Indoxyl Sulfate Upregulates Liver P-Glycoprotein Expression and Activity through Aryl Hydrocarbon Receptor Signaling.

In patients with CKD, not only renal but also, nonrenal clearance of drugs is altered. Uremic toxins could modify the expression and/or activity of drug transporters in the liver. We tested whether the uremic toxin indoxyl sulfate (IS), an endogenous ligand of the transcription factor aryl hydrocarbon receptor, could change the expression of the following liver transporters involved in drug clearance: SLC10A1, SLC22A1, SLC22A7, SLC47A1, SLCO1B1, SLCO1B3, SLCO2B1, ABCB1, ABCB11, ABCC2, ABCC3, ABCC4, ABCC6, and ABCG2 We showed that IS increases the expression and activity of the efflux transporter P-glycoprotein (P-gp) encoded by ABCB1 in human hepatoma cells (HepG2) without modifying the expression of the other transporters. This effect depended on the aryl hydrocarbon receptor pathway. Presence of human albumin at physiologic concentration in the culture medium did not abolish the effect of IS. In two mouse models of CKD, the decline in renal function associated with the accumulation of IS in serum and the specific upregulation of Abcb1a in the liver. Additionally, among 109 heart or kidney transplant recipients with CKD, those with higher serum levels of IS needed higher doses of cyclosporin, a P-gp substrate, to obtain the cyclosporin target blood concentration. This need associated with serum levels of IS independent of renal function. These findings suggest that increased activity of P-gp could be responsible for increased hepatic cyclosporin clearance. Altogether, these results suggest that uremic toxins, such as IS, through effects on drug transporters, may modify the nonrenal clearance of drugs in patients with CKD.

Genetic and Functional Profiling of CD16-Dependent Natural Killer Activation Identifies Patients at Higher Risk of Cardiac Allograft Vasculopathy.

BACKGROUND: Cardiac transplantation is an effective therapy for end-stage heart failure. Because cardiac allograft vasculopathy (CAV) is the major cause of late mortality after heart transplant (HT), there is a need to identify markers that reflect inflammatory or cytotoxic immune mechanisms contributing to its onset. Noninvasive and early stratification of patients at risk remains a challenge for adapting individualized therapy. The CD16 (Fc-gamma receptor 3A [FCGR3A]) receptor was recently identified as a major determinant of antibody-mediated natural killer (NK) cell activation in HT biopsies; however, little is known about the role of CD16 in promoting allograft vasculopathy. This study aimed to investigate whether markers that reflect CD16-dependent circulating NK cell activation may identify patients at higher risk of developing CAV after HT. METHODS: Blood samples were collected from 103 patients undergoing routine coronarography angiography for CAV diagnosis (median 5 years since HT). Genomic and phenotypic analyses of FCGR3A/CD16 Fc-receptor profiles were compared in CAV-positive (n=52) and CAV-free patients (n=51). The levels of CD16 expression and rituximab-dependent cell cytotoxic activity of peripheral NK cells in HT recipients were evaluated using a noninvasive NK-cellular humoral activation test. RESULTS: Enhanced levels of CD16 expression and antibody-dependent NK cell cytotoxic function of HT recipients were associated with the FCGR3A-VV genotype. The frequency of the FCGR3A-VV genotype was significantly higher in the CAV+ group (odds ratio, 3.9; P=0.0317) than in the CAV- group. The FCGR3A-VV genotype was identified as an independent marker correlated with the presence of CAV at the time of coronary angiography by using multivariate logistic regression models. The FCGR3A-VV genotype was also identified as a baseline-independent predictor of CAV risk (odds ratio, 4.7; P=0.023). CONCLUSIONS: This study unravels a prominent role for the CD16-dependent NK cell activation pathway in the complex array of factors that favor the progression of transplant arteriosclerosis. It highlights the clinical potential of a noninvasive evaluation of FCGR3A/CD16 in the early stratification of CAV risk. The recognition of CD16 as a major checkpoint that controls immune surveillance may promote the design of individualized NK cell-targeted therapies to limit vascular damage in highly responsive sensitized patients. CLINICAL TRIAL REGISTRATION: URL: https://www.clinicaltrials.gov. Unique identifier: NCT01569334.

Severe right ventricular dysfunction is an independent predictor of pre- and post-transplant mortality among candidates for heart transplantation.

