Olivier C. Manintveld

Intravenous adenosine protects the myocardium primarily by activation of a neurogenic pathway.

1 Endogenous adenosine is a trigger for ischemic myocardial preconditioning (IPC). Although intravascular administration of adenosine has been used to further unravel the mechanism of protection by IPC, it is questionable whether adenosine and IPC employ the same signaling pathways to exert cardioprotection. 2 We therefore investigated whether the active metabolic barrier of the endothelium prevents an increase in myocardial interstitial adenosine concentrations by intravenous adenosine, using microdialysis, and also the role of NO and activation of a neurogenic pathway in the cardioprotection by adenosine. 3 In pentobarbital‐anesthetized rats, area at risk and infarct size (IS) were determined 120 min after a 60‐min coronary artery occlusion (CAO), using trypan blue and nitro‐blue‐tetrazolium staining, respectively. 4 IPC with a single 15‐min CAO and a 15‐min adenosine infusion (ADO, 200 μg min−1 i.v.) limited IS to the same extent (IS=41±6% and IS=40±4%, respectively) compared to control rats (IS=63±3%, both P<0.05). However, IPC increased myocardial interstitial adenosine levels seven‐fold from 4.3±0.7 to 27.1±10.0 μM (P<0.05), while ADO had no effect on interstitial adenosine (4.1±1.2 μM), or any of the other purines. 5 The NO synthase inhibitor Nω‐nitro‐L‐arginine (LNNA), which did not affect IS (IS=62±3%), attenuated the protection by ADO (IS=56±3%; P<0.05 vs ADO, P=NS vs LNNA). The ganglion blocker hexamethonium, which had also no effect on IS (IS=66±3%), blunted the protection by ADO (IS=55±4%; P<0.05 vs ADO and vs hexamethonium). 6 These observations demonstrate that cardioprotection by ADO is dependent on NO, and is primarily mediated by activation of a neurogenic pathway.

Ischemic postconditioning in human DCD kidney transplantation is feasible and appears safe

Ischemic postconditioning may improve outcome after kidney transplantation. We performed a pilot study to assess feasibility and safety of ischemic postconditioning in human donation‐after‐circulatory‐death kidney transplantation. Twenty patients were included. Primary outcome was rate of serious adverse events. Secondary outcomes were incidence of DGF and renal function at 3 months. Data were compared to a historical control group (n = 40). Furthermore, we performed a paired kidney analysis using the contralateral kidney (n = 11). Donor age and serum creatinine were higher in the experimental group compared with historical control: 57.7 (20–71) vs. 51.5 (24–74) years (P = 0.01) and 79 (40–156) μmol/l vs. 64 (25–115) μmol/l (P = 0.047). Postconditioning could be applied all times. One complication, a venous tear, occurred related to postconditioning. The experimental group experienced more DGF (85% vs. 63%) (P = 0.07). Serum creatinine at month 3 was 166 (109–331) μmol/l vs. 159 (81–279) μmol/l (P = 0.71). Paired kidney analysis showed no significant differences in DGF (72.2% vs. 54.5%, P = 0.66) and serum creatinine 199 (90–473) μmol/l vs. 184 (117–368) μmol/l (P = 0.76). This is the first report of applying IPoC in human kidney transplantation. Although IPoC is feasible and appears to be safe, no benefit in terms of reduced DGF or better renal function was observed (Dutch trial registry number NTR 3117).

Interaction Between Pre- and Postconditioning in the In Vivo Rat Heart:

Patients with an impending myocardial infarction may be preconditioned by pre-infarct angina. Hence, it is important to establish whether ischemic postconditioning is still effective in preconditioned hearts. We therefore studied in anesthetized rats the effect of postconditioning after coronary artery occlusions (CAO) of 60 min in control hearts, hearts preconditioned by a single 15-min CAO (1IPC15) or a triple 3-min CAO (3IPC3). Furthermore, we studied the effect of postconditioning in hearts that had been pharmacologically preconditioned with intravenous adenosine and in hearts that had become tolerant to 1IPC15. Postconditioning limited infarct size in control hearts, but did not afford additional protection in preconditioned hearts, irrespective of the IPC stimulus. NO synthase inhibition abolished the cardioprotection by postconditioning, both IPC stimuli, and the combination of postconditioning and either IPC stimulus. Postconditioning also failed to afford cardioprotection in hearts protected by adenosine, and in hearts that had become tolerant to cardioprotection by 1IPC15. In accordance with previous observations, postconditioning paradoxically increased infarct size following a 30-min CAO. This detrimental effect was prevented by either IPC stimulus, in a NO synthase–dependent manner. In conclusion, postconditioning does not afford additional protection in preconditioned hearts, irrespective of the preconditioning stimulus and the presence of tolerance to preconditioning. Lack of additional protection may be related to the observation that postconditioning and preconditioning are both mediated via NO synthase. In contrast, the increase in infarct size by postconditioning following a 30-min CAO is abolished by either IPC stimulus. These findings indicate that the interaction between preconditioning and postconditioning is highly dependent on the duration of index ischemia, but independent of the preconditioning stimulus.

