Jaime Agüero

Different expression of adrenoceptors and GRKs in the human myocardium depends on heart failure ethiology and correlates to clinical variables

Downregulation of β(1)- adrenergic receptors (β(1)-ARs) and increased expression/function of G-protein-coupled receptor kinase 2 (GRK2) have been observed in human heart failure, but changes in expression of other ARs and GRKs have not been established. Another unresolved question is the incidence of these compensatory mechanisms depending on heart failure etiology and treatment. To analyze these questions, we quantified the mRNA/protein expressions of six ARs (α(1A), α(1B), α(1D), β(1), β(2), and β(3)) and three GRKs (GRK2, GRK3, and GRK5) in left (LV) and right ventricle (RV) from four donors, 10 patients with ischemic cardiomyopathy (IC), 14 patients with dilated cardiomyopathy (DC), and 10 patients with nonischemic, nondilated cardiopathies (NINDC). We correlated the changes in the expressions of ARs and GRKs with clinical variables such as left ventricular ejection fraction (LVEF) and left ventricular end-systolic and left ventricular end-diastolic diameter (LVESD and LVEDD, respectively). The main findings were 1) the expression of the α(1A)-AR in the LV positively correlates with LVEF; 2) the expression of GRK3 and GRK5 inversely correlates with LVESD and LVEDD, supporting previous observations about a protective role for both kinases in failing hearts; and 3) β(1)-AR expression is downregulated in the LV and RV of IC, in the LV of DC, and in the RV of NINDC. This difference, better than an increased expression of GRK2 (not observed in IC), determines the lower LVEF in IC and DC vs. NINDC.

Myocardial G protein receptor-coupled kinase expression correlates with functional parameters and clinical severity in advanced heart failure.

BACKGROUND In heart failure (HF), sympathetic hyperactivation induces deleterious effects in myocardial β-adrenergic signaling, with receptor down-regulation and desensitization mediated by G protein receptor-coupled kinases (GRKs). We hypothesised that changes in GRK isoforms may be associated with clinical status in advanced HF, using the Interagency Registry for Mechanically Assisted Circulatory Support (INTERMACS) scale. METHODS We included 31 patients with advanced HF undergoing transplantation. According to INTERMACS profiles, mRNA and protein levels of GRK isoforms in left ventricular (LV) myocardium were analyzed and compared with nonfailing LV samples. RESULTS In failing LV myocardium, GRK2 and GRK5 (but not GRK3) protein was up-regulated compared with control samples. Among HF patients, an increase in GRK2 and GRK5 mRNA and protein abundance was observed in β-agonist-treated patients (vs β-blockers: P < .05) and in higher-risk INTERMACS status (profiles 2 and 3 vs 4 and 5: P < .05). A significant negative correlation of GRK2 expression with LV stroke volume supported these findings. CONCLUSIONS Increased GRK2 correlates with clinical severity using the INTERMACS scale and LV stroke volume, supporting it as a potential target in advanced HF. These changes are paralleled by GRK5 expression in the failing myocardium, suggesting a relevant role in human HF.

Progression of renal dysfunction in cardiac transplantation after the introduction of everolimus in the immunosuppressive regime.

The aim of this study was to analyze, in heart transplant patients, if renal function improvement after cyclosporine replacement by everolimus persists at the middle term and its predictors. We studied prospectively 56 patients in whom conversion was consecutively made. Forty-five patients completed the follow-up period. Significant improvement was observed at 6 and 12 months in plasma creatinine levels (1.92±0.7 vs. 1.67±0.6 and 1.69±0.6 mg/dL; P=0.047) and glomerular filtration rate (43.9±17 vs. 52.5±23 and 51.3±22.3 mL/min; P=0.004). Glomerular filtration rate increased in 32 patients (71%). Baseline characteristics comparison showed a lower percentage of patients with smoking history and new onset diabetes in responders group, but only previous smoking was shown as independent factor (Exp B: 0.083; 95% confidence interval: 0.010–0.793; P=0.024). No differences regarding age, gender, body mass index, disease leading to transplantation, time between transplantation and replacement, cardiovascular risk factors, lipid levels, and hematologic parameters were found.

