Decreased clinical performance in TGA-ASO patients after RVOT interventions; a multicenter European collaboration.

BACKGROUND: In patients with transposition of the great arteries and an arterial switch operation (TGA-ASO) right ventricular outflow tract (RVOT) obstruction is a common complication requiring one or more RVOT interventions. OBJECTIVES: We aimed to assess cardiopulmonary exercise capacity and right ventricular function in patients stratified for type of RVOT intervention. METHODS: TGA-ASO patients (≥16 years) were stratified by type of RVOT intervention. The following outcome parameters were included: predicted (%) peak oxygen uptake (peak VO2), tricuspid annular plane systolic excursion (TAPSE), tricuspid Lateral Annular Systolic Velocity (TV S'), right ventricle (RV)-arterial coupling (defined as TAPSE/RV systolic pressure ratio), and N-terminal proBNP (NT-proBNP). RESULTS: 447 TGA patients with a mean age of 25.0 (interquartile range (IQR) 21-29) years were included. Patients without previous RVOT intervention (n = 338, 76%) had a significantly higher predicted peak VO2 (78.0 ± 17.4%) compared to patients with single approach catheter-based RVOT intervention (73.7 ± 12.7%), single approach surgical RVOT intervention (73.8 ± 28.1%), and patients with multiple approach RVOT intervention (66.2 ± 14.0%, p = 0.021). RV-arterial coupling was found to be significantly lower in patients with prior catheter-based and/or surgical RVOT intervention compared to patients without any RVOT intervention (p = 0.029). CONCLUSIONS: TGA patients after a successful arterial switch repair have a decreased exercise capacity. A considerable amount of TGA patients with either catheter or surgical RVOT intervention perform significantly worse compared to patients without RVOT interventions.

Left atrial strain in adults after the arterial switch operation for transposition of the great arteries.

BACKGROUND: No study has focused on left atrial (LA) function assessed by echocardiography in adult patients with simple D-TGA after arterial switch operation (ASO). We aimed to describe LA strain parameters in these patients. METHODS: A prospective cohort study including 42 adult patients with simple D-TGA after ASO and 33 aged-matched controls. Phasic LA and LV global longitudinal strain (GLS) were obtained by transthoracic 2D-speckle tracking echocardiography (STE). Volumetric and functional analysis of LA and LV were also evaluated by 2D and 3D analysis. A multivariable model was performed to investigate the variables that best differentiate patients with D-TGA from healthy controls. RESULTS: LA strain parameters in D-TGA patients were within the normal range described for healthy subjects. However, the three LA strain parameters (Reservoir, Conduit, and Contraction) were lower in patients (LASr: 31.13 ± 7.67 vs. 49.71 ± 8.38; LAS cd: -22.91 ± 5.69 vs. -34.55 ± 6.54; LASct: -8.14 ± 4.93 vs. -15.15 ± 6.07, p < .001 for all three comparisons). LA volumes were similar between patients and controls. LV-GLS remained significantly lower in the D-TGA group than in controls (-17.29 ± 2.68 vs. -21.98 ± 1.84, p < .001). D-TGA patients had evidence of worse LV ejection fraction measured by the Teichholz method (63.38 ± 8.23 vs. 69.28 ± 5.92, p = .001) and 3D analysis (57.97% ± 4.16 vs. 60.67 ± 3.39, p = .011) and diastolic dysfunction as compared to healthy controls. LV-GLS and conduit LAS were the variables best differentiating patients with D-TGA from healthy controls. CONCLUSIONS: LA strain is impaired in young adults with simple D-TGA late after the ASO, probably in agreement with some degree of LV dysfunction previously described.

Safety and feasibility of conduction system pacing in patients with congenital heart disease.

