Circulating delta‐like Notch ligand 1 is correlated with cardiac allograft vasculopathy and suppressed in heart transplant recipients on everolimus‐based immunosuppression

Cardiac allograft vasculopathy (CAV) causes heart failure after heart transplantation (HTx), but its pathogenesis is incompletely understood. Notch signaling, possibly modulated by everolimus (EVR), is essential for processes involved in CAV. We hypothesized that circulating Notch ligands would be dysregulated after HTx. We studied circulating delta‐like Notch ligand 1 (DLL1) and periostin (POSTN) and CAV in de novo HTx recipients (n = 70) randomized to standard or EVR‐based, calcineurin inhibitor‐free immunosuppression and in maintenance HTx recipients (n = 41). Compared to healthy controls, plasma DLL1 and POSTN were elevated in de novo (P < .01; P < .001) and maintenance HTx recipients (P < .001; P < .01). Use of EVR was associated with a treatment effect for DLL1. For de novo HTx recipients, a change in DLL1 correlated with a change in CAV at 1 (P = .021) and 3 years (P = .005). In vitro, activation of T cells increased DLL1 secretion, attenuated by EVR. In vitro data suggest that also endothelial cells and vascular smooth muscle cells (VSMCs) could contribute to circulating DLL1. Immunostaining of myocardial specimens showed colocalization of DLL1 with T cells, endothelial cells, and VSMCs. Our findings suggest a role of DLL1 in CAV progression, and that the beneficial effect of EVR on CAV could reflect a suppressive effect on DLL1. Trial registration numbers— SCHEDULE trial: ClinicalTrials.gov NCT01266148; NOCTET trial: ClinicalTrials.gov NCT00377962.     

Echocardiographic evaluation of left ventricular filling pressure in heart transplant recipients

Objectives. Diastolic dysfunction is a major cause of morbidity in heart transplant recipients. A reliable, non-invasive marker of left ventricular (LV) filling pressure would simplify follow-up in these patients. We aimed to test the validity of echocardiographic indices of LV filling pressure in a contemporary population of heart transplant recipients. Design. Eighty-three patients were examined by right-sided heart catheterisation and echocardiography one year after heart transplantation. We explored the association between echocardiographic parameters of LV filling pressure and invasively measured pulmonary capillary wedge pressure (PCWP). Results. Peak early mitral flow velocity divided by septal early mitral relaxation velocity (E/e’_septal) was the echocardiographic parameter that best correlated with PCWP (r = 0.47; p < 0.001). At a cut-off value of 22, E/e’_septal could identify patients with a PCWP above 12 mm Hg with a sensitivity of 56% and a specificity of 95%. Conclusions. The E/e’ index was moderately associated with LV filling pressure in heart transplant recipients. Echocardiographic parameters of diastolic function should be interpreted with caution when estimating left ventricular filling pressures in this population.     

Plasma N-terminal Proatrial Natriuretic Factor can Predict Normal Pulmonary Capillary Wedge Pressure in Cardiac Transplant Recipients

Background –Plasma N-terminal proatrial natriuretic factor (proANP) is closely related to atrial filling pressure, but this may be distorted in heart transplant recipients. Objective –The aim of this study was to examine the usefulness of proANP as a non-invasive marker of cardiac filling pressure in transplanted patients with normal to moderately elevated serum creatinine (s-creatinine). Methods –Blood was sampled at rest for analysis of proANP from 220 patients 1-13 (median 4) years after orthotopic heart transplantation undergoing routine diagnostic catheterization. Results –In multivariate analysis proANP was significantly positively related to s-creatinine, mean pulmonary capillary wedge pressure (PCWP) and time after transplantation and negatively related to haemoglobin and cardiac index. All the patients with proANP below 1140 pmol/l had normal PCWP (<13 mmHg). The area under the receiver-operating characteristic curve for proANP for the detection of PCWP &#83 13 mmHg was 0.81. The positive predictive value of proANP for detection of increased PCWP was very low. Conclusion –A low proANP had a 100% negative predictive value for increased atrial pressure but the low positive predictive value makes proANP unsuitable as an indicator of increased atrial pressures in heart transplanted patients.     