BACKGROUND: Heart transplantation is the gold-standard treatment for end-stage heart failure. However, the shortage of grafts has led to longer waiting times and increased mortality for candidates without priority. AIMS: To study waiting-list and post-transplant mortality, and their risk factors among patients registered for heart transplantation without initial high emergency procedure. METHODS: All patients registered on the heart transplantation waiting list (2004-2015) without initial high emergency procedure were included. Clinical, biological, echocardiographic and haemodynamic data were collected. Waiting list and 1-year post-transplant survival were analysed with a Kaplan-Meier model. RESULTS: Of 221 patients enrolled, 168 (76.0%) were men. Mean age was 50.0±12.0 years. Forty-seven patients died on the waiting list, resulting in mortality rates of 11.2±2.7% at 1 year, 31.9±5.4% at 2 years and 49.4±7.1% at 3 years. Median survival was 36.0±4.6 months. In the multivariable analysis, left ventricular ejection fraction<30% (hazard ratio [HR]: 3.76, 95% confidence interval [CI]: 1.38-10.24; P=0.010) and severe right ventricular systolic dysfunction (HR: 2.89, 95% CI: 1.41-5.92; P=0.004) were associated with increased waiting-list mortality. The post-transplant survival rate was 73.1±4.4% at 1 year. Pretransplant severe right ventricular dysfunction and age>50 years were strong predictors of death after transplantation (HR: 5.38, 95% CI: 1.38-10.24 [P=0.020] and HR: 6.16, 95% CI: 1.62-9.32 [P=0.0130], respectively). CONCLUSIONS: Mortality among candidates for heart transplantation remains high. Patients at highest risk of waiting-list mortality have to be promoted, but without compromising post-transplant outcomes. For this reason, candidates with severe right ventricular dysfunction are of concern, because, for them, transplantation is hazardous.

Severe decrease of cyclosporine levels in a heart transplant recipient receiving the direct thrombin inhibitor argatroban.

This case report is about a suspected interaction between argatroban, a direct thrombin inhibitor, and cyclosporine, which occurred in a 60-year-old patient after a second heart transplantation. We explored 4 possible mechanisms of interaction, which are an analytical interference, an idiopathic hemodilution, an increase of renal and hepatic clearance, and a metabolic drug-drug interaction.

Impact of the early reduction of cyclosporine on renal function in heart transplant patients: a French randomised controlled trial.

BACKGROUND: Using reduced doses of Cyclosporine A immediately after heart transplantation in clinical trials may suggest benefits for renal function by reducing serum creatinine levels without a significant change in clinical endpoints. However, these trials were not sufficiently powered to prove clinical outcomes. METHODS: In a prospective, multicentre, open-label, parallel-group controlled trial, 95 patients aged 18 to 65 years old, undergoing de novo heart transplantation were centrally randomised to receive either a low (130 < trough CsA concentrations <200 µg/L, n = 47) or a standard dose of Cyclosporine A (200 < trough CsA concentrations <300 µg/L, n = 48) for the three first post-transplant months along with mycophenolate mofetil and corticosteroids. Participants had a stable haemodynamic status, a serum creatinine level <250 µmol/L and the donors' cold ischemia time was under six hours; multiorgan transplants were excluded. The change in serum creatinine level over 12 months was used as the main criterion for renal function. Intention-to-treat analysis was performed on the 95 randomised patients and a mixed generalised linear model of covariance was applied. RESULTS: At 12 months, the mean (± SD) creatinine value was 120.7 µmol/L (± 35.8) in the low-dose group and 132.3 µmol/L (± 49.1) in the standard-dose group (P = 0.162). Post hoc analyses suggested that patients with higher creatinine levels at baseline benefited significantly from the lower Cyclosporine A target. The number of patients with at least one rejection episode was not significantly different but one patient in the low-dose group and six in the standard-dose group required dialysis. CONCLUSIONS: In patients with de novo cardiac transplantation, early Cyclosporine A dose reduction was not associated with renal benefit at 12 months. However, the strategy may benefit patients with high creatinine levels before transplantation. TRIAL REGISTRATION: ClinicalTrials.gov NCT00159159.

Short-term results of repeat valve replacement: a predictive factor analysis.

