G-protein beta3 subunit gene (GNB3) variant in causation of essential hypertension

-Essential hypertensives display enhanced signal transduction through pertussis toxin-sensitive G proteins. The T allele of a C825T variant in exon 10 of the G protein beta3 subunit gene (GNB3) induces formation of a splice variant (Gbeta3-s) with enhanced activity. The T allele of GNB3 was shown recently to be associated with hypertension in unselected German patients (frequency=0.31 versus 0.25 in control). To confirm and extend this finding in a different setting, we performed an association study in Australian white hypertensives. This involved an extensively examined cohort of 110 hypertensives, each of whom were the offspring of 2 hypertensive parents, and 189 normotensives whose parents were both normotensive beyond age 50 years. Genotyping was performed by polymerase chain reaction and digestion with BseDI, which either cut (C allele) or did not cut (T allele) the 268-bp polymerase chain reaction product. T allele frequency in the hypertensive group was 0.43 compared with 0.25 in the normotensive group (chi2=22; P=0.00002; odds ratio=2.3; 95% CI=1.7 to 3.3). The T allele tracked with higher pretreatment blood pressure: diastolic=105+/-7, 109+/-16, and 128+/-28 mm Hg (mean+/-SD) for CC, CT, and TT, respectively (P=0.001 by 1-way ANOVA). Blood pressures were higher in female hypertensives with a T allele (P=0.006 for systolic and 0.0003 for diastolic by ANOVA) than they were in male hypertensives. In conclusion, the present study of a group with strong family history supports a role for a genetically determined, physiologically active splice variant of the G protein beta3 subunit gene in the causation of essential hypertension.

New signal processing algorithms for automated external defibrillators

[ES]La fibrilación ventricular (VF) es el primer ritmo registrado en el 40\,\% de las muertes súbitas por paro cardiorrespiratorio extrahospitalario (PCRE). El único tratamiento eficaz para la FV es la desfibrilación mediante una descarga eléctrica. Fuera del hospital, la descarga se administra mediante un desfibrilador externo automático (DEA), que previamente analiza el electrocardiograma (ECG) del paciente y comprueba si presenta un ritmo desfibrilable. La supervivencia en un caso de PCRE depende fundamentalmente de dos factores: la desfibrilación temprana y la resucitación cardiopulmonar (RCP) temprana, que prolonga la FV y por lo tanto la oportunidad de desfibrilación. Para un correcto análisis del ritmo cardiaco es necesario interrumpir la RCP, ya que, debido a las compresiones torácicas, la RCP introduce artefactos en el ECG. Desafortunadamente, la interrupción de la RCP afecta negativamente al éxito en la desfibrilación. En 2003 se aprobó el uso del DEA en pacientes entre 1 y 8 años. Los DEA, que originalmente se diseñaron para pacientes adultos, deben discriminar de forma precisa las arritmias pediátricas para que su uso en niños sea seguro. Varios DEAs se han adaptado para uso pediátrico, bien demostrando la precisión de los algoritmos para adultos con arritmias pediátricas, o bien mediante algoritmos específicos para arritmias pediátricas. Esta tesis presenta un nuevo algoritmo DEA diseñado conjuntamente para pacientes adultos y pediátricos. El algoritmo se ha probado exhaustivamente en bases de datos acordes a los requisitos de la American Heart Association (AHA), y en registros de resucitación con y sin artefacto RCP. El trabajo comenzó con una larga fase experimental en la que se recopilaron y clasificaron retrospectivamente un total de 1090 ritmos pediátricos. Además, se revisó una base de arritmias de adultos y se añadieron 928 nuevos ritmos de adultos. La base de datos final contiene 2782 registros, 1270 se usaron para diseñar el algoritmo y 1512 para validarlo. A continuación, se diseñó un nuevo algoritmo DEA compuesto de cuatro subalgoritmos. Estos subalgoritmos están basados en un conjunto de nuevos parámetros para la detección de arritmias, calculados en diversos dominios de la señal, como el tiempo, la frecuencia, la pendiente o la función de autocorrelación. El algoritmo cumple las exigencias de la AHA para la detección de ritmos desfibrilables y no-desfibrilables tanto en pacientes adultos como en pediátricos. El trabajo concluyó con el análisis del comportamiento del algoritmo con episodios reales de resucitación. En los ritmos que no contenían artefacto RCP se cumplieron las exigencias de la AHA. Posteriormente, se estudió la precisión del algoritmo durante las compresiones torácicas, antes y después de filtrar el artefacto RCP. Para suprimir el artefacto se utilizó un nuevo método desarrollado a lo largo de la tesis. Los ritmos desfibrilables se detectaron de forma precisa tras el filtrado, los no-desfibrilables sin embargo no.