INTRODUCTION: Conduction system pacing (CSP) has emerged as an ideal physiologic pacing strategy for patients with permanent pacing indications. We sought to evaluate the safety and feasibility of CSP in a consecutive series of unselected patients with congenital heart disease (CHD). METHODS: Consecutive patients with CHD in which CSP was attempted were included. Safety and feasibility, implant tools and electrical parameters at implant and at follow-up were evaluated. RESULTS: A total of 20 patients were included (10 with a previous device). A total of 10 patients had complex forms of CHD, 9 moderate defects and 1 a simple defect. CSP was achieved in 75% of cases (10 His bundle pacing, 5 left bundle branch pacing) with left ventricular septal pacing in the remaining 5 patients. Procedure times and fluoroscopy times were prolongued (126 ± 82 min and 27 ± 30 min, respectively). Ventricular lead implant times widely varied ranging from 4 to 115 min, (mean 31 ± 28 min) and the use of multiple delivery sheaths was frequent (50%). The QRS width was reduced from 145 ± 36 ms at baseline to 116 ± 18 ms with CSP. Implant electrical parameters included: CSP pacing threshold 0.95 ± 0.65 V; R wave amplitude 9.2 ± 8.8 mV and pacing impedance 632 ± 183 Ohms, and remained stable at a median follow-up of 478 days (interquartile range: 225-567). Systemic ventricle systolic function and NYHA class (1.50 ± 0.51 vs. 1.10 ± 0.31; p = .008) significantly improved at follow-up. Lead revision was required in one patient at Day 4. CONCLUSIONS: Permanent CSP is safe and feasible in patients with CHD although implant technique is complex.

Clinical outcome of COVID-19 in patients with adult congenital heart disease.

AIMS: Patients with adult congenital heart disease (ACHD) are a potentially vulnerable patient cohort in case of COVID-19. Some cardiac defects may be associated with a poor COVID-19 outcome. Risk estimation in ACHD is currently based on expert opinion. The aim of this study was to collect clinical outcome data and to identify risk factors for a complicated course of COVID-19 in patients with ACHD. METHODS: Twenty-five ACHD centres in nine European countries participated in the study. Consecutive patients with ACHD diagnosed with COVID-19 presenting to one of the participating centres between 27 March and 6 June 2020 were included. A complicated disease course was defined as hospitalisation for COVID-19 requiring non-invasive or invasive ventilation and/or inotropic support, or a fatal outcome. RESULTS: Of 105 patients with a mean age of 38±13 years (58% women), 13 had a complicated disease course, of whom 5 died. In univariable analysis, age (OR 1.3, 95% CI 1.1 to 1.7, per 5 years), ≥2 comorbidities (OR 7.1, 95% CI 2.1 to 24.5), body mass index of >25 kg/m2 (OR 7.2, 95% CI 1.9 to 28.3) and cyanotic heart disease (OR 13.2, 95% CI 2.5 to 68.4) were associated with a complicated disease course. In a multivariable logistic regression model, cyanotic heart disease was the most important predictor (OR 60.0, 95% CI 7.6 to 474.0). CONCLUSIONS: Among patients with ACHD, general risk factors (age, obesity and multiple comorbidities) are associated with an increased risk of complicated COVID-19 course. Congenital cardiac defects at particularly high risk were cyanotic lesions, including unrepaired cyanotic defects or Eisenmenger syndrome.

Predicting sudden cardiac death in adults with congenital heart disease.

OBJECTIVES: To develop, calibrate, test and validate a logistic regression model for accurate risk prediction of sudden cardiac death (SCD) and non-fatal sudden cardiac arrest (SCA) in adults with congenital heart disease (ACHD), based on baseline lesion-specific risk stratification and individual's characteristics, to guide primary prevention strategies. METHODS: We combined data from a single-centre cohort of 3311 consecutive ACHD patients (50% male) at 25-year follow-up with 71 events (53 SCD and 18 non-fatal SCA) and a multicentre case-control group with 207 cases (110 SCD and 97 non-fatal SCA) and 2287 consecutive controls (50% males). Cumulative incidences of events up to 20 years for specific lesions were determined in the prospective cohort. Risk model and its 5-year risk predictions were derived by logistic regression modelling, using separate development (18 centres: 144 cases and 1501 controls) and validation (two centres: 63 cases and 786 controls) datasets. RESULTS: According to the combined SCD/SCA cumulative 20 years incidence, a lesion-specific stratification into four clusters-very-low (<1%), low (1%-4%), moderate (4%-12%) and high (>12%)-was built. Multivariable predictors were lesion-specific cluster, young age, male sex, unexplained syncope, ischaemic heart disease, non-life threatening ventricular arrhythmias, QRS duration and ventricular systolic dysfunction or hypertrophy. The model very accurately discriminated (C-index 0.91; 95% CI 0.88 to 0.94) and calibrated (p=0.3 for observed vs expected proportions) in the validation dataset. Compared with current guidelines approach, sensitivity increases 29% with less than 1% change in specificity. CONCLUSIONS: Predicting the risk of SCD/SCA in ACHD can be significantly improved using a baseline lesion-specific stratification and simple clinical variables.

