CA125 como nuevo biomarcador en pacientes con circulación de Fontan / CA125: a new biomarker in patients with Fontan circulation

Introducción y objetivos Los pacientes con circulación de Fontan (CF) presentan una gran incidencia de complicaciones y ningún biomarcador estratifica el riesgo. El objetivo es analizar la asociación de biomarcadores con un perfil clínico de disfunción de la CF, incluyendo por primera vez el antígeno carbohidrato 125 (CA125), y proponer una estimación del riesgo basada en la combinación de biomarcadores. Métodos Estudio transversal de adultos con CF. Se consideró perfil clínico desfavorable el combinado de insuficiencia cardiaca, arritmias auriculares, fístulas venovenosas, enteropatía pierdeproteínas o bronquitis plástica. Se analizaron variables clínicas y analíticas, incluidos CA125, NT-proBNP, función renal y hepática y amplitud de distribución eritrocitaria (ADE). Se realizó un estudio univariado y multivariado de la relación de dichas complicaciones clínicas y curvas ROC para obtener puntos de corte. Resultados Se incluyó a 56 pacientes (media de edad, 27,4±7,8 años). El 34% tenía un perfil clínico desfavorable, con valores de CA125 significativamente mayores (30,1 frente a 12,6 UI/ml; p=0,001). LnCA125 (OR=5,1; IC95%, 1,2-22), ADE (OR=1,8; IC95%, 1,1-3.1) y FIB4 (OR=38; IC95%, 1,7-855) se asociaron con un perfil de disfunción clínica. Los puntos de corte fueron CA125 ≥ 20 U/ml, FIB4 ≥ 0,75 y ADE ≥ 14,5%, y la probabilidad de un perfil clínico desfavorable fue del 81% con 2 o más biomarcadores elevados. Conclusiones El aumento de CA125 se asocia con mayor prevalencia de complicaciones en pacientes con CF. Los valores de CA125 ≥ 20 U/ml, FIB4 ≥ 0,75 y ADE ≥ 14,5% identifican con alta probabilidad fracaso clínico de la CF. (AU)

Introduction and objectives Patients with Fontan circulation (FC) have a high incidence of clinical complications. However, no biomarker is able to accurately stratify risk. The aim of this study was to analyze the relationship between biomarkers and clinical complications, including carbohydrate antigen 125 (CA125) for the first time, and to propose a risk estimation based on a combination of biomarkers. Methods Cross-sectional study of patients with FC. The clinical endpoint was the combination of heart failure, atrial arrhythmias, veno-venous fistulae, protein-losing enteropathy, or plastic bronchitis. Demographic, clinical, and laboratory variables were analyzed, including CA125, NT-proBNP, renal and liver function, and red cell distribution width (RDW). We performed univariate and multivariate analyses of the relationship between these variables and the composite endpoint. Cutoff values were calculated by ROC curves. Results We included 56 patients (27.4±7.8 years). A total of 34% showed the composite endpoint, with significantly higher CA125 levels (30.1 IU/mL vs 12.6 IU/mL; P=.001). In the multivariate model, the biomarkers related to the endpoint were LnCA125 (OR, 5.1; 95%CI, 1.2-22), RDW (OR, 1.8; 95%CI, 1.1-3.1), and FIB4 (OR, 38, 95%CI, 1.7-855). The cutoff points were CA125 ≥ 20 U/mL, FIB4 ≥ 0.75, and RDW ≥ 14.5%, and the probability of the occurrence of the endpoint was 81% if ≥ 2 biomarkers were elevated. Conclusions CA125 elevation is associated with a higher prevalence of complications in patients with Fontan-type circulation. CA125 levels ≥ 20U/mL, FIB4 ≥ 0.75 and RDW ≥ 14.5% identify with a high probability the clinical failure of FC. (AU)

CA125: a new biomarker in patients with Fontan circulation.