What is the best biomarker for diagnosis of rejection in heart transplantation

Abstract: Introduction:  Acute cellular rejection is a major cause of graft loss in heart transplantation (HT). Endomyocardial biopsy remains the gold standard for its diagnosis, but it is an invasive procedure not without risk. A proinflammatory state exists in rejection that could be assessed by determining plasma levels of inflammatory biomarkers.

Follow-up Study on the Utility of von Willebrand Factor Levels in the Diagnosis of Cardiac Allograft Vasculopathy

BACKGROUND Cardiac allograft vasculopathy (CAV) is the major cause of late death in patients undergoing heart transplantation (HT). The most validated method for its diagnosis is intravascular ultrasound (IVUS), and there are no sufficiently reliable non-invasive methods. von Willebrand factor (vWF) is a marker of endothelial dysfunction/activity that is rarely studied in the context of CAV. The purpose of this study was to determine whether patients with higher levels of vWF in the first year post-transplant will develop a greater degree of CAV. METHODS A prospective study of 113 consecutive cardiac transplant recipients was initiated in January 2002. vWF determinations were performed at 1, 2, 4, 6, 9 and 12 months post-transplant, at the same time as biopsies. Coronary arteriography and IVUS were performed on the first and last follow-up visits. Heart-lung transplants, retransplants and pediatric transplants were excluded from the study. Patients who died in the first month and those who refused consent were also excluded. The final analysis included 72 patients and 405 vWF determinations. CAV was defined as an intimal thickening of >or=0.5 mm on follow-up versus baseline IVUS. Patients with CAV (n = 41) and without CAV (n = 31) after 1 year of follow-up were compared. RESULTS Patients who developed CAV had a higher prevalence of prior dyslipidemia, ischemic heart disease as the cause of HT, and rate of rejection, as well as higher vWF levels (321 +/- 122 vs 243 +/- 100%, p < 0.05). The receiver-operator characteristic (ROC) curve showed that vWF values of 150% provided a sensitivity of 91%, and values of 400% a specificity of 91% (p < 0.0001). The variables associated with CAV in the multivariate analysis were prior dyslipidemia, rejections and vWF, both linearly and by groups. vWF levels of 300% to 400% increased the probability of developing CAV by 390%, and levels >400% by 500%, versus levels <200%. CONCLUSIONS vWF levels determined in the first year post-transplant help to distinguish a subgroup of patients with a higher incidence of CAV.

Influence of metabolic syndrome on development of cardiac allograft vasculopathy in the transplanted heart.

Background. Cardiac allograft vasculopathy (CAV) is the main cause of graft failure and death 1 year after heart transplantation (HTx). Metabolic syndrome (MS) increases the risk of cardiovascular events by endothelial dysfunction. The purpose of this study was to determine if patients with MS developed a higher risk of CAV 1 year after HTx. Methods. Since January 2004 until April 2009, 155 HTx patients were recruited. Cardiopulmonary transplants were excluded (12 patients), as well as retransplants (5 patients), pediatric transplants (11 patients), patients who refused to participate (3 patients), and those who died during the first year (35 patients). The final analysis included 89 patients. MS was diagnosed when Adult Treatment Panel III modified and revised criteria were met, before HTx or after the first 3 months. CAV was diagnosed through intravascular ultrasound performed 1 month and 1 year after HTx. CAV was defined as an intimal thickening ≥0.5 mm in the follow-up with regard to the one of the basal study. Results. Development of CAV was significantly higher in patients with MS (59% vs. 19%, P<0.0001). Patients with more criteria of MS had a higher development of CAV: no criteria (4%); one criterion (4%); two criteria (47%); three criteria (62%); four criteria (75%); and five criteria (100%). Variables related to CAV in a multivariate analysis were MS (odds ratio [OR] 7.97; 95% confidence interval [CI]: 2.77–22.96; P<0.001), donors age (OR 1.07; 95% CI: 1.01–1.13; P=0.019), low high-density lipoprotein cholesterol (OR 0.26; 95% CI: 0.09–0.71; P=0.009), and hypertriglyceridemia (OR 4.08; 95% CI: 1.45–11.50; P=0.008). Conclusions. Presence of MS distinguishes a subgroup of patients with high risk of developing CAV. Narrow and personalized monitoring of these patients would be recommendable.

