A comparison of quality of life and psychological distress in heart transplantation patients at adult and pediatric ages.

BACKGROUND: The aim of the current study was to evaluate and compare the quality of life (QOL) and psychological status of adult patients who underwent heart transplant (HTx) at pediatric or adult ages. METHODS: The population consisted of two groups: patients who received HTx after 18 years old and pediatrics who received HTx between the age of 1 and 18 years. At the time of the study, all patients were over 18 years old. QOL data were collected from patients using 36-item Short-Form Health Survey (SF-36) and psychological distress by the Symptom checklist 90-revised questionnaire (SCL-90-R). RESULTS: A total of 232 HTx patients were evaluated; 217 were transplanted at an adult age and 15 at a pediatric one. QOL improved significantly in pediatrics patients in the general health perceptions subscale and physical pain subscale than adult patients. The Global Index of the psychological distress did not differ in the two groups, but the pediatric patients registered statistically significant higher scores on the interpersonal sensitivity symptom subscale (adult group 36 ± 0.42 vs pediatric group 81 ± 0.79), the hostility subscale (adult group m 39 ± 0.44 vs pediatric group 73 ± 0.76) and the paranoid ideation subscale (adult group 46 ± 0.46 vs pediatric group 96 ± 1.02). CONCLUSION: The pediatric heart recipients showed better quality of life, but they show marked sensitivity, hostility and paranoid ideation which increases the risk of mental distress and therefore their adherence to medical treatment.

Interventricular conduction disorders after orthotopic heart transplantation: risk factors and clinical relevance.

BACKGROUND: Causes and significance of interventricular conduction disorders (IVCDs) after orthotopic heart transplantation (OHT) are still unknown. METHODS: We retrospectively researched the presence of IVCDs in 240 patients who underwent bicaval OHT in three time periods: at day 1, after 1 year, and after 3 years from OHT. To evaluate the impact of the surgical technique, a control population treated with biatrial anastomosis was used. RESULTS: The most common IVCD was right bundle branch block (RBBB). Its presence at day 1 correlated with transpulmonary gradient before OHT. Its presence after 1 year and its development correlated with a 1-month acute rejection score≥2 (p = .050 and p = .006). The incidence of RBBB was higher in the biatrial control population (40.7% vs 23.8%, p < .001). CONCLUSIONS: RBBB is the most common IVCD. Its presence can be explained by a susceptibility of the right branch to heart positioning, pressure overload, and acute rejection. IVCDs do not affect prognosis.

A Comprehensive Excursus of the Roles of Echocardiography in Heart Transplantation Follow-Up.

Current guidelines for the care of heart transplantation recipients recommend routine endomyocardial biopsy and invasive coronary angiography as the cornerstones in the surveillance for acute rejection (AR) and coronary allograft vasculopathy (CAV). Non-invasive tools, including coronary computed tomography angiography and cardiac magnetic resonance, have been introduced into guidelines without roles of their own as gold standards. These techniques also carry the risk of contrast-related kidney injury. There is a need to explore non-invasive approaches providing valuable information while minimizing risks and allowing their application independently of patient comorbidities. Echocardiographic examination can be performed at bedside, serially repeated, and does not carry the burden of contrast-related kidney injury and procedure-related risk. It provides comprehensive assessment of cardiac morphology and function. Advanced echocardiography techniques, including Doppler tissue imaging and strain imaging, may be sensitive tools for the detection of minor myocardial dysfunction, thus providing insight into early detection of AR and CAV. Stress echocardiography may offer a valuable tool in the detection of CAV, while the assessment of coronary flow reserve can unravel coronary microvascular impairment and add prognostic value to conventional stress echocardiography. The review highlights the role of Doppler echocardiography in heart transplantation follow-up, weighting advantages and limitations of the different techniques.

Human cytomegalovirus and Epstein-Barr virus infections occurring early after transplantation are risk factors for antibody-mediated rejection in heart transplant recipients.