BACKGROUND AND AIM OF THE STUDY: The new-generation bioprostheses are associated with a longer lifespan, and therefore tend to be implanted in younger patients. However, with the increase in life expectancy, the trend is towards a higher rate of repeat valve replacement. Hence, the study aim was to evaluate the present mortality and risk factors for repeat valvular surgery. METHODS: A total of 183 consecutive patients (87 males, 96 females; mean age 62 years; range: 28-88 years) who underwent repeat valve replacement at the authors' institution between 2001 and 2004 was reviewed. Reoperations in these patients were required due to structural degeneration of the bioprosthesis (50%), to paravalvular leak (20%), and to prosthetic endocarditis (14%), valve thrombosis (9%), and plasty failure (9%). In total, 105 patients (57%) had received at least one bioprosthesis during the previous operation, 58 (31%) had a mechanical valve, 15 (8%) had an isolated mitral plasty, and five (2%) hybrid procedures. All preoperative and operative risk factors were studied. RESULTS: The overall operative mortality rate was 6.6% (n = 12), but only 3.9% (n = 4) for the bioprosthesis reoperation. The risk factors for mortality included pulmonary hypertension (> 60 mmHg; p = 0.03), renal insufficiency (p = 0.02), more than one repeat valve replacement (p = 0.004), previous mechanical prosthesis (p = 0.02), previous mitral surgery (p = 0.019), and associated tricuspid surgery (p = 0.03). CONCLUSION: The data acquired tended to show that repeat valve replacement of bioprostheses may be carried out with an acceptable operative risk, in connection with the majority of operations on bioprostheses being secondary to structural degeneration of the implant. Hence, in most cases a well-controlled, programmed operation would lead to very low mortality (< 4%), despite a significant morbidity rate.

Heart transplantation in 7 patients from a single family with limb-girdle muscular dystrophy caused by lamin A/C mutation.

We describe 7 transplanted heart recipients from a single family with limb-girdle muscular dystrophy type 1B linked to a mutation of the LMNA gene in the splice donor site of the exon 9 (IVS 9+1:g>a). These patients did not display higher early postoperative or late complications than other heart transplant recipients at a mean follow-up of 8 years (range 1-17 years). Noticeably, there was no case of rhabdomyolysis and skeletal muscle symptoms were not markedly impaired.

Role of endogenous adenosine as a predictive marker of vasoplegia during cardiopulmonary bypass and postoperative severe systemic inflammatory response.

OBJECTIVE: Systemic inflammatory response (SIRS) and severe SIRS (SIRS with organ dysfunction) occurring after cardiopulmonary bypass (CPB) are common causes of morbidity and mortality among cardiac surgical patients. These syndromes are often preceded by a profound vasodilation, characterized by vasoplegia occurring during surgery. Many substances have been implicated in their pathophysiology. Adenosine is a strong endogenous vasodilating agent released by endothelial cells and myocytes under metabolic stress and may be involved in blood pressure failure during CPB induced by severe SIRS. DESIGN: A prospective comparative observational study. SETTING: The operating room and intensive care unit of a tertiary care university hospital. PATIENTS: Adenosine plasma levels (mean+/-sd; APLs) were measured before (baseline), during, and immediately after surgery in 35 patients who underwent aortic valve replacement involving CPB. APLs were correlated to operative and postoperative clinical courses. MEASUREMENTS AND MAIN RESULTS: APLs were significantly higher in seven patients with vasoplegia and postoperative severe SIRS (1.6 micromol.L [0.2-2.6] vs. 0.4 micromol.L [0.1-1.0]) at baseline and during surgery. The duration of mechanical ventilation and stay in the intensive care unit were significantly longer for patients with higher APLs. Mean arterial pressure was inversely correlated with mean arterial APLs (Pearson's correlation coefficient: R=-0.66; p<.001). CONCLUSIONS: High APLs were found in patients with operative vasoplegia and postoperative severe SIRS occurring after cardiopulmonary bypass. This suggests that adenosine release is involved in vasoplegia that occurs during the systemic inflammatory response to cardiac surgery. Further studies are needed to clarify the association between cytokine production and adenosine release in severe SIRS following cardiac surgery.

Non-invasive diagnostic of cardiac allograft vasculopathy by 31P magnetic resonance chemical shift imaging.

BACKGROUND: Coronary angiography is still the gold standard for the diagnosis of cardiac allograft vasculopathy (CAV) for which alternative non-invasive diagnostic approaches are currently investigated. In this study, we assessed whether 31P magnetic resonance chemical shift imaging can diagnose CAV by studying variations in cardiac high-energy phosphates in a population of adult heart transplant recipients. METHODS AND RESULTS: CAV was defined by coronary angiography as the presence of diffuse coronary irregularities with significant concentric narrowing on epicardial or distal coronary arteries. Eight patients with CAV (group A), and 18 patients without CAV (group B) were included in this study and compared to nine healthy volunteers (group C). Patients and volunteers underwent 31P three-dimensional chemical shift imaging to determine the ratio of phosphocreatine (PCr) and adenosine tri-phosphate (ATP). PCr/ATP was significantly lower in group A (1.51+/-0.50) than in groups B and C (1.98+/-0.53 (p=0.003) and 2.14+/-0.31 (p=0.001)), respectively. Time from transplant, number of episodes of acute rejection, and left ventricular ejection fraction (LVEF) were not significantly different between patient groups. A PCr/ATP value of 1.59 was the optimal cut-off value to predict CAV (specificity and sensitivity of 100% and 72%, respectively). CONCLUSION: Clinically, in vivo 31P chemical shift imaging is a promising, non-invasive method to detect the potential modifications of high-energy phosphates related to CAV and to better screen indications for coronary angiograms. This may be relevant for coronary angiography follow-up and adjustments of immunotherapy regimen.

