Joaquín Rueda

Endothelial protein C receptor polymorphisms and risk of myocardial infarction

Haplotypes A1 and A3 in the endothelial protein C receptor gene are tagged by the 4678G/C and 4600A/G polymorphisms, respectively, and have been reported to influence the risk of venous thromboembolism. This study shows that A1 and A3 haplotype carriers have a reduced risk of myocardial infarction. Background Haplotypes A1 and A3 in the endothelial protein C receptor gene are tagged by the 4678G/C and 4600A/G polymorphisms, respectively, and have been reported to influence the risk of venous thromboembolism. We assessed whether these haplotypes modify the risk of premature myocardial infarction. Design and Methods We genotyped these polymorphisms in 689 patients with premature myocardial infarction and 697 control subjects. Activated protein C and soluble endothelial protein C receptor levels were also measured. Results After adjustment for other cardiovascular risk factors, A1 and A3 haplotypes protected against premature myocardial infarction (odds ratio 0.7, 95% CI 0.4–0.8, p=0.044 and 0.5, 0.3–0.6, p<0.001, respectively). Moreover, the protective role of these haplotypes seemed to be additive, as carriers of both the A1 and A3 haplotypes had adjusted odds ratios of 0.3 (0.2–0.5, p<0.001) and 0.4 (0.2–0.8, p=0.006) compared to those carrying only the A1 or A3 haplotype, respectively. The presence of the A1 haplotype was associated with increased levels of activated protein C whereas individuals carrying the A3 haplotype showed the highest soluble endothelial protein C receptor levels. Conclusions These results show that A1 haplotype carriers have a reduced risk of premature myocardial infarction via the association of this haplotype with increased activated protein C plasma levels. The study also shows that carriers of the A3 haplotype have a reduced risk of myocardial infarction, only in part due to increased soluble endothelial protein C levels.

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.

Haemorheological parameters in young patients with acute myocardial infarction.

The role played by hemorheological alterations on acute myocardial infarction (AMI) in young patients remains a question of debate. We have carried out a case-control study of 84 AMI patients aged <45 years and 135 sex and age matched controls, in which blood viscosity (BV), plasma viscosity (PV), erythrocyte aggregation (EA) performed with the Myrenne (EA0, EA1) and the Sefam aggregometer (Ta, AI10, gammaD), erythrocyte deformability (ED) along with fibrinogen (Fbg), C-reactive protein (CRP) and plasmatic lipids i.e. total cholesterol (T-Chol) and triglycerides (TG) were determined. AMI patients showed higher, Fbg, TG, EA0, EA1, IA10, gammaD and lower Ta than controls (p=0.029, p<0.001, p=0.013, p=0.003, p=0.010, p=0.025) respectively. No differences in the other rheological parameters were observed. No differences in any rheological parameter were observed regarding the AMI type, number and score of stenosed vessels and the time elapsed since the thrombotic event. After multivariate adjustment, Fbg>380 ml/dl and TG>185 ml/dl were independently associated with a higher risk of erythrocyte hyperaggregability (OR: 5.5 CI 95% 1.04-29.27 and OR: 7.3 CI 95% 2.66-20.03) respectively. EA>8.85 was associated with a increased AMI risk (OR: 5.3 CI 95% 1.98-14.5). These results reinforces the view that in young AMI patients increased Fbg and TG may promote the development of ischaemic events not only through its known mechanism but also by altering rheological blood behaviour, mainly increasing EA.

Utilidad del electrocardiograma para predecir el lugar de la oclusión en el infarto agudo de miocardio anterior con enfermedad aislada de la arteria descendente anterior

Introduccion y objetivos En el infarto agudo de miocardio (IAM) anterior, el lugar de la oclusion de la arteria descendente anterior (DA) se relaciona con la extension de la necrosis y con el pronostico. El proposito del estudio fue valorar la utilidad del electrocardiograma (ECG) para predecir el lugar de la oclusion de la DA en pacientes con IAM anterior y enfermedad aislada de la DA. Metodos Estudio retrospectivo en el que se incluyen a 45 pacientes consecutivos con un primer IAM de localizacion anterior y enfermedad aislada de la DA. Analizamos el ECG que mostro la mayor desviacion del segmento ST (ST) previo al tratamiento fibrinolitico y lo correlacionamos con el nivel lesional en la DA en coronariografia realizada antes del alta hospitalaria en relacion con la primera septal dominante y primera diagonal, distinguiendo: territorio septal afectado («S»), territorio diagonal afectado («D»), ambos afectados («S + D») o ninguno. Resultados El descenso del segmento ST en las derivaciones II, III o aVF fue un potente predictor de lesion proximal en la DA en las localizaciones angiograficas «S + D», «S» y «D» (p = 0,003, p = 0,04 y p = 0,02, respectivamente). El ascenso del ST en II, III o aVF unicamente se observo en pacientes con una DA desarrollada que daba la vuelta al apex y se relaciono con lesion distal a la diagonal dominante (p Conclusiones En el IAM anterior y enfermedad exclusiva de la DA, el ECG puede ser una herramienta util en la prediccion del nivel lesional de la DA en relacion con sus ramas principales.