Background: Antibody-mediated rejection (AMR) is a serious complication affecting the survival of patients receiving transplantation. Human cytomegalovirus (CMV) and Epstein-Barr virus (EBV) are common viral infections that occur after transplantation, frequently emerging as viral reactivation in donor grafts or transplant recipients. The present study aimed to investigate the association between CMV and EBV infections and early-onset AMR. Materials and methods: This study was conducted at the Heart Transplantation Center of Padova General Hospital and included a cohort of 47 heart transplant recipients (HTxs), including 24 HTxs diagnosed with AMR and 23 control HTxs with no episodes of AMR. Only early cases of CMV and/or EBV infections (1-90 days after transplantation) were considered. Fisher's exact test and logistic regression analysis were used to statistically analyze the correlation and association between AMR and CMV or EBV infection. Results: We observed a positive statistical association between CMV and EBV infections (two-sided Fisher's exact test, p = 0.0136) and between EBV infection and AMR (two-sided Fisher's exact test, p = 0.0034). Logistic regression analysis revealed a direct statistical association between CMV and EBV infections and AMR risk (p = 0.037 and 0.006 and odds ratio = 1.72 and 2.19, respectively). AMR occurrence was associated with increased viral loads of both CMV and EBV early after transplantation. Discussion: These findings suggest the role of CMV and EBV infections as relevant risk factors for AMR in HTxs for the first time.

Coronary Collateral Circulation: A New Predictor of Mortality in Heart Transplant Recipients With Allograft Vasculopathy.

Coronary collateral arteries (CCAs) are anastomotic channels between vessels; although beneficial in atherosclerosis, their role in heart transplantation (HT) recipients is underinvestigated. CCAs initially develop as microcirculation and cardiac allograft vasculopathy (CAV), promoting immune-dependent proliferative angiogenic response, and play a role in their development. In our hypothesis, ischemia induced by coronary microvascular dysfunction (CMD) triggers the development of CCAs, which are, in turn, less functional as affected by CAV themselves. Methods: One hundred twenty-one patients receiving HT at our institution were retrospectively evaluated and were included if transthoracic echocardiography with coronary flow velocity reserve (CFVR) assessment and coronary angiography were performed. CMD was defined as CFVR of ≤2.5. Patients with CAV were enrolled, and their angiograms were reviewed to evaluate the presence of CCAs. Cardiovascular mortality was assessed as the main clinical outcome. Results: Forty patients were found to have CCAs. Patients with CCAs have lower CFVR than those without CCAs (2.22 ± 0.72 versus 2.69 ± 0.92;P = 0.003), reflecting in different rates of CMD in the 2 groups (72.5% versus 37%; P < 0.001). CMD is associated with higher CAV grades (P < 0.001), which are also associated with CCAs (P < 0.001). Patients with poorly developed CCAs have lower CFVR (P < 0.001). At multivariable analysis, CMD (P = 0.008) and higher CAV grades (P = 0.005) are independent predictors of CCAs. During the median follow-up time of 10.2 (6.6-13.3) y, patients with CCAs have been found to have higher mortality than those without CCAs (57.5% versus 32.1%; P = 0.007). CCAs are associated with a lower probability of survival also in patients with CMD (P < 0.001) and are independent predictors of mortality (P < 0.001). Conclusions: Our results demonstrate an interplay between CAV, CMD, and CCAs. We confirm that CAV is associated with CMD, and we show, for the first time, that CMD is associated with CCAs. CCAs are pathophysiologically associated with more severe graft vasculopathy and independently predict mortality after HT.

Human cytomegalovirus-specific T-cell immune reconstitution in preemptively treated heart transplant recipients identifies subjects at critical risk for infection.