31P MRS of heart grafts provides metabolic markers of early dysfunction.

OBJECTIVE: Early graft failure (EGF) is a life-threatening event still accounting for a significant percentage of early deaths after heart transplantation. We tested whether selected metabolic markers, including high-energy phosphate concentrations measured ex vivo in pre-transplant heart grafts by (31)P magnetic resonance spectroscopy (MRS) are related with early post-transplant outcome. METHODS: During a 3-year period, 26 heart grafts harvested in the vicinity of the transplantation centre were studied. Evaluation of transplantability was done conventionally. (31)P MRS was performed ex vivo approximately 60min after aortic cross-clamp to quantify ATP, P(i) and PCr concentration ratios. A MRS-score was defined as a combination of intracellular pH (pHi) and the PCr/P(i) ratio. EGF was defined as the need to abnormally extend circulatory support or to use more than two inotropes before weaning the patient from CPB after transplantation. The grafts were attributed to three groups as follows: A1, transplanted with uneventful outcome (n=14); A2, transplanted with subsequent EGF (n=3) and B, not suitable for transplantation (n=9). RESULTS: Significant differences between groups existed for the following metabolic markers: PCr/ATP (P=0.013), PCr/P(i) (P=0.0004), pHi (P=0.0016) and MRS-score (P=0.0001). The sensitivity, specificity and positive likelihood ratio for EGF with a MRS-score

Complete atrioventricular block decreases left ventricular assist device flow rate.

A 52-year-old man, living at home, had been on left ventricular assistance for 15 months with a Novacor pump (Worldheart, Ottawa, ON, Canada). Following the onset of effort dyspnea that had recently become worse, he was admitted to the hospital. A review of the pump showed that its flow rate had significantly decreased. An electrocardiogram showed a third-degree atrioventricular block. A pacemaker was implanted and the patient became asymptomatic immediately afterwards. This clinical case report shows the importance of satisfactory right ventricle filling in these patients. Right ventricle filling can be impaired by conduction disorders.

Primary valvular surgery in octogenarians: perioperative outcome.

BACKGROUND AND AIM OF THE STUDY: Cardiac surgery in octogenarians is now performed routinely, and generally results in a good improvement in functional capacity. The study aim was to evaluate operative mortality and to identify preoperative and postoperative risk factors of mortality. METHODS: A total of 200 consecutive patients (79 males, 121 females; mean age 83 years; range: 80-90 years) who underwent valvular surgery at the authors' institution between 1991 and 2002 was reviewed. Among patients, 154 underwent aortic valve replacement (77.0%), 35 mitral surgery (17.5%), and 11 aortic and mitral valve surgery (5.5%). Forty-five patients (22.5%) had concomitant myocardial revascularization, and 23 (11.5%) were operated on in an emergency setting. Preoperative risk factors studied included endocarditis (2.0%), ventricular dysfunction (22.5%), pulmonary hypertension (33.5%), renal dysfunction (31.5%), chronic obstructive pulmonary disease (7.0%) and arteriopathy (9.0%). The mean EuroSCORE, which was used to assess predicted operative risk, was 9.1; the score was < 9 in 104 patients (52%) and > 9 in 96 (48%). RESULTS: Hospital mortality was 7% (n = 14). There were no significant preoperative risk factors of mortality. Postoperative complications occurred in 115 patients (57.5%), including low cardiac output (16.0%), supraventricular arrhythmia (29.5%), pulmonary complications (9.5%), gastrointestinal ischemia (2.0%), wound infection (2.0%) and surgical re-exploration (5.5%). Low cardiac output (p < 0.001), gastrointestinal ischemia (p = 0.03) and surgical reexploration (p = 0.004) were significant risk factors of mortality. CONCLUSION: Valvular surgery in octogenarians is a safe and low-risk procedure. The present data tended to show that the EuroSCORE overestimates mortality in this group of patients.

Valvular surgery in octogenarians: operative risks factors, evaluation of Euroscore and long term results.