The use of fluorescence in situ hybridization analysis on sperm: indications to perform and assisted reproduction technology outcomes.

PURPOSE: To determine the consequences of an altered sperm fluorescence in situ hybridization (FISH) result for ART outcomes and the indications for a sperm FISH analysis. METHODS: Data from 439 infertile men were collected. Bivariate analyses were performed to determine the association of men's age, seminal alterations, and sperm FISH indication, with the incidence of X, Y, 13, 18, and 21 sperm chromosomal abnormalities. A multivariate logistic regression analysis was performed to establish the most predictive variables for altered sperm FISH. Results from the IVF/ICSI cycles were collected for 248 out of 439 patients. Two distinct groups were established: 151 couples that used their own oocytes and 97 couples involved in egg donation programs. In both groups, ART outcomes were compared between normal and altered sperm FISH. RESULTS: Teratozoospermia and oligozoospermia were associated with sperm chromosome anomalies (p < 0.05). Indications for sperm FISH analysis with the highest predictability were teratozoospermia, male age, oligozoospermia, and implantation failure (AUC = 0.702). Embryo quality (p = 0.096), pregnancy rate (p = 0.054), and implantation rate (p = 0.089) were higher in own-oocytes couples with normal sperm FISH than in altered sperm FISH couples, although differences were not statistically significant. In donor-oocytes couples, in which high-quality embryos were transferred later than in own-oocytes couples (3.8 vs. 3.0 days), we did not identify differences in the ART outcome between normal and altered sperm FISH couples. In both groups, the possible interference of woman age was negligible. CONCLUSIONS: Sperm FISH is indicated in middle-aged oligoteratozoospermic patients with implantation failures in previous IVF/ICSI cycles. Sperm chromosome anomalies have a moderate detrimental impact on embryo quality, implantation, and pregnancy rates.

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.

Evaluation of a near-zero fluoroscopic approach for catheter ablation in patients with congenital heart disease.

PURPOSE: Radiation exposure (RE) is a matter of concern for patients with congenital heart disease (CHD) who not infrequently need multiple interventional procedures under fluoroscopy guidance. We sought to evaluate the safety and feasibility of a minimally fluoroscopic approach in patients with CHD undergoing catheter ablation using a new image integration module (IIM). METHODS: Consecutive patients with CHD undergoing catheter ablation using the Carto Univu™ IIM were included. A near-zero fluoroscopy procedure was defined by an effective dose (ED) ≤ 1 mSv. RE parameters (total fluoroscopy time [TFT], total dose area product [tDAP], and ED), ablation outcomes, and complications were evaluated. RESULTS: Fifty-five patients with CHD underwent 63 ablation procedures (supraventricular tachycardia, n = 53; ventricular tachycardia, n = 10). The CHD was simple in 25%, moderate in 42%, and complex in 33%. The use of the IIM resulted in very low levels of RE (median TFT 0.13 min [IQR 0-1.04], median tDAP 54.5 cGy cm2 [IQR 9.5-176.4], median ED 0.136 mSv [IQR 0.02-0.49]). Patients with complex CHD had significantly higher RE when compared with patients with simple and moderate defects. A total of 56/63 ablation procedures (89%) were performed with an ED ≤ 1 mSv. One patient developed sinus node dysfunction requiring pacemaker implantation. CONCLUSIONS: The use of a minimally fluoroscopic approach was safe and feasible resulting in very low RE during catheter ablation of patients with CHD. A near-zero fluoroscopy ablation was possible in up to 89% of the procedures.

Prenatal diagnosis and molecular cytogenetic characterization of a de novo duplication of 15q24.3-q26.1.