Human cytomegalovirus (CMV) infection represents a major threat for heart transplant recipients (HTXs). CMV-specific T cells effectively control virus infection, and thus, assessment of antiviral immune recovery may have clinical utility in identifying HTXs at risk of infection. In this study, 10 CMV-seropositive (R(+)) pretransplant patients and 48 preemptively treated R(+) HTXs were examined before and after 100 days posttransplant. Preemptive treatment is supposed to favor the immune recovery. CMV DNAemia and gamma interferon enzyme-linked immunosorbent spot (ELISPOT) assay were employed to assess the viremia and immune reconstitution. HTXs could be categorized into three groups characterized by high (>100), medium (50 to 100), and low (<50) spot levels. Early-identified high responders efficiently controlled the infection and also maintained high immunity levels after 100 days after transplant. No episodes of grade ≥2R rejection occurred in the high responders. Midresponders were identified as a group with heterogeneous trends of immune reconstitution. Low responders were 41% and 21% of HTXs before and after 100 days posttransplant, respectively. Low responders were associated with a higher incidence of infection. The effect of viremia on immune recovery was investigated: a statistically significant inverse correlation between magnitude of viremia and immune recovery emerged; in particular, each 10-fold increase in viremia (>4 log(10) DNAemia/ml) was associated with a 36% decrease of the ELISPOT assay spot levels. All episodes of high viremia (>4 log(10) DNAemia/ml) occurred from 1 to 60 days after transplant. Thus, the concomitant evaluation of viremia and CMV immune reconstitution has clinical utility in identifying HTXs at risk of infection and may represent a helpful guide in making therapeutic choices.

Coronary Flow Evaluation in Heart Transplant Patients Compared to Healthy Controls Documents the Superiority of Coronary Flow Velocity Reserve Companion as Diagnostic and Prognostic Tool.

Background: Distinct contributions by functional or structural alterations of coronary microcirculation in heart transplantation (HT) and their prognostic role have not been fully elucidated. We aimed to identify the mechanisms of coronary microvascular dysfunction (CMD) in HT and their prognostic implications. Methods: 134 patients, surviving at least 5 years after HT, without evidence of angiographic vasculopathy or symptoms/signs of rejection were included. 50 healthy volunteers served as controls. All underwent the assessment of rest and hyperemic coronary diastolic peak flow velocity (DPVr and DPVh) and coronary flow velocity reserve (CFVR) and its inherent companion that is based on the adjusted quadratic mean: CCFVR = √{(DPVr)2 + (DPVh)2}. Additionally, basal and hyperemic coronary microvascular resistance (BMR and HMR) were estimated. Results: Based on CFVR and DPVh, HT patients can be assigned to four endotypes: endotype 1, discordant with preserved CFVR (3.1 ± 0.4); endotype 2, concordant with preserved CFVR (3.4 ± 0.5); endotype 3, concordant with impaired CFVR (1.8 ± 0.3) and endotype 4, discordant with impaired CFVR (2.0 ± 0.2). Intriguingly, endotype 1 showed lower DPVr (p < 0.0001) and lower DPVh (p < 0.0001) than controls with lower CFVR (p < 0.0001) and lower CCFVR (p < 0.0001) than controls. Moreover, both BMR and HMR were higher in endotype 1 than in controls (p = 0.001 and p < 0.0001, respectively), suggesting structural microvascular remodeling. Conversely, endotype 2 was comparable to controls. A 13/32 (41%) patients in endotype 1 died in a follow up of 28 years and mortality rate was comparable to endotype 3 (14/31, 45%). However, CCFVR was < 80 cm/s in all 13 deaths of endotype 1 (characterized by preserved CFVR). At multivariable analysis, CMD, DPVh < 75 cm/s and CCFVR < 80 cm/s were independent predictors of mortality. The inclusion of CCFVR < 80 cm/s to models with clinical indicators of mortality better predicted survival, compared to only adding CMD or DPVh < 75 cm/s (p < 0.0001 and p = 0.03, respectively). Conclusion: A normal CFVR could hide detection of microvasculopathy with high flow resistance and low flow velocities at rest. This microvasculopathy seems to be secondary to factors unrelated to HT (less rejections and more often diabetes). The combined use of CFVR and CCFVR provides more complete clinical and prognostic information on coronary microvasculopathy in HT.

Impact of Continuous Flow Left Ventricular Assist Device on Heart Transplant Candidates: A Multi-State Survival Analysis.