A prospective randomized study comparing cyclosporine versus tacrolimus combined with daclizumab, mycophenolate mofetil, and steroids in heart transplantation.

Sánchez‐Lázaro IJ, Almenar L, Martínez‐Dolz L, Buendía‐Fuentes F, Agüero J, Navarro‐Manchón J, Vicente J‐L, Salvador A. A prospective randomized study comparing cyclosporine versus tacrolimus combined with daclizumab, mycophenolate mofetil and steroids in heart transplantation.
Clin Transplant 2011: 25: 606–613.

Can We Accept Donors Who Have Suffered a Resuscitated Cardiac Arrest

INTRODUCTION AND AIMS The shortage of donor organs has prompted increased acceptance of hearts from donors with more comorbidities. With increasing frequency, hearts are being offered from patients who have undergone a resuscitated cardiac arrest (RCA). Our aim was to compare the rate of complications in the postoperative and follow-up periods, depending on whether the transplanted organ came from a donor who had undergone an RCA. MATERIALS AND METHODS We included all 604 heart transplantations (HTs) performed in our center from 1987 to 2009, including 25 recipients who received an organ from a donor who had undergone RCA. We considered RCA to be an in-hospital cardiac arrest that was resuscitated from the onset, with a duration of <30 minutes, and with total recovery of cardiac and hemodynamic function. We analyzed ischemia time, incidence of acute graft failure (AGF), intubation period, recovery room stay, and long-term survival. The statistical methods were Student t and chi-square tests. RESULTS There were no differences in baseline characteristics, except that patients in the RCA group were younger (47±13 vs 51±11 years; P=.50). There were also no differences between the RCA group and the other patients in ischemia time (151±50 vs 154±53 minutes; P=.826), incidence of AGF (33% vs 24.7%; P=.311), hours of intubation (76±204 vs 72±249; P=.926), days of recovery room stay (6±7 vs 8±6; P=.453), or survival after HT (53±54 vs 53±52 months; P=.982). CONCLUSIONS Patients receiving a heart from a patient with an in-hospital RCA and subsequent hemodynamic stability have a similar outcomes to other HT patients.

Predictor factors for the development of arterial hypertension following heart transplantation

Abstract:  Introduction:  Up to 95% of the patients with heart transplantation (HT) suffer from arterial hypertension (AHT). The development of de novo AHT after HT has not been greatly studied.

Correlation between beta-adrenoceptors and G-protein-coupled receptor kinases in pretransplantation heart failure.

INTRODUCTION Prolonged catecholamine overstimulation of the myocardium in chronic heart failure causes a reduction in the number and functionality of beta1-adrenoceptors (beta1-AR) of the heart. Desensitization of beta1-AR is mediated by their phosphorylation by a group of cytosolic kinases (G-protein-coupled receptor kinases GRK). In advanced heart failure, an increase in GRK levels associated with the severity of the disease has been observed. OBJECTIVE The objective of this study was to analyze messenger RNA (mRNA) levels of beta1-AR in the myocardium of patients who underwent transplantation for advanced heart failure and their correlation with expression of the major cardiac isoenzymes of GRK. MATERIALS AND METHODS Myocardial tissue samples were obtained from the left ventricles of 14 explanted hearts of patients who underwent transplantation for dilated (n = 7) and ischemic (n = 7) cardiomyopathy. RT-PCR techniques were used to analyze mRNA levels of beta1-AR and the isoenzymes GRK2, GRK3, and GRK5. RESULTS We observed a significant correlation between beta1-AR and the 3 subtypes of GRK (R(2) = 0.668, 0.71, and 0.318, respectively). CONCLUSIONS In patients with advanced heart failure pretransplantation, we observed a significant correlation between beta1-AR and GRK2 and GRK3 levels. GRK5, the subtype predominantly expressed in the myocardium, showed a lesser correlation with beta1-AR levels.