INTRODUCTION AND OBJECTIVES: Patients with Fontan circulation (FC) have a high incidence of clinical complications. However, no biomarker is able to accurately stratify risk. The aim of this study was to analyze the relationship between biomarkers and clinical complications, including carbohydrate antigen 125 (CA125) for the first time, and to propose a risk estimation based on a combination of biomarkers. METHODS: Cross-sectional study of patients with FC. The clinical endpoint was the combination of heart failure, atrial arrhythmias, veno-venous fistulae, protein-losing enteropathy, or plastic bronchitis. Demographic, clinical, and laboratory variables were analyzed, including CA125, NT-proBNP, renal and liver function, and red cell distribution width (RDW). We performed univariate and multivariate analyses of the relationship between these variables and the composite endpoint. Cutoff values were calculated by ROC curves. RESULTS: We included 56 patients (27.4±7.8 years). A total of 34% showed the composite endpoint, with significantly higher CA125 levels (30.1 IU/mL vs 12.6 IU/mL; P=.001). In the multivariate model, the biomarkers related to the endpoint were LnCA125 (OR, 5.1; 95%CI, 1.2-22), RDW (OR, 1.8; 95%CI, 1.1-3.1), and FIB4 (OR, 38, 95%CI, 1.7-855). The cutoff points were CA125 ≥ 20 U/mL, FIB4 ≥ 0.75, and RDW ≥ 14.5%, and the probability of the occurrence of the endpoint was 81% if ≥ 2 biomarkers were elevated. CONCLUSIONS: CA125 elevation is associated with a higher prevalence of complications in patients with Fontan-type circulation. CA125 levels ≥ 20U/mL, FIB4 ≥ 0.75 and RDW ≥ 14.5% identify with a high probability the clinical failure of FC.

ß2-Adrenoceptors and GRK2 as Potential Biomarkers in Patients With Chronic Pulmonary Regurgitation.

Pulmonary regurgitation (PR) is a frequent complication after repair of congenital heart disease. Three different GRK isoforms (GRK2, GRK5, and GRK3) and two ß-adrenoceptors (ß1-AR and ß2-AR) are present in peripheral blood mononuclear cells (PBMC) and their expression changes as a consequence of the hemodynamic and neurohumoral alterations that occur in some cardiovascular diseases. Therefore, they could be useful as biomarkers in PR. A prospective study was conducted to describe the expression (TaqMan Gene Expression Assays) of ß-ARs and GRKs in PBMC isolated (Ficoll® gradient) from patients with severe PR before and after pulmonary valve replacement and establish if this expression correlates to clinical status. 23 patients with severe PR were included and compared with 22 healthy volunteers (controls). PR patients before the PVR had a significantly lower expression of ß2-AR (513.8 ± 261.2 mRNA copies) vs. controls (812.5 ± 497.2 mRNA copies), so as GRK2 expression (503.4 ± 364.9 copies vs. 858.1 ± 380.3 mRNA copies). The expression of ß2-AR and GRK2 significantly decreases in symptomatic and asymptomatic patients, as well as in patients under treatment with beta-blockers and non-treated patients. The expression of ß2-AR and GRK2 in PR patients recovers the normal values after pulmonary valve replacement (754,8 ± 77,1 and 897,8 ± 87,4 copies, respectively). Therefore, changes in the expression of ß2-AR and GRK2 in PBMC of PR patients, could be considered as potential biomarkers to determine clinical decisions.

Activation of α1A -adrenoceptors desensitizes the rat aorta response to phenylephrine through a neuronal NOS pathway, a mechanism lost with ageing.

BACKGROUND AND PURPOSE: A NO-mediated desensitization of vasoconstrictor responses evoked by stimulation of α1 -adrenoceptors has been reported in different vessels. We investigated the involvement of each α1 -adrenoceptor subtype and constitutive NOS isoforms and the influence of ageing and hypertension on this process. EXPERIMENTAL APPROACH: Wistar and spontaneously hypertensive rats (SHR), 16, 32, 52 and 72 weeks-old, were used to evaluate the desensitization process. Expression of α1 -adrenoceptor subtypes, endothelial NOS (eNOS) and neuronal NOS (nNOS) were determined in rat aorta and left ventricle (LV). Expression levels were also evaluated in LV of a group of heart failure patients with a wide age range. KEY RESULTS: Repeated application of phenylephrine decreased subsequent α1 -adrenoceptor-mediated vasoconstriction by increasing nNOS protein expression in aorta, but not in tail or mesenteric resistance arteries, where mRNA levels of nNOS were undetectable. This desensitization process disappeared in the absence of endothelium or in the presence of L-NAME (100 µM), nNOS inhibitors, SMTC (1 µM) and TRIM (100 µM), and 5-methylurapidil (100 nM, α1A -antagonist), but not BMY7378 (10 nM, α1D -antagonist). The α1A /nNOS-mediated desensitization was absent in aged SHR and Wistar animals, where the expression of α1A -adrenoceptors was reduced in aorta and LV. In human LV, a negative correlation was found between age and α1A -adrenoceptor expression. CONCLUSIONS AND IMPLICATIONS: The α1A -adrenoceptor subtype, through endothelial nNOS-derived NO, may act as a physiological 'brake' against the detrimental effects of excessive α1 -adrenoceptor-mediated vasoconstriction. Reduced α1A -adrenoceptor- and nNOS-mediated desensitization in aged patients could be involved in the age-dependent elevation of adrenergic activity.