Hemodynamic Changes During Laparoscopic Gastroplasty in Morbidly Obese Patients

Background: In nonobese patients, peritoneal insufflation has consistently been shown to influence parameters of preload and afterload as well as cardiac output. Obese patients have an abnormal and particular cardiovascular status. The aim of this study was to investigate the hemodynamic changes induced by an increase of intra-abdominal pressure in morbidly obese patients (MOP). Methods: Standard general anesthetia was administered to 15 informed MOP (body mass index > 40 kg/m²) scheduled for laparoscopic gastroplasty. Hemodynamic parameters were measured by thermodilution through a pulmonary artery catheter and through invasive blood pressure monitoring. Results: CO₂ insufflation with an intra-abdominal pressure of 17 mmHg caused a significant increase of mean arterial pressure (MAP) (33%, P = 0.005), mean pulmonary arterial pressure (MPAP) (40%, P = 0.001), pulmonary capillary wedge pressure (PCWP) (41%, P = 0.001), and central venous pressure (CVP) (55%, P = 0.001). The increase in diastolic filling pressures could be due to an increase in the filling volume or to a decrease in diastolic compliance. Ventricular volumes were not measured but we speculate that the rise in CVP, PCWP and MPAP is due to an increase in intrathoracic pressure as judged by the increase of pulmonary airway pressure. Stroke volume fell slightly (11%, P = 0.008), because of a reduction in transmural pressure and a fall ineffective preload. Cardiac output rose slightly (16%, P = 0.005) because of an increase in heart rate (15%, P = 0.014) probably induced by sympathetic stimulation, which only became fully operative after 15 minutes. Conclusions: When compared to nonobese patients our obese patients tolerated the pneumoperitoneum surprisingly well, without experiencing fall in cardiac output. The hemodynamic consequences of peritoneal insufflation seem to be different in obese and nonobese patients.     

Mild chronic anemia following heart transplantation: a syndrome with prognostic relevance?

The clinical relevance of mild chronic anemia in patients after heart transplantation (HTX) has not yet been demonstrated. Forty-five outpatients who had undergone HTX 2–99 months prior to investigation and who had not received blood transfusions or erythropoietin (EPO) before data acquisition were observed over a period of 37 months. Anemia was found in 36 of the 45 patients and was normocytic, normochromic, and slightly anisocytotic (coefficient of variation = 16 ± 2, normal 11.5–14.5). Anemic patients showed elevated EPO levels, whereas in nonanemic patients EPO levels were normal. Survival after HTX differed significantly in anemic and nonanemic patients (P < 0.02), with 100 % survival in the nonanemic and 85 % in the anemic group. Chronic anemia in patients after HTX shows a typical pattern. Even when mild, anemia in patients after HTX seems to be of prognostic value and thus might be an indicator of chronic disorders. Received: 9 March 1998 Received after revision: 20 May 1998 Accepted: 26 June 1998     

Primary preventive cardioverter‐defibrillator implantation (Pro‐ICD) in patients awaiting heart transplantation. A prospective,randomized, controlled 12‐year follow‐up study

The aim of this study was to evaluate whether short‐term primary preventive cardioverter‐defibrillator (ICD) implantation as bridge to heart transplantation (HTX) provides any survival benefit. Thirty‐three patients awaiting HTX were randomized to either conventional therapy (control group) or primary preventive ICD implantation (ICD group). Fourteen patients had ischemic cardiomyopathy (ICM) and 19 patients had dilated cardiomyopathy (DCM). Sixteen patients were randomized to the ICD group and 17 patients were randomized to the control group. Twenty patients (61%) were transplanted after a waiting time of 10 ± 9 months. The remaining 13 patients (39%) were not transplanted because of clinical improvement (n = 5), cerebral hemorrhage (n = 3), or death (n = 5). On the waiting list, 3 ICD patients with DCM developed slow VTs without ICD intervention, two patients with ICM (6%) had fast VT terminated by the ICD, and no arrhythmic death was observed. After 11.9 years (median), 13 of 20 HTX patients (65%) and 5 of 13 non‐HTX patients (38%) were alive. Survivors had a higher LVEF (22 ± 6 vs. 17 ± 4%, P = 0.0092) and a better exercise capacity (75 ± 29 vs. 57 ± 24 Watt, P = 0.0566) at baseline as compared to nonsurvivors. This study may not support the general use of primary preventive ICDs as a short‐term bridge to heart transplantation.     