(1) Objectives: The aim of this study was to investigate the impact of the prolonged use of continuous-flow left ventricular assist devices (LVADs) on heart transplant (HTx) candidates. (2) Methods: Between January 2012 and December 2019, we included all consecutive patients diagnosed with end-stage heart failure considered for HTx at our institution, who were also eligible for LVAD therapy as a bridge to transplant (BTT). Patients were divided into two groups: those who received an LVAD as BTT (LVAD group) and those who were listed without durable support (No-LVAD group). (3) Results: A total of 250 patients were analyzed. Of these, 70 patients (28%) were directly implanted with an LVAD as BTT, 11 (4.4%) received delayed LVAD implantation, and 169 (67%) were never assisted with an implantable device. The mean follow-up time was 36 ± 29 months. In the multivariate analysis of survival before HTx, LVAD implantation showed a protective effect: LVAD vs. No-LVAD HR 0.01 (p < 0.01) and LVAD vs. LVAD delayed HR 0.13 (p = 0.02). Mortality and adverse events after HTx were similar between LVAD and No-LVAD (p = 0.65 and p = 0.39, respectively). The multi-state survival analysis showed a significantly higher probability of death for No-LVAD vs. LVAD patients with (p = 0.03) or without (p = 0.04) HTx. (4) Conclusions: The use of LVAD as a bridge to transplant was associated with an overall survival benefit, compared to patients listed without LVAD support.

Peripheral adaptation mechanisms in physical training and cardiac rehabilitation: the case of a patient supported by a CardioWest total artificial heart.

BACKGROUND: The benefits of exercise training in patients with chronic heart failure (CHF) are due to a combination of cardiac and peripheral adaptations. Separating these 2 components is normally impossible, except for patients implanted with total artificial heart (TAH), where cardiac adaptation cannot occur. METHODS AND RESULTS: We report the case of a patient implanted with a CardioWest-TAH who underwent a comprehensive strength and endurance training program and was evaluated by repeated peak cardiopulmonary exercise tests. The patient experienced a 24% increase of peak oxygen consumption and an improvement in recovery kinetics during the training period of 29 months. CONCLUSION: This unique situation of a patient with a TAH, and therefore a fixed peak cardiac output, allows us to isolate training-induced changes in the periphery, that suggest greater oxygen extraction and more efficient metabolic gas kinetics during the exercise and recovery phases.

Can Patients Be Transplanted or Undergo Ventricular Assist Device Placement During the COVID-19 Pandemic? Padova Perspective.

The SARS-CoV-2 pandemic is nowadays an international emergency and the North-Italian regions have faced a high rate of infection and case fatality. A logistic and structural rearrangement has been required to ensure COVID-19-free areas, to save human and economic resources, and to solve all incoming urgencies. Herein, we report the Padova experience in heart transplantation and mechanical circulatory support implantation for severe INTERMACS class patients with satisfactory results during COVID-19 pandemic.

Effect of neridronate in osteopenic patients after heart, liver or lung transplant: a multicenter, randomized, double-blind, placebo-controlled study.

BACKGROUND: Transplantation (Tx) is an effective therapeutic option in patients with end-stage organ failure and osteoporosis and related fractures are a recognized complication in these patients. Aim of this study was to evaluate the efficacy of neridronate in patients with reduced bone mass after Tx of the heart, liver or lung. METHODS: In this multicenter randomized double-blind controlled trial (RCT), 22 patients were treated with neridronate (25 mg i.m./month) and 17 received placebo. All patients received daily oral calcium (500 mg) and vitamin D (400 IU). Dual-energy X-ray absorptiometry (DXA) was evaluated at 0, 6 and 12 months and markers of bone turnover at 0, 3, 6, 9 and 12 months. RESULTS: Thirty-nine patients (11 heart Tx, 21 liver Tx, 7 lung Tx), aged 49.3±9.1 years, with a T-score <-2.0 SD at lumbar spine or femoral level were included. In neridronate-treated patients, a significant increase in lumbar bone mineral density (BMD) was observed after 12 months vs. placebo control (0.92±0.13 g/cm2 vs. 0.84±0.08 g/cm2; P=0.005). Femur and hip BMD remained unchanged between groups. Total alkaline phosphatase, bone alkaline phosphatase and beta-cross-laps significantly decreased over the 12 months in neridronate-treated patients vs. placebo, respectively (107.4±74 U/L vs. 157.6±107.1 U/L, P=0.002; 5.7±3.3 µg/L vs. 11.7±4.3 µg/L, P<0.001 and 0.25±0.13 ng/mL vs. 0.73±0.57 ng/mL, P<0.001). No difference was observed between neridronate and placebo groups regarding safety profile. CONCLUSIONS: This is the first RCT that demonstrates the efficacy of neridronate in increasing bone density and reducing bone turnover in organ Tx recipients with significant skeletal morbidity.