Rhythm Analysis during Cardiopulmonary Resuscitation: Past, Present, and Future

Survival from out-of-hospital cardiac arrest depends largely on two factors: early cardiopulmonary resuscitation (CPR) and early defibrillation. CPR must be interrupted for a reliable automated rhythm analysis because chest compressions induce artifacts in the ECG. Unfortunately, interrupting CPR adversely affects survival. In the last twenty years, research has been focused on designing methods for analysis of ECG during chest compressions. Most approaches are based either on adaptive filters to remove the CPR artifact or on robust algorithms which directly diagnose the corrupted ECG. In general, all the methods report low specificity values when tested on short ECG segments, but how to evaluate the real impact on CPR delivery of continuous rhythm analysis during CPR is still unknown. Recently, researchers have proposed a new methodology to measure this impact. Moreover, new strategies for fast rhythm analysis during ventilation pauses or high-specificity algorithms have been reported. Our objective is to present a thorough review of the field as the starting point for these late developments and to underline the open questions and future lines of research to be explored in the following years.

A New Method for Feedback on the Quality of Chest Compressions during Cardiopulmonary Resuscitation

Quality of cardiopulmonary resuscitation (CPR) improves through the use of CPR feedback devices. Most feedback devices integrate the acceleration twice to estimate compression depth. However, they use additional sensors or processing techniques to compensate for large displacement drifts caused by integration. This study introduces an accelerometer-based method that avoids integration by using spectral techniques on short duration acceleration intervals. We used a manikin placed on a hard surface, a sternal triaxial accelerometer, and a photoelectric distance sensor (gold standard). Twenty volunteers provided 60 s of continuous compressions to test various rates (80-140 min(-1)), depths (3-5 cm), and accelerometer misalignment conditions. A total of 320 records with 35312 compressions were analysed. The global root-mean-square errors in rate and depth were below 1.5 min(-1) and 2 mm for analysis intervals between 2 and 5 s. For 3 s analysis intervals the 95% levels of agreement between the method and the gold standard were within -1.64-1.67 min(-1) and -1.69-1.72 mm, respectively. Accurate feedback on chest compression rate and depth is feasible applying spectral techniques to the acceleration. The method avoids additional techniques to compensate for the integration displacement drift, improving accuracy, and simplifying current accelerometer-based devices.

A Reliable Method for Rhythm Analysis during Cardiopulmonary Resuscitation

nterruptions in cardiopulmonary resuscitation (CPR) compromise defibrillation success. However, CPR must be interrupted to analyze the rhythm because although current methods for rhythm analysis during CPR have high sensitivity for shockable rhythms, the specificity for nonshockable rhythms is still too low. This paper introduces a new approach to rhythm analysis during CPR that combines two strategies: a state-of-the-art CPR artifact suppression filter and a shock advice algorithm (SAA) designed to optimally classify the filtered signal. Emphasis is on designing an algorithm with high specificity. The SAA includes a detector for low electrical activity rhythms to increase the specificity, and a shock/no-shock decision algorithm based on a support vector machine classifier using slope and frequency features. For this study, 1185 shockable and 6482 nonshockable 9-s segments corrupted by CPR artifacts were obtained from 247 patients suffering out-of-hospital cardiac arrest. The segments were split into a training and a test set. For the test set, the sensitivity and specificity for rhythm analysis during CPR were 91.0% and 96.6%, respectively. This new approach shows an important increase in specificity without compromising the sensitivity when compared to previous studies.

High-density lipoprotein subfractions display proatherogenic properties in overweight and obese children

BACKGROUND: In adults, obesity-driven inflammation can lead to increased cardiovascular disease (CVD). However, information regarding childhood obesity and its inflammatory sequelae is less well defined. Serum amyloid-A (SAA) is an inflammatory molecule that rapidly associates with high-density lipoproteins (HDLs) and renders them dysfunctional. Therefore, SAA may be a useful biomarker to identify increased CVD potential in overweight and obese children.

METHODS: Young Hearts 2000 is a cross-sectional cohort study in which 92 children who were obese were matched for age and sex with 92 overweight and 92 lean children. HDL2 and HDL3 (HDL2&3) were isolated from plasma by a three-step rapid-ultracentrifugation procedure. SAA was measured in serum and HDL2&3 by an enzyme-linked immunosorbent assay procedure, and the activities of cholesterol ester transfer protein (CETP) and lecithin cholesteryl acyltransferase (LCAT) were measured by fluorimetric assays.

RESULTS: Trends across the groups indicated that SAA increased in serum and HDL2&3 as BMI increased, as did HDL2-CETP and HDL2-LCAT activities.

CONCLUSION: These results have provided evidence that overweight and obese children are exposed to an inflammatory milieu that impacts the antiatherogenic properties of HDL and that could increase CVD risk. This supports the concept that it is important to target childhood obesity to help minimize future cardiovascular events.