A Novel Subcutaneous Counterpulsation Device: Acute Hemodynamic Efficacy During Pharmacologically Induced Hypertension,Hypotension, and Heart Failure

The miniaturization of mechanical assist devices and less invasive implantation techniques may lead to earlier intervention in patients with heart failure. As such, we evaluated the effectiveness of a novel, minimally invasive, implantable counterpulsation device (CPD) in augmenting cardiac function during impaired hemodynamics. We compared the efficacy of a 32‐mL stroke volume CPD with a standard 40‐mL intra‐aortic balloon pump (IABP) over a range of clinically relevant pathophysiological conditions. Male calves were instrumented via thoracotomy, the CPD was anastomosed to the left carotid artery, and the IABP was positioned in the descending aorta. Hemodynamic conditions of hypertension, hypotension, and heart failure were pharmacologically simulated and data were recorded during CPD and IABP support (off, 1:2, 1:1 modes) for each condition. In all three pathophysiological conditions, the CPD and IABP produced similar and statistically significant (P < 0.05) increases in coronary artery blood flow normalized to the left ventricular (LV) workload. During hypotension and heart failure conditions, however, the CPD produced significantly greater reductions in LV workload and myocardial oxygen consumption as compared with the IABP. A novel 32‐mL CPD connected to a peripheral artery produced equivalent or greater hemodynamic benefits than a standard 40‐mL IABP during pharmacologically induced hypertension, hypotension, and heart failure conditions.     

Coronary computed tomography–angiography quantitative plaque analysis improves detection of early cardiac allograft vasculopathy: A pilot study

Cardiac allograft vasculopathy (CAV) is an increasingly important complication after cardiac transplant. We assessed the additive diagnostic benefit of quantitative plaque analysis in patients undergoing coronary computed tomography–angiography (CCTA). Consecutive patients undergoing CCTA for CAV surveillance were identified. Scans were visually interpreted for coronary stenosis. Semiautomated software was used to quantify noncalcified plaque (NCP), as well as its components. Optimal diagnostic cut‐offs for CAV, with coronary angiography as gold standard, were defined using receiver operating characteristic curves. In total, 36 scans were identified in 17 patients. CAV was present in 17 (46.0%) reference coronary angiograms, at a median of 1.9 years before CCTA. Median NCP (147 vs 58, P < .001), low‐density NCP (median 4.5 vs 0.9, P = .003), fibrous plaque (median 76.1 vs 31.1, P = .003), and fibrofatty plaque (median 63.6 vs 27.6, P < .001) volumes were higher in patients with CAV, whereas calcified plaque was not (median 0.0 vs 0.0, P = .510). Visual assessment of CCTA alone was 70.6% sensitive and 100% specific for CAV. The addition of total NCP volume increased sensitivity to 82.4% while maintaining 100% specificity. NCP volume is significantly higher in patients with CAV. The addition of quantitative analysis to visual interpretation improves the sensitivity for detecting CAV without reducing specificity.     

Diminished impact of cytomegalovirus infection on graft vasculopathy development in the antiviral prophylaxis era – a retrospective study