Atrial fibrillation after orthotopic heart transplantatation: Pathophysiology and clinical impact.

BACKGROUND: Atrial fibrillation (AF) is a well-established post-cardiac surgery complication. Orthotopic heart transplantation (OHT) represents a peculiar condition where surgical thoracic veins isolation and autonomic denervation occur. This study aims at investigating AF incidence in OHT in order to define its risk factors and to evaluate its prognostic impact. METHODS: 278 patients affected by OHT were recruited in our Cardiac Surgery Unit and retrospectively analyzed, using clinical, surgical and instrumental data. RESULTS: The patients cohort showed 45 post-operative (16.5%) and 20 late AF cases (7.2%). Only paroxysmal AF episodes were observed. Elderly donors and acute rejection resulted as risk factors in patients with post-operative AF episodes, who presented higher all-cause mortality at 11 years post-OHT (p < 0.001, Kaplan Meier analysis). The majority of late AF episodes occurred during hospitalization, due to renal failure or infections and more frequently in male patients; no significant correlation was observed with acute or chronic rejection or other characteristics. CONCLUSION: Pulmonary vein isolation and vagal denervation lead to low AF incidence in OHT recipients. Acute rejection and graft status are the main risk factors for post-operative AF episodes, while other systemic conditions act as late AF triggers. The occurrence of AF episodes is associated with poor outcome and AF should be considered as a marker of clinical frailty.

Results of new-generation intrapericardial continuous flow left ventricular assist devices as a bridge-to-transplant.

AIMS: We analysed the outcomes with the use of a new-generation continuous-flow left ventricular assist device (CF-LVAD) as a bridge-to-transplant (BTT). MATERIALS AND METHODS: We included all patients implanted with an intrapericardial CF-LVAD as BTT, between January 2012 and December 2016. Primary outcomes were overall survival, survival on waiting list and postheart transplant (HTx) survival. The outcomes after HTx were compared with those of a contemporary cohort of patients transplanted without previous CF-LVAD (No-LVAD group, n = 73). RESULTS: We included 53 patients with a median age of 52 years (interquartile range: 43-59 years). Seventy-two percent were in INTERMACS profile 1-2 before implant; all entered the HTx waiting list after receiving the CF-LVAD. HTx was performed in 42 (79%) cases (LVAD group). Overall estimated survival (considering both pre-HTx and post-HTx) was 89% [95% confidence interval (CI) 81-98%] at 1 year and 80% (CI 70-92%) at 2 years. The estimated survival on waiting list was 91% (CI 80-100%) at 6 months, whereas the 1-year estimated post-HTx survival was 88% (CI 79-98%). The Kaplan-Meier curves of survival after HTx of LVAD versus No-LVAD group were comparable (log-rank P = 0.54), as well as the rates of post-HTx adverse events. A multivariable model of survival after HTx, accounting for the most relevant patient characteristics, identified LVAD use as a significant protective factor [LVAD versus No-LVAD hazard ratio 0.22 (CI 0.06-0.91)]. CONCLUSION: The use of new-generation intrapericardial CF-LVADs as a BTT resulted, in our series, in satisfactory pre-HTx and post-HTx outcomes.

Coronary flow velocity pattern and coronary flow reserve by contrast-enhanced transthoracic echocardiography predict long-term outcome in heart transplantation.