ß2- and ß1-Adrenoceptor Expression Exhibits a Common Regulatory Pattern With GRK2 and GRK5 in Human and Animal Models of Cardiovascular Diseases.

To explore if genic expression of ß(1)- or ß(2)-adrenoceptors (ARs) exhibits a common regulatory pattern with G protein-coupled receptor kinase (GRK) 2, GRK3, or GRK5 expression, we determined messenger RNA levels for these genes in different tissues from human and animal models of cardiovascular disease. We measured genic expression by qRT polymerase chain reaction in the left and right ventricles or peripheral blood mononuclear cells from healthy (n = 21), hypertensive (n = 20), heart failure (n = 24), and heart transplanted patients (n = 17) or in left ventricle, peripheral blood mononuclear cells, and kidney from spontaneously hypertensive rats or L-N-methyl-arginine-induced hypertensive rats and their respective controls (n = 4-5). In diseased versus healthy subjects and rats, parallel changes in messenger RNA levels of GRK2 and ß(2)-AR or GRK5 and ß(1)-AR were observed in each territory. Therefore, without excluding other regulatory mechanisms, the parallelism observed suggests a common regulatory pattern for the ß(1)-AR/GRK5 and ß(2)-AR/GRK2 genes, which is independent of cellular type or pathology. This highlights the need to focus not only on GRKs but also on ß(1)- or ß(2)-AR changes to completely understand the involvement of ß-AR/GRK pathways in cardiovascular diseases.

Myocardial and lymphocytic expression of eNOS and nNOS before and after heart transplantation: relationship to clinical status.

AIMS: The present study investigates the expression and clinical relevance of the constitutive NO synthases in heart and peripheral blood mononuclear cells (PBMCs) obtained from heart failure patients. MAIN METHODS: mRNA and protein levels (qRT-PCR and immunoblot) of eNOS and nNOS were determined in: i) Left ventricle (LV, n=4) and PBMCs (n=10) from healthy donors; ii) LV, right ventricle (RV) and PBMCs of heart failure (HF) patients (n=32); and iii) biopsies and PBMCs of the HF patients after cardiac transplant (n=15). KEY FINDINGS: Expression of constitutive NOS isoforms in heart exhibits wide variability in HF patients, but this variability was not related to aetiology, disease severity, concomitant pathologies or drug regimes. A significantly increased eNOS expression was found in LV from HF patients without vs. with pulmonary hypertension. Overall, higher eNOS expression in this chamber was associated with lower pulmonary arterial pressure. Furthermore, a higher eNOS expression in HF is associated with smaller LV diameter, whereas, a higher post-transplant eNOS expression is related to greater cardiac distensibility. In the RV, nNOS increased after transplant. The positive correlation found between the nNOS expression in the LV of HF patients and the cardiac index suggests a role for this isoform in facilitating cardiac work. A decreased expression of eNOS was observed in PBMCs from HF patients vs. healthy donors, which recovers after transplant. SIGNIFICANCE: A selective up-regulation of the cardiac expression of each NOS isoform in the failing heart, which is not mirrored by PBMCs, is related to an improved health status.

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

Downregulation of ß(1)- adrenergic receptors (ß(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), ß(1), ß(2), and ß(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) ß(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.

Assessing left ventricular systolic dysfunction after myocardial infarction: are ejection fraction and dP/dt(max) complementary or redundant?