Evidence concerning an association between cytomegalovirus (CMV) infection and accelerated cardiac allograft vasculopathy (CAV) is inconclusive. Data were analyzed retrospectively from 297 consecutive heart transplants between 1.1.2002 and 31.12.2012. Patients ≤18 years of age, survival, and follow‐up ≤1‐year post‐transplant and patients with early CAV were excluded. CMV‐infection was diagnosed and monitored closely in the first year. CAV was diagnosed by coronary angiography via left heart catheterization, and results were categorized according to the International Society of Heart and Lung Transplantation (ISHLT) scoring system. Risk factors for CAV were tested in a multivariable model. Median follow‐up was 7.5 years (IQR: 5.6–10.3). CMV infection in the first year after transplantation occurred in 26% of patients (n = 78), CMV disease in 5% (n = 15). CAV ≥1 ISHLT was detected in 36% (n = 108). Incidence of CAV >1 ISHLT and severity of CAV increased over time. No statistically significant association between CMV infection and disease within the first year and risk of CAV after 1‐year post‐HTx was detected in the univariate (P = 0.16) and multivariable [hazard ratio (HR), 1.36; confidence interval (CI), 0.89–2.07; P = 0.16] Cox regression. In the multivariable Cox regression, donor age (HR, 1.04; 95% CI, 1.02–1.06; P < 0.01) and acute cellular rejection (ACR) ≥2R in the first year after HTx (HR, 1.77; 95% CI, 1.06–2.95; P = 0.03) were independent risk factors for CAV development. In our cohort, CMV infection and disease in the first year after transplantation did not significantly influence the risk of CAV in the long‐term follow‐up.     

Echocardiographic and Hemodynamic Evaluation of Cardiovascular Performance during Laparoscopy of Morbidly Obese Patients

Background: The effects of morbid obesity, pneumoperitoneum (PP) and body position on cardiac function during laparoscopy were studied. Methods: Transesophageal echocardiography (TEE) was performed on 10 obese patients (body mass index, BMI, 48.1±1.8 kg/m²) and 10 normal weight patients (BMI = 22.6±0.8 kg/m²) in supine, Trendelenburg and reverse Trendelenburg positions before and after PP. Left ventricular end-systolic wall stress (LVESWS) was calculated from invasive blood pressure (BP) values and LV dimensions obtained by TEE. Diastolic filling was assessed by mitral valve and pulmonary vein flow velocities. Results: LVESWS was higher in obese patients both at baseline (46.0±4.0x10³ dyn/cm²) and with PP (69.3±8.2x10³ dyn/cm²), than normal weight subjects (31.9±3.7x10³ dyn/cm² and 45.7±5.9x10³ dyn/cm²; P <0.05 obese vs normal weight patients at baseline). Systolic BP was not different between groups at baseline (normal weight 111±4 mmHg, obese 119±3 mmHg), but increased significantly with PP only in obese patients (normal weight 129±6 mmHg, obese 157±8 mmHg; P <0.05). Postural changes during PP had no impact on cardiac function in either obese or normal weight subjects. Conclusions: Anesthetized obese patients undergoing laparoscopy have higher LVESWS before pneumoperitoneum (due to increased end-systolic left ventricular dimensions) and during pneumoperitoneum (due to more pronounced increases in blood pressure). Since LVESWS is a determinant of myocardial oxygen demand, more aggressive control of blood pressure (ventricular afterload) in MO patients may be warranted to optimize the myocardial oxygen requirements.     

The adverse hemodynamic effects of anesthesia, head-up tilt, and carbon dioxide pneumoperitoneum during laparoscopic cholecystectomy

Background: The increased intra-abdominal pressure during pneumoperitoneum, together with the head-up tilt used in upper abdominal laparoscopies, would be expected to decrease venous return to the heart. The goal of our study was to determine whether laparoscopy impairs cardiac performance when preventive measures to improve venous return are taken, and to analyze the effects of positioning, anesthesia, and increased intra-abdominal pressure. Methods: Using invasive monitoring, hemodynamic changes were investigated in 15 ASA class I or II patients under isoflurane–fentanyl anesthesia during laparoscopic cholecystectomy. Before laparoscopy, the patients received an intravenous (IV) infusion of colloid solution if cardiac filling pressures were low, and their legs were wrapped from toes to groin with elastic bandages. Measurements were taken while the patients were awake in the supine (baseline) and head-up tilt (15–20°) positions, and after the induction of anesthesia in the same positions. Measurements were repeated at regular intervals during laparoscopy (intra-abdominal pressure at 13–16 mmHg), after deflation of the gas, and in the recovery room. Results: With the passive head-up tilt in awake and anesthetized patients, the cardiac index (CI), stroke index (SI), central venous pressure (CVP), and pulmonary capillary wedge pressure (PCWP) decreased, and systemic vascular resistance increased. With the patient under anesthesia, SI decreased, but CI did not change significantly as a result of the compensatory increase in heart rate. Carbon dioxide (CO₂) insufflation at the start of laparoscopy produced increases in CVP and PCWP as well as mean systemic and mean pulmonary arterial pressures without changes in CI or SI. Toward the end of the laparoscopy, CI decreased by 15%. The hemodynamic values returned to nearly prelaparoscopic levels after deflation of the gas, and CI was elevated during the recovery period, whereas systemic vascular resistance was decreased in comparison with the baseline. Conclusions: By correcting relative dehydration and preventing the pooling of blood, CI decreased less than 20% during pneumoperitoneum as compared with the baseline awake level. The head-up positioning accounts for many of the adverse effects in hemodynamics during laparoscopic cholecystectomy. Received: 6 November 1998/Accepted: 8 July 1999     

