Meta-analysis of genome-wide association studies for cancer therapy-related cardiovascular dysfunction and functional mapping highlight an intergenic region close to TP63.

Cancer therapy-related cardiac dysfunction (CTRCD), which commonly includes left ventricular dysfunction and heart failure, is the main adverse effect of anticancer therapy. In recent years several candidate genes studies and genome-wide association studies have identified common genetic variants associated with CTRCD, but evidence remains limited and few genetic variants are robust. A genome-wide meta-analysis of CTRCD was performed with 852 oncology patients receiving cancer therapy. DNA samples were genotyped and imputed to perform a GWAS meta-analysis for case-control (N = 852 (380 cases and 472 controls) and extreme phenotypes (N = 618 (78 cases and 472 controls) looking for genetic variants that predispose to CTRCD. The results were validated in a replicate cohort of 1,191 oncology patients (245 cases and 946 controls). Functional mapping of the replicated loci was then performed. The meta-analysis showed 9 and 17 loci suggestively associated (P-value < 1 × 10-5) with CTRCD in case-control and extreme phenotypes analyses, respectively. The 3q28 locus (rs rs7652759, P = 5.64 × 10-6) in the case-control analysis was the strongest signal, with up to 64 SNPs above the suggestive significance threshold. The rs7652759, an intergenic variant between TPRG1 and TP63 genes, was the only variant validated in the replication cohort (P-value = 0.01). Functional mapping of this significant locus revealed up to 5 new genes potentially involved in the CTRCD. We identified the intergenic region near TP63 as a novel CTRCD susceptibility locus. In the future, the genotyping of these markers could be considered in new CTRCD risk scores to improve preventive strategies in cardio-oncology.

Prevalence and prognostic influence of peripheral arterial disease in patients >or=40 years old admitted into hospital following an acute coronary event.

OBJECTIVE: A significant proportion of patients with ischemic heart disease have associated peripheral arterial disease (PAD), but many are asymptomatic and this condition remains underdiagnosed. We aimed to study the prevalence of PAD in patients with an acute coronary syndrome (ACS) and to evaluate its influence in hospital clinical outcomes. METHODS: The PAMISCA register is a prospective, multicenter study involving patients >or=40 years old with ACS admitted to selected Spanish hospitals. All patients had their ankle-brachial index (ABI) measured between days 3 and 7 after the ischemic event. RESULTS: 1410 ACS patients (71.4% male) were included. PAD determined by ABI was documented in 561 patients (39.8%). Factors independently related to PAD were age (OR: 1.04; 95% CI: 1.03-1.06; p<0.001), smoking (OR: 1.88; 95% CI: 1.41-2.49; p<0.0001), diabetes (OR: 1.30; 95% CI: 1.02-1.65; p<0.05), previous cardiac disease (OR: 1.54; 95% CI: 1.22-1.95; p<0.001) and previous cerebrovascular disease (OR: 1.90; 95% CI: 1.28-2.80; p<0.001). Following the ACS, an ABIor=40 years presenting with ACS is high and it is associated with increased cardiovascular risk.

[Underestimation of renal risk in cardiology clinics. RICAR study]. / Infravaloración del riesgo renal en consultas de cardiología. Estudio RICAR.

AIMS: The aim of this study was to assess the rate of patients attended in cardiology outpatient clinics in whom microalbumine or glomerular filtration rate had been determined, at least once, in the previous 12 months. METHODS: It was an observational, transversal, multicentric study. 1224 patients were included from 124 centers in Spain. Epidemiological, anthropometric, analytic and electrocardiographic data were recruited. Glomerular filtration rate was calculated thereafter by means of the simplified equation of the MDRD. Results. Microalbumine was determined in 34% of the patients, of those 49% had positive microalbumine. Microalbumine rates were higher in patients with diabetes, heart failure, atrial fibrillation, peripheral artery disease or serum creatinine levels > 1.3 mg/dl. However, only young patients, diabetics and those with left ventricular hypertrophy had this exam performed more often. The glomerular filtration rate was determined in 11% of the patients. 30% of the population had moderate or severe renal dysfunction (filtration rate < 60 ml/min) and only 21% of the population hat normal renal function (filtration rate > 90 ml/min). Glomerular filtration rate was assessed more frequently in patients with serum creatinine > 1.3 mg/dl and those with history of heart failure. CONCLUSIONS: The prevalence of renal dysfunction in hypertensive patients attended in Cardiology clinics is high. However, the methods recommended for early detection of renal dysfunction are scarcely used by cardiologists. These figures do not improve significantly in high risk patients.