Among the various cardiac contractility parameters, left ventricular (LV) ejection fraction (EF) and maximum dP/dt (dP/dt(max)) are the simplest and most used. However, these parameters are often reported together, and it is not clear if they are complementary or redundant. We sought to compare the discriminative value of EF and dP/dt(max) in assessing systolic dysfunction after myocardial infarction (MI) in swine. A total of 220 measurements were obtained. All measurements included LV volumes and EF analysis by left ventriculography, invasive ventricular pressure tracings, and echocardiography. Baseline measurements were performed in 132 pigs, and 88 measurements were obtained at different time points after MI creation. Receiver operator characteristic (ROC) curves to distinguish the presence or absence of an MI revealed a good predictive value for EF [area under the curve (AUC): 0.998] but not by dP/dt(max) (AUC: 0.69, P < 0.001 vs. EF). Dividing dP/dt(max) by LV end-diastolic pressure and heart rate (HR) significantly increased the AUC to 0.87 (P < 0.001 vs. dP/dt(max) and P < 0.001 vs. EF). In naïve pigs, the coefficient of variation of dP/dt(max) was twice than that of EF (22.5% vs. 9.5%, respectively). Furthermore, in n = 19 pigs, dP/dt(max) increased after MI. However, echocardiographic strain analysis of 23 pigs with EF ranging only from 36% to 40% after MI revealed significant correlations between dP/dt(max) and strain parameters in the noninfarcted area (circumferential strain: r = 0.42, P = 0.05; radial strain: r = 0.71, P < 0.001). In conclusion, EF is a more accurate measure of systolic dysfunction than dP/dt(max) in a swine model of MI. Despite the variability of dP/dt(max) both in naïve pigs and after MI, it may sensitively reflect the small changes of myocardial contractility.

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), donor's 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.

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 ß-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 ß-agonist-treated patients (vs ß-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.

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

BACKGROUND: Cyclosporine (CsA) and tacrolimus (Tac) in heart transplantation (HTx) have been compared but with certain drawbacks. We compared both drugs in a prospective analysis with medium-term follow-up. METHODS: Hundred and six patients were randomized to receive CsA or Tac (53 per group). Target levels of CsA were 200-300 ng/mL in the first six months and 100-200 ng/mL thereafter. Tac levels were 10-15 and 5-10 ng/mL, respectively. We also used daclizumab as induction and mycophenolate mofetil (MMF) and steroids as maintenance therapy. RESULTS: Baseline characteristics were similar. Survival (CsA 88.7% vs. Tac 81.1%; p = 0.493) was similar. There was a tendency for longer time to first rejection with CsA (93 ± 110 vs. 55 ± 81 d; p = 0.122). There were more rejection-free patients with Tac (39 vs. 28%; p = 0.233). CsA patients suffered more viral infections (0.41 ± 0.58 vs. 0.11 ± 0.31; p = 0.003). CsA patients developed hypertension often (64 vs. 43%; p = 0.032). Tac patients suffered more gastrointestinal complications (16 vs. 6%; p = 0.042). Renal function and the development of diabetes, dyslipidemia, or neurological complications was similar. CONCLUSIONS: Tac patients showed a tendency for longer time to first rejection, and there were more rejection-free patients with Tac and suffered fewer viral infections. Tac patients developed less hypertension and needed less drugs for its control. Renal function was similar in both groups.

Prognostic value of glomerular filtration rate 1 year after heart transplantation.

INTRODUCTION AND OBJECTIVES: The development of renal failure is one of the most important problems after heart transplantation (HT), but the wide range of definitions means that estimates of its prevalence vary considerably. Furthermore, its impact on mortality has not been adequately studied. The objective was to investigate the relationship between the glomerular filtration rate (GFR) 1 year after transplantation and mortality during follow-up. METHODS: The GFR was determined in 316 patients still living 1 year after transplantation using the abbreviated Modification of Diet in Renal Disease Study formula. Patients were divided into three groups according to GFR (i.e. <30, 30-59 and > or =60 mL/min per 1.73 m2) and pretransplant variables and rejection and infection rates within the first year were analyzed. The association between GFR at 1 year and mortality during follow-up was evaluated and reasons for the association were examined. RESULTS: There was no difference in the number of rejections or infections in the first year between the three groups. During a mean follow-up period of 6.3 years, 74% of patients with a GFR <30 mL/min per 1.73 m2 died, compared with 24% and 30% of those with a GFR > or =60 and 30-59 mL/min per 1.73 m2, respectively. Survival analysis (i.e. Cox regression analysis) demonstrated a significant difference between patients with a GFR <30 mL/min per 1.73 m2 and other patients (P< .001). A very low GFR at 1 year was the only independent predictor that remained statistically significant on multivariate analysis (hazard ratio =2.87; 95% confidence interval, 1.52-5.41). CONCLUSIONS: Severe renal dysfunction at 1 year was an independent predictor of long-term all-cause mortality in heart transplant patients.