Plasma N-terminal proatrial natriuretic factor can predict normal pulmonary capillary wedge pressure in cardiac transplant recipients

BACKGROUND: Plasma N-terminal proatrial natriuretic factor (proANP) is closely related to atrial filling pressure, but this may be distorted in heart transplant recipients. OBJECTIVE: The aim of this study was to examine the usefulness of proANP as a non-invasive marker of cardiac filling pressure in transplanted patients with normal to moderately elevated serum creatinine (s-creatinine). METHODS: Blood was sampled at rest for analysis of proANP from 220 patients 1-13 (median 4) years after orthotopic heart transplantation undergoing routine diagnostic catheterization. RESULTS: In multivariate analysis proANP was significantly positively related to s-creatinine, mean pulmonary capillary wedge pressure (PCWP) and time after transplantation and negatively related to haemoglobin and cardiac index. All the patients with proANP below 1140 pmol/l had normal PCWP (<13 mmHg). The area under the receiver-operating characteristic curve for proANP for the detection of PCWP > 13 mmHg was 0.81. The positive predictive value of proANP for detection of increased PCWP was very low. CONCLUSION: A low proANP had a 100% negative predictive value for increased atrial pressure but the low positive predictive value makes proANP unsuitable as an indicator of increased atrial pressures in heart transplanted patients.     

Cardiac Index Declines During Long‐Term Left Ventricular Device Support

To investigate longitudinal trends in valvular and ventricular function with long‐term left ventricular assist device (LVAD) therapy, we analyzed hemodynamic and echocardiographic data of patients with at least 2 years of continuous LVAD support. All 130 patients who underwent HeartMate II implantation at our institution between 2005 and 2012 were reviewed. Twenty patients had hemodynamic and echocardiographic evaluations in both the early (0–6 months) and late (2–3 years) postoperative period. Patients on inotropic therapy or temporary mechanical support were excluded. The average times of early and late hemodynamic evaluations were 59 ± 41 days and 889 ± 160 days, respectively. Cardiac index (CI) declined by an average of 0.4 L/min/m² (P = 0.04) with concomitant increase in pulmonary capillary wedge pressure (PCWP; P = 0.02). The right atrial pressure to PCWP (RAP:PCWP) ratio decreased during LVAD support suggesting improvement in right ventricular function. While there was an increase in degree of aortic insufficiency (AI) at the late follow‐up period (P = 0.008), dichotomization by median decline in CI (?0.4 L/min/m²) indicated no difference in prevalence of AI among the groups. CI declined in patients with HeartMate II after 2 years of continuous support. An increase in preload and afterload was observed in those with the greatest decline in CI.     