Reported cases of distal 15q interstitial duplications are uncommon and do not result in a recognizable pattern of abnormalities. Some studies report prenatal overgrowth, while others describe growth retardation. We present molecular cytogenetic characterization of a 14 Mb interstitial duplication, encompassing 81 Online Mendelian Inheritance in Man (OMIM) genes, in a fetus with single umbilical artery and short limbs. We propose that growth restriction, previously described and present in our patient, may be due to duplication of a gene or genes contained in the 15q24 region.

Conventional and right-sided screening for subcutaneous ICD in a population with congenital heart disease at high risk of sudden cardiac death.

BACKGROUND: Information regarding suitability for subcutaneous defibrillator (sICD) implantation in tetralogy of Fallot (ToF) and systemic right ventricle is scarce and needs to be further explored. The main objective of our study was to determine the proportion of patients with ToF and systemic right ventricle eligible for sICD with both, standard and right-sided screening methods. Secondary objectives were: (i) to study sICD eligibility specifically in patients at high risk of sudden cardiac death, (ii) to identify independent predictors for sICD eligibility, and (iii) to compare the proportion of eligible patients in a nonselected ICD population. METHODS: We recruited 102 patients with ToF, 33 with systemic right ventricle, and 40 consecutive nonselected patients. Conventional electrocardiographic screening was performed as usual. Right-sided alternative screening was studied by positioning the left-arm and right-arm electrodes 1 cm right lateral of the xiphoid midline. The Boston Scientific ECG screening tool was utilized. RESULTS: In high-risk patients with ToF, eligibility was higher with right-sided screening in comparison with standard screening (61% vs. 44%; p = .018). Eligibility in high-risk right ventricle population was identical with both screening methods (77%, p = ns). The only independent predictor for sICD eligibility was QRS duration. CONCLUSION: In high-risk patients with ToF, right-sided implantation of the sICD could be an alternative to a conventional ICD. In patients with a systemic right ventricle, implantation of a sICD is an alternative to a conventional sICD.

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.

The Role of Conventional and Right-Sided ECG Screening for Subcutaneous ICD in a Tetralogy of Fallot Population.

BACKGROUND: Information regarding suitability for subcutaneous implantable cardioverter-defibrillator (S-ICD) implant in tetralogy of Fallot (ToF) population is scarce and needs to be further explored. THE AIMS OF OUR STUDY WERE: (1) to determine the proportion of patients with ToF eligible for S-ICD, (2) to identify the optimal sensing vector in ToF patients, (3) to test specifically the eligibility for S-ICD with right-sided screening, and (4) to compare with the proportion of eligible patients in a nonselected ICD population. METHODS: We recruited 60 consecutive patients with ToF and 40 consecutive nonselected patients. Conventional electrocardiographic screening was performed as usual. Right-sided alternative screening was studied by positioning the left arm and right arm electrodes 1 cm right lateral to the xiphoid midline. The Boston Scientific electrocardiogram (ECG) screening tool was utilized. RESULTS: We found a higher proportion of patients with right-sided positive screening in comparison with standard screening (77 ± 0.4% vs. 67 ± 0.4%; P < 0.0001) and a trend to higher number of appropriate leads in right-sided screening (1.3 ± 1 vs. 1.1 ± 1 ms; P = 0.07). Patients who failed the screening had a longer QRS duration and longer QT interval. Standard and right-sided screening showed a higher percent of positive patients in the control group compared to ToF patients (P < 0.001). CONCLUSION: Right-sided screening was associated with a significant 10% increase in S-ICD eligibility in ToF patients. When comparing with an acquired cardiomyopathies group, ToF showed a lower eligibility for S-ICD. The most appropriate ECG vector was the alternate vector in contrast to what is observed in the general population.

Essential ECG clues in patients with congenital heart disease and arrhythmias.

The prevalence of adults with congenital heart disease has dramatically increased during the last decades due to significant advances in the surgical correction of these conditions. As a result, patient's survival has been prolonged and arrhythmias have become one of the principal causes of morbidity and mortality for these patients. The surface 12-lead ECG may play a critical role in the identification of the underlying heart disease of the patient, the recognition of the arrhythmia mechanism and may also help in the planification of the ablation procedure in this setting. Finally, important prognostic information can be also obtained from the ECG in these patients. The present review will offer an overview of the principal utilities of the surface ECG in the diagnosis and management of patients with CHD and arrhythmias.