Percutaneous Treatment of Mitral Valve Regurgitation: Initial Experience with the MitraClip Device

INTRODUCTION: Mitral regurgitation (MR) is the most common valvular disease and has recently become the target of a number of percutaneous approaches. The MitraClip is virtually the only device for which there is considerable experience, with more than 20,000 procedures performed worldwide. OBJECTIVE: To describe our initial experience of the percutaneous treatment of MR with the MitraClip device. METHODS: We describe the first six MitraClip cases performed in this institution (mean age 58.5 ± 13.1 years), with functional MR grade 4+ and New York Heart Association (NYHA) heart failure class III or IV (n=3), with a mean follow-up of 290 ± 145 days. RESULTS: Procedural success (MR ≤ 2+) was 100%. Total procedure time was 115.8 ± 23.7 min, with no in-hospital adverse events and discharge between the fourth and eighth day, and consistent improvement in the six-minute walk test (329.8 ± 98.42 vs. 385.33 ± 106.95 m) and in NYHA class (three patients improved by two NYHA classes). During follow-up there were two deaths, in two of the four patients who had been initially considered for heart transplantation. CONCLUSION: In patients with functional MR the MitraClip procedure is safe, with both a high implantation and immediate in-hospital success rate. A longer follow-up suggests that the clinical benefit decreases or disappears completely in patients with more advanced heart disease, namely those denied transplantation or on the heart transplant waiting list.

Long-term miR-669a therapy alleviates chronic dilated cardiomyopathy in dystrophic mice.

BACKGROUND: Dilated cardiomyopathy (DCM) is a leading cause of chronic morbidity and mortality in muscular dystrophy (MD) patients. Current pharmacological treatments are not yet able to counteract chronic myocardial wastage, thus novel therapies are being intensely explored. MicroRNAs have been implicated as fine regulators of cardiomyopathic progression. Previously, miR-669a downregulation has been linked to the severe DCM progression displayed by Sgcb-null dystrophic mice. However, the impact of long-term overexpression of miR-669a on muscle structure and functionality of the dystrophic heart is yet unknown. METHODS AND RESULTS: Here, we demonstrate that intraventricular delivery of adeno-associated viral (AAV) vectors induces long-term (18 months) miR-669a overexpression and improves survival of Sgcb-null mice. Treated hearts display significant decrease in hypertrophic remodeling, fibrosis, and cardiomyocyte apoptosis. Moreover, miR-669a treatment increases sarcomere organization, reduces ventricular atrial natriuretic peptide (ANP) levels, and ameliorates gene/miRNA profile of DCM markers. Furthermore, long-term miR-669a overexpression significantly reduces adverse remodeling and enhances systolic fractional shortening of the left ventricle in treated dystrophic mice, without significant detrimental consequences on skeletal muscle wastage. CONCLUSIONS: Our findings provide the first evidence of long-term beneficial impact of AAV-mediated miRNA therapy in a transgenic model of severe, chronic MD-associated DCM.

Primary isolated aortic valve surgery in octogenarians.

We reviewed our surgery registry, to identify predictive risk factors for operative results, and to analyse the long-term survival outcome in octogenarians operated for primary isolated aortic valve replacement (AVR). A total of 124 consecutive octogenarians underwent open AVR from January 1990 to December 2005. Combined procedures and redo surgery were excluded. Selected variables were studied as risk factors for hospital mortality and early neurological events. A follow-up (FU; mean FU time: 77 months) was obtained (90% complete), and Kaplan-Meier plots were used to determine survival rates. The mean age was 82+/-2.2 (range: 80-90 years; 63% females). Of the group, four patients (3%) required urgent procedures, 10 (8%) had a previous myocardial infarction, six (5%) had a previous coronary angioplasty and stenting, 13 patients (10%) suffered from angina and 59 (48%) were in the New York Heart Association (NYHA) class III-IV. We identified 114 (92%) degenerative stenosis, six (5%) post-rheumatic stenosis and four (3%) active endocarditis. The predicted mortality calculated by logistic European System for Cardiac Operative Risk Evaluation (EuroSCORE) was 12.6+/-5.7%, and the observed hospital mortality was 5.6%. Causes of death included severe cardiac failure (four patients), multi-organ failure (two) and sepsis (one). Complications were transitory neurological events in three patients (2%), short-term haemodialysis in three (2%), atrial fibrillation in 60 (48%) and six patients were re-operated for bleeding. Atrio-ventricular block, myocardial infarction or permanent stroke was not detected. The age at surgery and the postoperative renal failure were predictors for hospital mortality (p value <0.05), whereas we did not find predictors for neurological events. The mean FU time was 77 months (6.5 years) and the mean age of surviving patients was 87+/-4 years (81-95 years). The actuarial survival estimates at 5 and 10 years were 88% and 50%, respectively. Our experience shows good short-term results after primary isolated standard AVR in patients more than 80 years of age. The FU suggests that aortic valve surgery in octogenarians guarantees satisfactory long-term survival rates and a good quality of life, free from cardiac re-operations. In the era of catheter-based aortic valve implantation, open-heart surgery for AVR remains the standard of care for healthy octogenarians.