Early Prediction of Cardiac Allograft Vasculopathy and Heart Transplant Failure

Early risk‐prediction is essential to prevent cardiac allograft vasculopathy (CAV) and graft failure in heart transplant patients. We developed multivariate models to identify patients likely to experience CAV, severe CAV, and failure due to CAV, at 1, 5 and 10 years. A cohort of 172 patients was followed prospectively for 6.7 ± 3.9 years. Logistic regression models were developed and cross‐validated using bootstrap resampling. Predictive markers of atherothrombosis (myocardial fibrin deposition, and loss of vascular antithrombin and tissue plasminogen activator) and arterial endothelial activation (intercellular adhesion molecule‐1 expression) were measured in serial biopsies obtained within 3 months posttransplant. Most markers were univariately associated with outcome. Multivariate models showed that loss of tissue plasminogen activator was the dominant and, in most cases, only predictor of long‐term CAV (p < 0.001), severe CAV (p < 0.001), and graft failure due to CAV (p < 0.001). The models discriminated patients having adverse outcomes, had particularly high negative predictive values (graft failure due to CAV: 99%, 99% and 95% at 1, 5 and 10 years) and predicted event incidence and time to event. Early absence of atherothrombotic risk identifies a patient subgroup that rarely develops CAV or graft failure, implying that this low‐risk subgroup could possibly be followed with fewer invasive procedures.     

Effect of intraabdominal pressure elevation and positioning on hemodynamic reponses during carbon dioxide pneumoperitoneum for laparoscopic donor nephrectomy: a prospective controlled clinical study

Background Carbon dioxide (CO₂) pneumoperitoneum (PP) increases mean arterial blood pressure (MAP) and systemic vascular resistance (SVR) but decreases stroke volume (SV) and cardiac output (CO). This study evaluated the hemodynamic effects of elevated intraabdominal pressure (IAP) occurring during laparoscopic donor nephrectomy (LDN).Methods Twenty-two patients undergoing LDN were investigated and hemodynamic parameters, P_vCO₂ (carbon dioxide partial pressure), and VCO₂ (carbon dioxide production) were monitored during the procedure. Before and after PP, IAP was raised from 12 to 20 mmHg and the hemodynamic effects were measured every 30 s.Results During IAP of 12 mmHg and stable serum CO₂, there was no change in SV compared to preinsufflation levels. When IAP was elevated from 12 to 20 mmHg, SV initially decreased (p < 05), followed by an increase in MAP and SVR (p < 0.05).Conclusion This study shows that with the fluid and ventilation protocol used, PP has no significant effect on SV at an IAP of 12 mmHg, whereas increasing IAP to 20 mmHg does. In this study, the hemodynamic effects induced by CO₂ PP of 12 mmHg are not due to changes in serum CO₂ . Compression of the venous system during a PP of 20 mmHg reduces preload, with an subsequent increase in SVR.     

Anaesthesia for abdominal aortic surgery in patients with coronary artery disease, part II: effects of nitrous oxide on systemic and coronary haemodynamics, regional ventricular function and incidence of myocardial ischaemia

This study examines the effects of nitrous oxide on haemodynamics, anterior left ventricular (LV) function and incidence of myocardial ischaemia in abdominal vascular surgical patients with coronary artery disease. Forty–seven patients were randomly assigned to isoflurane–fentanyl anaesthesia with nitrous oxide–oxygen vs airoxygen (control). Systemic and coronary haemodynamics, 12–lead ECG, LV anterior wall modon by cardiokymography (CKG) and myocardial lactate balance were recorded at four intervals: before and during anaesthesia and 10 and 30 minutes into surgery. Systemic haemodynamics were controlled by anaesthetic dose, and, when insufficient, by iv nitroglycerine (NG) in case of LV failure (PCWP > 18 mmHg) and by phenylephrine during hypotension.
We found that nitrous oxide was associated with greater need for iv nitroglycerin (patients: P = 0.031, episodes P = 0.005) and more myocardial ischaemia (patients P = 0.012, episodes P = 0.00l) despite systemic and coronary haemodynamics comparable to the control group. We conclude that nitrous oxide, known to have both sympathomimetic and cardiodepressive actions, produced cardiodepression in the face of sympathetic stimulation. Our study design did not allow us to conclude if myocardial ischaemia was the consequence of increased wall stress or a reason for the observed LV dysfunction. The higher incidence of introperative myocardial ischaemia and need for NG did not cause increased cardiac morbidity.     