BACKGROUND: We assessed coronary flow velocity pattern and coronary flow reserve (CFR) by contrast-enhanced transthoracic echocardiography (CE-TTE) as markers of major adverse cardiac events (MACE) related to cardiac allograft vasculopathy (CAV) after heart transplantation (HT). METHODS AND RESULTS: Deceleration time of diastolic flow velocity (DDT) and CFR were measured in the left anterior descending coronary artery (LAD) by CE-TTE in 66 consecutive HT patients (follow-up 19+/-5 months). CFR was calculated as the ratio of hyperemic to basal diastolic flow velocity. Angiographies were analyzed by a qualitative grading system; CAV was defined as changes grade II or higher. MACE were cardiac death, stent implantation, and heart failure. Patients with MACE had higher CAV incidence (P=0.004) and grade (P=0.008), shorter DDT (P=0.006), and lower CFR (P=0.008). A receiver-operating characteristic-derived DDT cutpoint < or = 840 ms (area under the curve 0.793; P=0.01) was 75% specific and 86% sensitive for predicting MACE, with positive predictive value (PPV) and negative predictive value (NPV) of 33% and 97%, respectively (P=0.002). A CFR cutpoint of < or =2.6 (area under the curve 0.746; P=0.01) was 62% specific and 91% sensitive for predicting MACE (PPV =32%, NPV =97%) (P=0.001). Patients with CFR < or = 2.6 and patients with DDT < or = 840 ms had a lower survival free from MACE (P=0.006 and P=0.009, respectively). By Cox regression, only a lower CFR predicted the risk of MACE (relative risk 3.1; 95% CI, 1.26 to 7.9; P=0.01). CONCLUSIONS: In HT patients, shorter DDT and lower CFR by CE-TTE are reliable markers for CAV-related MACE. CFR is the main independent predictor of MACE.

Outcome after pediatric heart transplantation: two decades of a single center experience.

BACKGROUND: Twenty years after the first successful pediatric heart transplantation (HTx), the long-term outcome of this population is still unknown. Current study analyzes our results in pediatric HTx population. METHODS AND RESULTS: Between 1985 and 2005, we performed 604 HTx. Forty-three patients (7%) were less than 18-years old and six patients were less than 1-year old. Mean age at HTx was 9.7+/-6.3 years (38 days-18 years). Indications were: cardiomyopathy in 33 patients (76%), congenital in 9 (21%), tumor in 1 (3%). Chronic immunosuppression was Cyclosporine A and Azathioprine-based. Overall survival at Kaplan-Meier analysis (CI 95%) was 82.5% at 1-year post-HTx, 73.5% at 5 years, 72.2% at 10 years, 62.1% at 15 years, and 49.3% at 20 years, respectively. We had 14 deaths (32%): 7 within the first year after HTx (early mortality, EM), 7 occurred later (late mortality, LM). Causes of EM were: graft failure (43%), acute rejection (43%) and post transplant lymphoproliferative disease (14%). Causes of LM were: neoplasms (57%), infection (28%), graft vasculopathy (15%). At late follow-up, cardiac function, somatic and psycoaffective development were normal. Fifteen patients (34%) developed neoplasms, nine patients (21%) hypertension, and three patients (8%) developed kidney dysfunction. Neoplasms were found to be an independent predictor of outcome (p=0.039) (OR=7). CONCLUSIONS: Overall survival in the pediatric population is better than adults' population (62.1 vs 48% at 15 years after HTx). Neoplasms were the main comorbidities and causes of LM: at multivariate analysis, their incidence was related with hematic Cyclosporine A levels after 10 years from HTx (p=0.01).

Endomyocardial biopsy under echocardiographic monitoring.

Endomyocardial biopsy is a common procedure for monitoring cardiac allograft rejection; several techniques have been described so far, throughout different access sites and under echocardiographic or X-ray control. We describe the routine technique adopted at our centre based on echo-guided puncture of jugular vein and echocardiographic assessment of endomyocardial sampling with direct visualization of the bioptome tip. We also report the most common complications of the procedure, especially concerning the risk of iatrogenic tricuspid regurgitation, and same examples of histopathological findings drawn from our own iconographic collection.

Orthotopic heart transplantation: the bicaval technique.