Valor pronóstico de la tasa de filtración glomerular al año del trasplante cardiaco / Prognostic value of glomerular filtration rate 1 year after heart transplantation

Introducción y objetivos. Uno de los problemas más relevantes tras el trasplante cardiaco es el desarrollo de insuficiencia renal. La heterogeneidad en su definición hace que la estimación de su prevalencia sea variable. Por otro lado, su impacto en la mortalidad no ha sido suficientemente estudiado. El objetivo fue evaluar la relación entre la tasa de filtración glomerular al año (TFG) y la mortalidad en el seguimiento. Métodos. Se analizó la TFG de 316 pacientes vivos al año del trasplante mediante la fórmula abreviada Modification of Diet in Renal Disease Study. Se clasificaron en tres grupos según su TFG ( < 30, 30-59 y ≥ 60 ml/ min/1,73 m2, respectivamente) y se analizaron variables antes del trasplante, tasa de rechazo e infección durante el primer año. Se evaluó la relación entre la TFG al año y la mortalidad en el seguimiento y se revisaron sus causas. Resultados. No hubo diferencias en el número de rechazos ni infecciones durante el primer año en los tres grupos. En el seguimiento medio (6,3 años) falleció el 74% de los pacientes con TFG < 30, frente al 24% y al 30% de aquellos con TFG ≥ 60 y 30-59, respectivamente. El análisis de supervivencia (regresión de Cox) mostró diferencias estadísticamente significativas entre aquellos con TFG < 30 y el resto (p < 0,001). La TFG gravemente disminuida al año se mantuvo como el único predictor independiente en el análisis multivariable (hazard ratio = 2,87; intervalo de confianza del 95%, 1,52-5,41). Conclusiones. La disfunción grave de la función renal al año es un predictor independiente de mortalidad por todas las causas a largo plazo en el paciente con trasplante cardiaco (AU)

Introduction and objectives. The development of renal failure is one of the most important problems after heart transplantation (HT), but the wide range of definitions means that estimates of its prevalence vary considerably. Furthermore, its impact on mortality has not been adequately studied. The objective was to investigate the relationship between the glomerular filtration rate (GFR) 1 year after transplantation and mortality during follow-up. Methods. The GFR was determined in 316 patients still living 1 year after transplantation using the abbreviated Modification of Diet in Renal Disease Study formula. Patients were divided into three groups according to GFR (i.e. <30 30-59 and 8805 60 ml min per 1 73 m2 pretransplant variables rejection infection rates within the first year were analyzed association between gfr at mortality during follow-up was evaluated reasons for examined results there no difference in number of rejections or infections three groups a mean period 6 3 years 74 patients with <30 ml min per 1 73 m2 died compared with 24 and 30 of those a gfr 8805 60 30-59 respectively survival analysis i e cox regression demonstrated significant difference between patients <30 ml min per 1 73 m2 and other patients p <.001). A very low GFR at 1 year was the only independent predictor that remained statistically significant on multivariate analysis (hazard ratio =2.87; 95% confidence interval, 1.52-5.41). Conclusions. Severe renal dysfunction at 1 year was an independent predictor of long-term all-cause mortality in heart transplant patients (AU)

Myocardial and peripheral lymphocytic transcriptomic dissociation of beta-adrenoceptors and G protein-coupled receptor kinases in heart transplantation.