OBJECTIVES: In the last decade, cardiac surgery in octogenarians is becoming a routinely performed procedure in our Western countries. The functional benefit of this surgery had already been proved. The aim of this study was to evaluate operative mortality, to identify pre- and post-operative risk factors of early and late mortality, to assess the Euroscore count in this high-risk group of patient and to evaluate late results of this surgery. METHODS: We reviewed 215 consecutive patients with a mean age of 83+/-2 years having undergone valvular surgery. There were 127 female patients (57.1%) and 88 males (42.9%). One hundred and fifty-nine patients (74%) underwent aortic valve replacement 42 (19.5%) mitral surgery and 14 (6.5%) double valve surgery. There were 32 (14.9%) re-operative cases. Twenty-seven patients (12.6%) were operated on in emergency. There were 32 re-operations (14%). The EuroSCORE was used to assess predicted operative risk. Mean Euroscore additive count was 9.5+/-2.3 and mean logistic Euroscore was 15.1%. RESULTS: Operative mortality was 8.8% (19 patients). Left ventricular dysfunction was the only pre-operative significant risk factors of mortality (P=0.05). Low cardiac output (P<0.001), gastrointestinal complications (P=0.03) and surgical reexploration (P=0.001) were significant risk factors of mortality. Mean survival was 84% after one year and 56% after 5 years. CONCLUSIONS: Valvular surgery in octogenarians is a safe and low risk procedure compared to functional benefit and long-term survival. Our data how that logistic Euroscore overestimates the mortality in this high-risk group of patients.

Toxoplasma gondii retinochoroiditis after cardiac transplantation.

PURPOSE: To report 4 cases of Toxoplasma gondii retinochoroiditis in patients having recently undergone cardiac transplantation. METHODS: Review of medical records for 4 patients presenting retinochoroiditis and evidence of T. gondii infection. RESULTS: Patient ranged in age from 25 to 53 years. Ocular symptoms began between 3 and 6 months after transplantation. All patients were under immunosuppressive therapy. Foci of retinochoroiditis were observed unilaterally in three patients and bilaterally in one. Intraocular inflammation was minimal in all cases. Serologic responses were highly suggestive of T. gondii as the etiology in all cases; other causes (CMV retinitis and syphilis) were actively sought and were not found. All patients underwent classic therapy. The three unilateral cases evolved favorably, but the bilateral case, seen late, showed extensive macular scarring. CONCLUSION: Infectious retinochoroiditis is a potentially blinding complication seen after cardiac transplantation, justifying close clinical and serological surveillance or, in certain cases such as mismatched donors, anti-parasitic prophylaxis.

Transdiaphragmatic hernia 1 year after heart transplantation following implantable LVAD.

Complications after ventricular assist devices placement most frequently consist of bleeding, infection, and thromboembolic events. We describe a late complication after transplantation caused by transdiaphragmatic connection of the device placed in the abdominal position that presented as an acute pulmonary syndrome, misleading initial diagnosis.

Q fever endocarditis: over 14 years of surgical experience in a referral center for rickettsioses.

BACKGROUND AND AIM OF THE STUDY: Q fever endocarditis caused by Coxiella burnetii is the most important etiology of negative blood culture endocarditis. Without specific clinical findings, diagnosis is difficult and prevalence of this life-threatening disease is underestimated. METHODS: Q fever endocarditis was assessed in 19 patients (15 men, four women; age range: 36-79 years) by evaluating clinical and echocardiographic criteria and specific serology. All patients had evidence of pre-existing valvular disease, and 10 had a valvular prosthesis. Diagnosis was assessed in: the presence of unexplained fever (n = 5), heart failure with valvular dysfunction (n = 10), hemolysis (n = 1), glomerulonephritis (n = 1) and stroke (n = 2). A late diagnosis was made in eight patients, either during or after surgery. RESULTS: In all cases, usual blood cultures remained negative, despite specific serology being positive. Transthoracic and transesophageal echocardiography were conclusive in only six cases (four vegetations, two periannular abscesses). Surgery was indicated in 15 patients for heart failure or valvular dysfunction (n = 12), hemolysis (n = 1) and periannular abscess (n = 2). Intraoperative findings were suggestive of endocarditis in seven cases; valvular cultures were positive in 92% of cases. All patients were treated with combined doxycycline/ hydrochloroquine or quinolone, for a mean of 24 months (range: 6-60 months). Mean follow up was 40 months (range: 6-144 months). Two patients died from heart failure, one patient was lost to follow up, and 16 patients had no late relapses. CONCLUSION: Q fever is an underestimated cause of endocardititis, and early diagnosis is the key to good prognosis. The need for systematic serologic examination in case of valvular dysfunction, with or without endocarditis symptoms, is emphasized.