Improved long-term survival in Dutch heart transplant patients despite increasing donor age: the Rotterdam experience.

Over the past decades donor and recipient characteristics and medical management of heart transplantation (HT) patients have changed markedly. We studied the impact of these changes on long‐term clinical outcome. Data of all consecutive HT recipients in our center have been collected prospectively. Cohort A (n = 353) was defined as the adult pts transplanted between 1984 and 1999 and was compared with cohort B (n = 227) transplanted between 2000 and 2013. Compared with cohort A, recipients in cohort B had older donors (mean age 29 vs. 43 years, donors aged >50 year: 2% vs. 33%, respectively). Survival at 1 and 10 years in cohort A vs. B was 89% vs. 86% and 53% vs. 68%, respectively (P = 0.02). Cohort B pts were treated more often with tacrolimus‐based immunosuppression (77% vs. 22%; P = <0.0001) and early statins post‐HT (88% vs. 18%; P = 0.0001), while renal function was better conserved at 5 and 10 years (P = 0.001 and 0.02). Multivariate analysis showed significant reduction in 10‐year mortality with tacrolimus‐based immunosuppression (HR 0.27 and 95% CI 0.17–0.42), hypertension post‐HT (HR 0.5, 95% CI 0.36–0.72), and revascularization (HR 0.28, 95% CI 0.15–0.52). In spite of the use of much older donors, the long‐term outcome after HT has improved considerably in the last decade, probably due to the introduction of newer treatment modalities.

Acute Kidney Injury as a Complication of Cardiac Transplantation: Incidence, Risk Factors, and Impact on 1-year Mortality and Renal Function.

Background Although chronic deterioration in renal function is frequently seen after cardiac transplantation, which is partly explained by the use of calcineurin inhibitors, data on the consequences of acute kidney injury (AKI) after cardiac transplantation are scarce. In the current study, the incidence of AKI and its impact on mortality and renal function was evaluated. Methods Five hundred thirty-one cardiac transplant recipients (age ≥18 years) were evaluated for the postoperative incidence of AKI defined by the Kidney Disease Improving Global Outcome criteria. Secondary outcomes were renal function and mortality during the first postoperative year. Results Overall, 405 (76%) recipients met the AKI criteria of which 211 (40%) had AKI stage I, 119 (22%) stage II, 75 (14%) stage III, and 25 patients (5%) required renal replacement therapy (RRT). One-year mortality rates in patients without AKI, stages I, II, and III were 4.8%, 7.6%, 11.8%, and 14.7%, respectively (log-rank test for trend, P = 0.008). In patients that required RRT 1-year mortality was 28.2% (log-rank test P = 0.001). In multivariable analysis only AKI requiring RRT was an independent predictor of 1-year mortality (hazard ratio, 2.75; P = 0.03). Improvement in renal function, compared with baseline values, occurred in 27% of recipients 1 month after transplantation. This was less likely to occur after previous AKI (P ⩽ 0.04). The AKI stages I to III were independently proportionally associated with a worse renal function 1 year after transplantation (P ⩽ 0.01). Conclusions Acute kidney injury is highly frequent after cardiac transplantation, and the stage of AKI is associated with increased mortality and impaired renal function in the first postoperative year.

Predictors of changes in health status between and within patients 12 months post left ventricular assist device implantation

Improving patient‐reported outcomes (e.g. health status) has become an important goal in left ventricular assist device (LVAD) therapy, in addition to reducing mortality and morbidity. We examined predictors of changes in health status scores between and within patients 12 months post LVAD implantation.

Repeated measurements of NT-pro-B-type natriuretic peptide, troponin T or C-reactive protein do not predict future allograft rejection in heart transplant recipients.

Background Studies on the prognostic value of serial biomarker assays for future occurrence of allograft rejection (AR) are scarce. We examined whether repeated measurements of NT-pro-B-type natriuretic peptide (NT-proBNP), troponin T (TropT) and C-reactive protein (CRP) predict AR. Methods From 2005 to 2010, 77 consecutive heart transplantation (HTx) recipients were included. The NT-proBNP, TropT, and CRP were measured at 16 ± 4 (mean ± standard deviation) consecutive routine endomyocardial biopsy surveillance visits during the first year of follow-up. Allograft rejection was defined as International Society for Heart and Lung Transplantation (ISHLT) grade 2R or higher at endomyocardial biopsy. Joint modeling was used to assess the association between repeated biomarker measurements and occurrence of future AR. Joint modeling accounts for dependence among repeated observations in individual patients. Results The mean age of the patients at HTx was 49 ± 9.2 years, and 68% were men. During the first year of follow-up, 1,136 biopsies and concurrent blood samples were obtained, and 56 patients (73%) experienced at least one episode of AR. All biomarkers were elevated directly after HTx and achieved steady-state after ∼12 weeks, both in patients with or without AR. No associations were present between the repeated measurements of NT-proBNP, TropT, or CRP and AR both early (weeks 0–12) and late (weeks 13–52) in the course after HTx (hazard ratios for weeks 13–52: 0.96 (95% confidence interval, 0.55–1.68), 0.67 (0.27–1.69), and 1.44 (0.90–2.30), respectively, per ln[unit]). Combining the three biomarkers in one model also rendered null results. Conclusion The temporal evolution of NT-proBNP, TropT, and CRP before AR did not predict occurrence of acute AR both in the early and late course of the first year after HTx.

