the second Cardiac Allograft Rejection Gene Expression Observational Study (CARGO II).

BACKGROUND: There has been no large evaluation of the ISHLT 2004 acute cellular rejection grading scheme for heart graft endomyocardial biopsy specimens (EMBs). METHODS: We evaluated agreement within the CARGO II pathology panel and between the panel (acting by majority) and the collaborating centers (treated as a single entity), regarding the ISHLT grades of 937 EMBs (with all grades ≥2R merged because of small numbers). RESULTS: Overall all-grade agreement was almost 71% both within the panel and between the panel and the collaborating centers but, in both cases, was largely because of agreement on grade 0: for the average pair of pathologists, fewer than a third of the EMBs assigned grade ≥2R by at least one were assigned this grade by both. CONCLUSION: The 2004 revision has done little to improve agreement on the higher ISHLT grades. An EMB grade ≥2R is not by itself sufficient as a basis for clinical decisions or as a research criterion. Steps should be taken toward greater uniformity in EMB grading, and efforts should be made to replace the ISHLT classification with diagnostic criteria--EMB based or otherwise--that correspond better with the pathophysiology of the transplanted heart.

Vascular abnormalities and cardiomyocyte lipofuscin deposits in endomyocardial biopsy specimens of heart transplant recipients: are they related to the development of cardiac allograft vasculopathy?

OBJECTIVE: The aim of this study was to assess the predictive value of microvascular abnormalities and lipofuscin observed in endomyocardial biopsy samples for the development of cardiac allograft vasculopathy. METHODS: The study group consisted of 68 cardiac allograft recipients (63 men and 5 women, 43 +/- 12 years old). We performed a re-evaluation of 1071 endomyocardial biopsy specimens to search for microvascular diseases and lipofuscin in cardiocytes. Endomyocardial biopsy specimens with an International Society for Heart and Lung Transplantation rejection grade of 2 or more and those without arterioles were excluded. Abnormalities found in the remaining 517 specimens were correlated with the grade of rejection. Biopsy specimens obtained 2 weeks, 12 months, and 36 months after transplantation were compared with coronary angiography results, clinical events of cardiac allograft vasculopathies, and survivals. Kaplan-Meier curves were constructed to compare the time to the development of cardiac allograft vasculopathy or death. RESULTS: Enlarged endothelial cells, lymphocytes inside the arteriolar wall, occluded arteriolar lumen, endothelial vacuolization, and hypertrophy of the vascular muscle were significantly correlated with rejection grade. Although none of the vascular abnormalities predicted cardiac allograft vasculopathy, patients with lipofuscin deposits at the 12-month biopsy specimens were characterized by the rapid development of angiography-confirmed cardiac allograft vasculopathy (P < .08) and events related to cardiac allograft vasculopathy (P < .03, log-rank test). CONCLUSION: Microvascular abnormalities correlate with mild cellular rejection, but they do not seem to be predictive for development of cardiac allograft vasculopathy detected by angiography. The presence of lipofuscin in 12-month endomyocardial biopsy specimens may be predictive of development of angiographically confirmed cardiac allograft vasculopathy.

Quilty effect correlates with biopsy-proven acute cellular rejection but does not predict transplanted heart coronary artery vasculopathy.

BACKGROUND: The appropriate therapy after orthotopic heart transplantation (OHT) is determined by the results of endomyocardial biopsies (EMBs). The Quilty effect (QE) is a recognized cause of discrepancies in EMB grading, but its clinical implications remain unclear. In this study we assess the correlation of the QE with biopsy-proven acute cellular rejection (AR) and coronary artery vasculopathy (CAV). METHODS: We reassessed 5,361 EMB samples, obtained from 429 patients, based on QE occurrence and its impact on EMB score. Next, we divided all patients with at least 1 year of follow-up into two groups: a QE(+) group (n = 202, 58.7% of sample, 172 males/30 females, 44.8 +/- 12 years of age) and a QE(-) group (n = 142, 41.3% of sample, 124 males/18 females, 45.4 +/- 12 years of age), and compared AR and CAV occurrences. RESULTS: The QE was observed in 669 EMBs (12.5%), and at least 1 EMB with QE was found among the 231 patients (53.8%). The initial QE occurrence took place during the first 3 months after OHT in 68% of QE(+) patients, and >1 year post-OHT in 13% of patients. The average EMB score was significantly higher in QE(+) biopsies. A comparison of the two groups revealed a significantly higher number of AR episodes and number of patients with at least one episode of AR in QE(+) patients. There was no significant difference in number of CAV occurrences between groups. CONCLUSIONS: The QE seems to be a marker of the same increased immune system activity that can lead to AR. A relationship between QE and CAV was not supported by the present results.

Surgical wound-healing complications in heart transplant recipients treated with rapamycin.

The aim of this retrospective analysis was to assess the influence of rapamycin (RAPA) used perioperatively on surgical complications in heart transplant recipients. The study group consisted of 28 heart transplant recipients (26M/2F, 49.2+/-11 years) receiving 15 mg of RAPA before operation, 10 mg of RAPA on the first postoperative day (POD) and 5 mg daily (n=20) thereafter, or 5 mg daily starting on POD 2 (n=8), until the introduction of cyclosporine-A. A matched historical control group was composed of 28 patients (26M/2F, 49.7+/-9 years) receiving cyclosporine-A from POD 1. We compared a number of surgical complications and reinterventions among groups. Statistical significance was assessed using the chi-square test and the Mann-Whitney U-test. There were 16 (57%) patients in the study group vs. six (21%) in the control group requiring reintervention (p=0.014). Pericardial tamponade decompression was performed in seven (25%) vs. zero patients, and sternum refixation in seven (25%) vs. zero patients (p=0.015). None of the wounds was infected. The overall drainage volume was 4,213+/-5,996 vs. 1,911+/-1,728 mL (p=NS). The frequencies of biopsy-proven rejection and infection were comparable, except lower cytomegalovirus infection rates in the study group: three (11%) vs. 11 (39%) for the control group (p=0.023). The use of RAPA in the perioperative period of heart transplantation increases the risk of surgical wound-healing complications.