Análisis de los factores que pueden influir en la aparición del fallo agudo del corazón trasplantado

Introduction and objective. Acute graft failure (AGF) is defined as significant failure of myocardial function in a newly implanted heart. The aim of the present study was to investigate a series of factors related to heart transplantation (HT) in relation to AGF. Material and method. In a study of 287 consecutive HTs performed over a 14-year period, AGF was defined when: a) the surgeon observed ventricular dysfunction before closing the sternotomy; b) various inotropic drugs were required at high doses in the first days after surgery, or c) ventricular dysfunction was identified by routine echocardiography in the immediate postoperative period. Statistical analysis comprised a descriptive and univariate comparative study, followed by multivariate analysis based on application of a logistical regression model. Results. The incidence of AGF was 22%. Predictors of AGF were female donor status (OR = 2.2; 95% CI, 1.2-4.4; p = 0.02), a disproportion of more than 20% in donor-recipient body weight (OR = 2.2; 95% CI, 1.1-4.3; p = 0.02), and background ischemic heart disease (OR = 2.5; 95% CI, 5.5-1.1; p = 0.03) or valve pathology (OR = 5.0; 95% CI, 7.0-1.5; p = 0.01). Conclusions. AGF is a frequent pathology, which was present in 22% of our heart transplantation patients. Among the modifiable factors related to AGF was a clear disproportion in body weight and the size of grafts from female donors. Unmodifiable factors related to AGF were ischemic heart disease and valvular heart disease as a cause of heart transplantation.

Is the prognosis poorer in heart transplanted patients who develop a right bundle branch block

BACKGROUND Currently studies conflict on the impact on mortality of right bundle branch block development after transplantation. Most studies conclude that right bundle branch block does not affect patient survival. However, no distinction is made between patients in whom right bundle branch block progresses and those in whom it remains unchanged during follow-up. The objective of this study is to assess clinical or survival differences between patients who develop right bundle branch block and those who do not, and also to analyze these differences depending on progression of this conduction abnormality. MATERIALS AND METHODS Ninety-seven consecutive heart transplant recipients with more than 1 years survival were analyzed. Twelve-lead standard ECGs were performed during the first week after transplantation, which allowed for classification of patients depending on the presence or absence of right bundle branch block. Subsequently, throughout the first year, 2 groups were identified, depending on increase of the conduction defect. The groups were compared and factors determining the presence of right bundle branch block and progression of the conduction defect were found. Survival curves for the conduction defect were also compared. RESULTS Fifty percent of the patients developed right bundle branch block after transplantation; it was progressive in 10. Progressive right bundle branch block was related to greater renal dysfunction (odds ration [OR] = 10.8; confidence interval [CI] = 2-58; p = 0.006), a larger number of rejections (p = 0.01), and a greater death rate (OR = 12.8; CI = 2.5-64; p = 0.002). The presence of progressive right bundle branch block was an independent predictor of long-term mortality (OR = 27.9; CI = 4.2-186.3; p = 0.0006). CONCLUSIONS The development of right bundle branch block after transplantation is related to intraoperative factors and to a greater number of rejections. The presence of this conduction disorder, particularly if it progresses during the first year, identifies a sub-group of patients with a poorer long-term prognosis.

The presence of epsilon waves in a patient with acute right ventricular infarction

Epsilon wave is an unusual electrocardiographical finding, which may appear in other pathological conditions besides the arrhythmogenic right ventricular dysplasia, particularly in the acute myocardial infarction of the right ventricle, the inferior, or the posterior wall of the left ventricle. Its real incidence in these acute coronary syndromes remains unknown and will be probably difficult to assert, since it may be unnoticed by inexperienced physicians because of its little voltage. The outstanding interest of this case lies in the clear electrocardiographical images and in the step‐by‐step differential diagnosis discussed by the authors.

Myocardial and Peripheral Lymphocytic Transcriptomic Dissociation of β-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.

Influence of immunosuppressive regimens on short-term morbidity and mortality in heart transplantation

Abstract:  Background:  The goal of immunosuppressive therapy in heart transplantation is to maximize safety and efficacy while minimizing morbidity and mortality. We now have numerous drug combinations, but few have been compared with each other.