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.

Value of the Electrocardiogram as a Predictor of Right Ventricular Dysfunction in Patients With Chronic Right Ventricular Volume Overload.

INTRODUCTION AND OBJECTIVES: Pulmonary regurgitation is a common complication in patients with repaired tetralogy of Fallot or congenital pulmonary stenosis. Electrocardiographic variables have been correlated with parameters used to evaluate right ventricular function. We aimed to analyze the diagnostic value of the width and fragmentation of the electrocardiogram in the identification of patients with right ventricular dysfunction and/or dilation. METHODS: We selected 107 consecutive patients diagnosed with severe pulmonary insufficiency after repair of pulmonary stenosis or tetralogy of Fallot. The tests included electrocardiography, echocardiography, and magnetic resonance. Each electrocardiogram was analyzed manually to measure QRS duration. We defined QRS fragmentation as the presence of low-voltage waves in the terminal portion of the QRS complex in at least 2 contiguous leads. RESULTS: We found a significant negative correlation between QRS width and right ventricular function, as well as a positive correlation with right ventricular volume. The receiver operating characteristic curve indicated a cut-off point for QRS width of 140ms, which showed good sensitivity for a diagnosis of right ventricular dilation (> 80%) and dysfunction (> 95%). In logistic regression models, a QRS duration > 140ms was found to be the only independent predictor of right ventricular dilation and dysfunction. CONCLUSIONS: Electrocardiography is a rapid, widely available, and reproducible tool. QRS width constitutes an independent predictor of the presence of right ventricular dilation and dysfunction. This study is the first to provide a cutoff value for QRS width to screen for right ventricle involvement.

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.

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.

Clinical and molecular characterization of a patient with a combination of a deletion and a duplication of 22q13 using array CGH.

Phelan-McDermid syndrome is caused by the loss of terminal regions of different sizes at 22q13. There is a wide range of severity of symptoms in patients with a 22q13 deletion, but these patients usually show neonatal hypotonia, global developmental delay, and dysmorphic traits. We carried out a clinical and molecular characterization of a patient with neonatal hypotonia and dysmorphic features. Array-based comparative genomic hybridization showed an 8.24 Mb terminal deletion associated with a 0.20 Mb duplication. Characterization of patients with Phelan-McDermid syndrome both clinically and at the molecular level allows genotype-phenotype correlations that provide clues to help elucidate the clinical implications.

Evolution in the management of acute myocardial infarction in the autonomous community of valencia (Spain): ten years of the primvac registry (1995-2004).

INTRODUCTION AND OBJECTIVES: Several registries of acute myocardial infarction (AMI) have been carried out in Spain, but few remain active. This work analyses the evolution of the characteristics and control of patients with AMI during the first 10 years of the PRIMVAC registry, initiated in 1995. METHODS: The demographical and clinical characteristics, therapeutic-diagnostic procedures and pharmacological treatment of patients admitted with AMI between January 1995 and December 2004, were analysed in 17 coronary centres in the Autonomous Community of Valencia (South eastern Spain). RESULTS: The mean age of the 19,719 patients recruited was of 65. The percentage of women, hypertension, hypercholestrolemia and diabetes increased during registry period. The median time of symptoms onset-hospital arrival was 151 minutes, without a decrease over the time, and the delay of thrombolysis fell from 200 to 154 minutes (p<0.01). Percentage of thrombolytic treatment oscillated between 39% and 48%. The mortality in the coronary units decreased (14.1% vs. 8.9%; p<0.001). The number of coronary angiography and percutaneous revascularisation performed increased up to 61% and 32%, respectively, of patients included. On discharge, the use of beta-blockers (29.3% vs. 66.7%), angiotensin-converting enzyme (ACE) inhibitors (41.7% vs. 57.9%) and statins (29.3% vs. 71%) went up. CONCLUSIONS: Overall mortality in the coronary unit decreased, without any variation in the incidence of serious complications. Time to thrombolysis was reduced over the time, with no significant increment in its use. The performance of coronary angiography and percutaneous revascularisation increased, with a low use of primary angioplasty. The use of beta-blockers, ACE inhibitors and statins increased at discharge.