BACKGROUND: The genetic expression of adrenergic receptors plays an important pathophysiologic role in heart failure. G protein-coupled receptor kinases (GRKs) desensitize the beta-receptor to catecholaminergic stimulation. It has been suggested that their mRNA expression in peripheral lymphocytes could mirror the changes in their myocardial expression in the failing heart, but this relationship between the myocyte and lymphocyte has not been studied in heart transplantation (HT). The objective of this study was to analyze adrenergic receptor and GRK mRNA expression in myocardium and lymphocytes and their correlation. METHODS: Twenty-three HT patients without evidence of acute rejection or echocardiographic dysfunction were assessed. Myocardial biopsy samples and peripheral blood lymphocytes were obtained, and alpha(1)- and beta-adrenoceptor subtype and GRK subtype mRNA was analyzed using reverse transcript-polymerase chain reaction (RT-PCR). RESULTS: Mean age was 45 +/- 15 years, with a median of time since HT of 205 (351) days. In biopsies, the beta(1)/beta(2)-adrenoceptor ratio was 57%/42%, and GRK5 was the most commonly expressed, followed by GRK2. In lymphocytes, the beta(1)/beta(2) ratio was 3%/96%, whereas GRK2 mRNA expression was greater than that of other subtypes. There was no correlation between myocardial and lymphocyte parameters. There were no correlations with clinical variables, but lymphocyte beta(2) and GRK2 were increased with time since HT. CONCLUSIONS: In the transplanted heart, there is no correlation between mRNA expression of adrenoceptors and GRKs in myocardium and peripheral lymphocytes. With time since transplant, mRNA expression of lymphocyte but not myocardial beta(2)-adrenoceptor and GRK2 increases. Therefore, this dissociation between myocardial and lymphocyte mRNA expression limits the potential use of peripheral blood samples for diagnosis of graft dysfunction.

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.

Predictor factors for the development of arterial hypertension following heart transplantation.

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. AIM: To identify the predictor variables for the development of de novo AHT after HT. MATERIALS AND METHODS: We retrospectively studied 253 patients with HT and who did not previously have AHT. We excluded cases of early mortality, re-transplants and combined transplants. We considered AHT as the constant need to take anti-hypertensive drugs to maintain blood pressure < 140/90 mmHg. We studied all the variables relating to recipient, donor, surgical procedure, immunosuppression and follow-up. The statistics used were the Student's t-test, chi-square statistic and a logistic regression analysis. RESULTS: Of the 253 patients, 109 (43%) developed AHT. The variables associated with more prevalent AHT were male recipient/donor, idiopathic dilated cardiomyopathy (IDCM) as cause of HT, having been a smoker as well as renal deterioration (RD) and hypercholesterolemia after HT. The multivariate analysis found smoking prior to the HT and hypercholesterolemia during follow-up as independent risk factors and urgent HT as a protective variable. CONCLUSIONS: AHT after HT is frequent. The variables associated in our population were smoking before HT, male recipient/donor, IDCM prior to HT and hypercholesterolemia and RD after HT.

Prognostic relationship between two serial determinations of B-type natriuretic peptide and medium-long-term events in heart transplantation.

BACKGROUND: Persistent elevation of B-type natriuretic peptide (BNP) levels in the first year after transplant appears to be associated with an adverse prognosis. However, there are no data on the prognostic value of two serial determinations of BNP at the end of the first year after transplant in clinically stable patients. OBJECTIVES: The purpose of this study was to analyze the association between the increase in two serial determinations of BNP at the end of the first year and the subsequent development of events in medium-long-term follow-up. METHODS: An observational study was conducted in a consecutive series of 71 patients transplanted between January 1999 and January 2001. Patients who were "unstable" or had other conditions that could elevate BNP levels (rejection, elevated pulmonary pressures, renal dysfunction, depressed ventricular function or severe graft vascular disease) were also excluded. The final number of patients included was 51. BNP determinations were performed at 9 and 12 months post-transplant at the same time as biopsies. Three groups were formed depending on the relationship between the two determinations: Group 1 (20 patients), decrease >20%; Group 2 (16 patients), change <20%; and Group 3 (15 patients), increase >20%. The following were considered events: death; late rejection; and ventricular dysfunction associated or not with graft vascular disease. RESULTS: The baseline clinical profile was similar in the three groups. There was a significant difference in the rate of events (Group 1, 10%; Group 2, 32%; Group 3, 53%; p < 0.017). Event-free survival was statistically different between the groups (p = 0.017), mainly because of the large difference between Groups 1 and 3 (p = 0.003). Thus, cumulative event-free survival at 3,000 days was 89.4% for Group 1, 68.3% for Group 2 and 48.2% for Group 3. CONCLUSIONS: The increase between two serial determinations of BNP levels at the end of the first year post-transplant could identify a subgroup of patients with poor outcome.

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.

Infiltración miocárdica tras exéresis de schwannoma melanótico pulmonar / Myocardial infiltration after excision of a pulmonary melanotic schwannoma

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