Heart transplantation still remains the gold standard therapy for end-stage heart failure, although several other approaches have emerged, such as biventricular pacing, left ventricular assist devices (LVADs) and total artificial heart. Moreover, the increasing use of LVADs as a bridge to transplant is posing the technical challenge of LVAD removal during the procedure. We in this paper describe the bicaval technique, which currently represents the routine approach for orthotopic heart transplantation.

Intravascular macrophages in cardiac allograft biopsies for diagnosis of early and late antibody-mediated rejection.

BACKGROUND: The aim of our study was to evaluate the role of intravascular macrophages in the diagnosis of early and late antibody-mediated rejection (AMR) on endomyocardial biopsies (EMBs). METHODS: We reviewed 1,420 consecutive EMBs from 131 patients and selected 75 C4d+ EMBs. The C4d+ group was compared with a control group (66 patients) matched for age, gender, date of transplantation, follow-up, immunosuppressive regimen and primary heart disease. A total of 141 EMBs were evaluated. Immunoperoxidase staining for C4d and CD68 were performed. Post-transplant IgG anti-HLA reactivity was investigated by Luminex technology. Clinical data were also collected. Fourteen EMBs were available from 11 symptomatic AMR patients. RESULTS: Of the 141 EMBs evaluated, 53 were positive for intravascular macrophages (CD68); among them, 32 were also positive for C4d (32 of 53, 60.4%). Of the 88 CD68- EMBs, 43 were also C4d+ (43 of 88, 48.9%). Of the 53 CD68+ EMBs, 30 EMBs were within the first year since transplantation (30 of 53, 57.8%), and among these 21 were also positive for C4d (21 of 30, 70.0%). In the late period, among the 23 CD68+ EMBs (23 of 53, 42.2%) 11 were also positive for C4d (11 of 23, 47.8%). In the early period, intravascular macrophages were more common in symptomatic (3 of 3, 100%) than asymptomatic (3 of 11, 27.3%) patients. Sensitivity and specificity of intravascular macrophages in predicting donor-specific antibodies (DSA) within the first year were 50.0% and 100.0%, respectively. CONCLUSIONS: Intravascular macrophages predict C4d, DSA and symptoms early after transplantation; however, in the late period, they are unable to identify patients with circulating DSA, C4d and/or symptoms.

Impaired endothelial progenitor cell recruitment may contribute to heart transplant microvasculopathy.

BACKGROUND: Circulating progenitor cells (PCs) may play a role in the pathogenesis of cardiac allograft vasculopathy, the leading cause of morbidity and mortality in heart transplantation (HTx). We assessed the relationship between circulating PCs and their incorporation into allografts and coronary microvascular function in HTx. METHODS: PCs were quantified by flow cytometry on the basis of the surface expression of CD34, CD133, and kinase domain receptor (KDR) antigens. Biopsy specimens at 2 different times were examined. Immunohistochemistry for the stem cell marker c-Kit, endothelial PC (EPC) marker KDR, and CD34 was performed in serial sections in all specimens. Cells positive for each marker were counted in all specimen area sections, and the number obtained was corrected by area section. Coronary flow in the left anterior descending coronary artery was detected at rest and during intravenous adenosine by transthoracic echocardiography. Coronary flow reserve (CFR) was the ratio of hyperemic diastolic mean velocity (DMV)/resting DMV. RESULTS: CFR was measured in 29 patients and was abnormal (CFR < 2) in 6 (Group A) and normal in 23 (Group B). CFR was lower in Group A (1.5 ± 0.1 vs 3.3 ± 0.8, p < 0.0001). CD34(+)KDR(+), CD133(+)KDR(+), and CD34(+)CD133(+)KDR(+) cell counts were lower in Group A (p < 0.05). EPCs in biopsy sections tended to be lower in Group A (p = 0.06) and correlated to circulating CD133(+)KDR(+) and CD34(+)CD133(+)KDR(+) (p = 0.003 and p = 0.052, respectively). CONCLUSIONS: EPCs are decreased in the circulation and in the allograft in patients with microvasculopathy. Defective mobilization and engraftment of EPCs may be involved in the pathogenesis of cardiac allograft vasculopathy.