Derivation and Validation of a Novel Right-Sided Heart Failure Model After Implantation of Continuous Flow Left Ventricular Assist Devices:The EUROMACS (European Registry for Patients with Mechanical Circulatory Support) Right-Sided Heart Failure Risk Score

Background: The aim of the study was to derive and validate a novel risk score for early right-sided heart failure (RHF) after left ventricular assist device implantation. Methods: The EUROMACS (European Registry for Patients with Mechanical Circulatory Support) was used to identify adult patients undergoing continuous-flow left ventricular assist device implantation with mainstream devices. Eligible patients (n=2988) were randomly divided into derivation (n=2000) and validation (n=988) cohorts. The primary outcome was early (<30 days) severe postoperative RHF, defined as receiving short- or long-term right-sided circulatory support, continuous inotropic support for ≥14 days, or nitric oxide ventilation for ≥48 hours. The secondary outcome was all-cause mortality and length of stay in the intensive care unit. Covariates found to be associated with RHF (exploratory univariate P<0.10) were entered into a multivariable logistic regression model. A risk score was then generated using the relative magnitude of the exponential regression model coefficients of independent predictors at the last step after checking for collinearity, likelihood ratio test, c index, and clinical weight at each step. Results: A 9.5-point risk score incorporating 5 variables (Interagency Registry for Mechanically Assisted Circulatory Support class, use of multiple inotropes, severe right ventricular dysfunction on echocardiography, ratio of right atrial/pulmonary capillary wedge pressure, hemoglobin) was created. The mean scores in the derivation and validation cohorts were 2.7±1.9 and 2.6±2.0, respectively (P=0.32). RHF in the derivation cohort occurred in 433 patients (21.7%) after left ventricular assist device implantation and was associated with a lower 1-year (53% versus 71%; P<0.001) and 2-year (45% versus 58%; P<0.001) survival compared with patients without RHF. RHF risk ranged from 11% (low risk score 0–2) to 43.1% (high risk score >4; P<0.0001). Median intensive care unit stay was 7 days (interquartile range, 4–15 days) versus 24 days (interquartile range, 14–38 days) in patients without versus with RHF, respectively (P<0.001). The c index of the composite score was 0.70 in the derivation and 0.67 in the validation cohort. The EUROMACS-RHF risk score outperformed (P<0.0001) previously published scores and known individual echocardiographic and hemodynamic markers of RHF. Conclusions: This novel EUROMACS-RHF risk score outperformed currently known risk scores and clinical predictors of early postoperative RHF. This novel score may be useful for tailored risk-based clinical assessment and management of patients with advanced HF evaluated for ventricular assist device therapy.

Computed tomography coronary imaging as a gatekeeper for invasive coronary angiography in patients with newly diagnosed heart failure of unknown aetiology.

To evaluate the accuracy of cardiac computed tomography (CT) in distinguishing CAD and non‐CAD heart failure (HF) and its effectiveness as a gatekeeper for invasive coronary angiography (ICA).

Neutrophil Gelatinase-Associated Lipocalin, but Not Kidney Injury Marker 1, Correlates with Duration of Delayed Graft Function.

Background: No specific early biomarker is available to measure kidney injury after kidney transplantation (KT). Both neutrophil gelatinase-associated lipocalin (NGAL) and kidney injury marker 1 (KIM-1) increase after oxidative injury. Their potential as early biomarkers was evaluated in this one-arm pilot study. Materials and Methods: Twenty consecutive KT patients receiving a kidney from a donation after circulatory death donor were included. Graft perfusate was collected, as well as serum samples before transplantation, at the end of surgery, and 1, 4, and 7 days after transplantation. NGAL and KIM-1 were measured using ELISA. Kidney function and delayed graft function (DGF) were monitored. Results: In this cohort, 85% of the KT patients developed DGF. Perfusate NGAL correlated with donor age (r2 = 0.094, p = 0.01) and serum creatinine (r2 = 0.243, p = 0.05). A cardiac cause of death was associated with higher NGAL in the perfusate (p = 0.03). Serum NGAL at day 1 was significantly higher in patients with DGF (730 ng/ml, range 490-1,655, vs. 417 ng/ml, range 232-481; p = 0.01). Serum NGAL levels at day 1, 4, and 7 correlated with the duration of DGF. KIM-1 was not detectable in the perfusate or in the serum until postoperative day 4 in 80% of patients. Conclusions: NGAL in the perfusate correlates with known donor risk factors for DGF. For the first time, we describe that serum NGAL at day 1 can discriminate between DGF and immediate graft function. Also, serum NGAL levels at day 1, 4, and 7 correlate with the duration of DGF. No association with KIM-1 was found. These data suggest that NGAL may be used as an early biomarker to detect DGF and warrants further study.