Myocardial injury in patients with hemodynamic derangements during and/or after liver transplantation

Myocardial injury, defined as an elevation of cardiac troponin (cTn) resulting from ischemia, is associated with substantial mortality in surgical patients, and its incidence, risk factors, and impact on patients undergoing liver transplantation (LT) are poorly understood. In this study, adult patients who experienced perioperative hemodynamic derangements and had cTn measurements within 30 days after LT between 2006 and 2013 were studied. Of 502 patients, 203 (40.4%) met the diagnostic criteria (cTn I ≥0.1 ng/mL) of myocardial injury. The majority of myocardial injury occurred within the first three postoperative days and presented without clinical signs or symptoms of myocardial infarction. Thirty‐day mortality in patients with myocardial injury was 11.4%, significantly higher compared with that in patients without myocardial injury (3.4%, P<.01). Cox analysis indicated the peak cTn was significantly associated with 30‐day mortality. Multivariable logistic analysis identified three independent risk factors: requirement of ventilation before transplant (odds ratios (OR) 1.6, P=.006), RBC≥15 units (OR 1.7, P=.006), and the presence of PRS (OR 2.0, P=.028). We concluded that post‐LT myocardial injury in this high‐risk population was common and associated with mortality. Our findings may be used in pretransplant stratification. Further studies to investigate this postoperative cardiac complication in all LT patients are warranted.     

Epstein‐Barr virus load in whole blood is associated with immunosuppression,but not with post‐transplant lymphoproliferative disease in stable adult heart transplant patients

Development of Epstein‐Barr virus (EBV)‐associated post‐transplant lymphoproliferative disease (PTLD) is a serious complication following heart transplantation (HTX). This study investigates EBV DNA load in adult heart transplant recipients, its association with immunosuppression, and its potential as a marker for development of PTLD. EBV DNA load was measured prospectively by quantitative real‐time polymerase chain reaction (PCR) in 172 stable HTX patients. Sixty‐seven patients (39.0% of total) had a positive EBV PCR at initial examination [median 4.9 (range 1.1–16.9) years post‐HTX]. In follow‐up testing of 67 positive patients 6 months later, 36 patients continued to have a positive EBV PCR. Overall incidence of EBV DNA was significantly associated with calcineurin inihibitors, azathioprine medication, and with the absence of mycophenolate mofetil (MMF) treatment. In patients with positive EBV DNA levels at initial examination and negative levels at retesting, cyclosporine A levels were found to be significantly higher at initial examination (148.4 ± 70.2 vs. 119.6 ± 53.5 ng/ml, P < 0.05). Three patients (1.7%, 3/172) were diagnosed with PTLD during the course of the study (mean follow up 4.0 years). EBV DNA viral load determination does not appear to be useful for risk prediction or early diagnosis of PTLD in adults after HTX, but an association of EBV DNA load with qualitative and quantitative immunosuppression is demonstrated.     

Visfatin serum concentration is associated with cardiac allograft vasculopathy in heart transplant recipients

Cardiac allograft vasculopathy (CAV) still is one of the most important limiting factors of long‐term survival following heart transplant (HT). This study aimed to investigate the association between proinflammatory adipokine‐visfatin and the incidence of CAV in HT recipients. After HT, 182 patients who had a follow‐up visit at the Transplantation Clinic between 2016 and 2017 were analyzed. The median age was 60.5 years, and 76.4% were men. The incidence of CAV was 54.9%. According to the multivariable proportional hazard regression analysis, visfatin level (1.795 [1.539‐2.094]; P < .001) was significantly associated with CAV, and statin use was protective against CAV (0.504 [0.32‐0.793]; P = .003). The area under the receiver operating characteristic curve indicated an excellent discriminatory power of visfatin (0.9548 [0.9281‐0.9816]) for CAV detection. The cutoff value of 5.42 ng/mL for visfatin yielded a sensitivity of 89% and specificity of 91%. This is the first study to demonstrate that visfatin serum concentrations are independently associated with the incidence of CAV in HT recipients. Visfatin allows for simple and cheap detection of CAV given its excellent discriminatory ability and high sensitivity and specificity. In addition, we have found an independent association between the statin use and a lower risk of CAV.