[Medical expert consensus in AH on the clinical use of triple fixed-dose antihypertensive therapy in Spain]. / Consenso de médicos expertos en HTA sobre el uso clínico de la triple terapia antihipertensiva a dosis fija en España.

INTRODUCTION: The opinion of experts (different specialties) on the triple fixed-dose antihypertensive therapy in clinical practice may differ. MATERIALS AND METHODS: Online questionnaire with controversial aspects of the triple therapy answered by panel of experts in hypertension (HT) using two-round modified Delphi method. RESULTS: The questionnaire was completed by 158 experts: Internal Medicine (49), Nephrology (26), Cardiology (83). Consensus was reached (agreement) on 27/45 items (60%); 7 items showed differences statistically significant. Consensus was reached regarding: Predictive factors in the need for combination therapy and its efficacy vs. increasing the dose of a pretreatment, and advantage of triple therapy (prescription/adherence/cost/pressure control) vs. free combination. CONCLUSIONS: This consensus provides an overview of the clinical use of triple therapy in moderate-severe and resistant/difficult to control HT.

Ischaemic preconditioning delays ischaemia induced cellular electrical uncoupling in rabbit myocardium by activation of ATP sensitive potassium channels.

OBJECTIVE: The aim was to examine whether ischaemic preconditioning delays the onset of cellular electrical uncoupling during ischaemia, and whether the effect of preconditioning is mediated by the activation of ATP sensitive K+ channels (IK-ATP). METHODS: Onset of uncoupling, action potential duration (APD80), and conduction velocity were measured in an isolated perfused rabbit papillary muscle. Preconditioning consisted of 10 min occlusion and 10 min reperfusion prior to 40 min sustained ischaemia. Five groups were studied: (1) control (sustained ischaemia only); (2) preconditioning; (3) preconditioning with 20 microM glibenclamide, a blocker of IK-ATP, added for 10 min during the reperfusion period; (4) sustained ischaemia after 15 min perfusion with 20 microM cromakalim (BRL 34915), an opener of IK-ATP; (5) sustained ischaemia after 10 min perfusion with 20 microM glibenclamide without preconditioning. RESULTS: Uncoupling started at 15.0(SEM 0.7) min of ischaemia in the control group and at 22.8(1.5) min after preconditioning (p < 0.001 v control group). Blocking IK-ATP during the preconditioning protocol with glibenclamide abolished the delay of uncoupling: onset was at 14.7(1.2) min. Activation of IK-ATP with cromakalim resulted in uncoupling at 23.3(1.9) min (p < 0.002 v control). Glibenclamide without preconditioning had no effect on uncoupling: onset was at 15.6(1.0) min. APD80 during ischaemia was significantly shorter in the preconditioning and cromakalim groups than in the control group from 5 min of ischaemia onward. In the preconditioning+glibenclamide group and the glibenclamide group APD80 was at no point significantly different from the control group. Conduction velocity during ischaemia decreased to about 70% of baseline after 10 min and was not different between the five groups. CONCLUSIONS: (1) Preconditioning delays the onset of electrical uncoupling; (2) the protective effect of preconditioning may be caused by activation of the IK-ATP channel; (3) the protective effect is associated with reduction of action potential duration, but not with changes of conduction velocity.

Clustering of target organ damage increases mortality after acute coronary syndromes in patients with arterial hypertension.

The impact of target organ damage (TOD) clustering in hypertensive patients with established cardiovascular disease has not been clearly defined. Multicentre, observational and prospective study of 1054 consecutive patients with acute coronary syndromes (ACSs). The objective was describing the impact of TOD on first-year mortality. Ankle-brachial index (ABI), left ventricular hypertrophy and renal dysfunction were assessed during hospital stay. Hypertensive patients accounted for 80% of the cohort and had slightly higher mean age, higher prevalence of risk factors, previous cardiovascular disease and TOD. During follow-up, mean time 387.9 (7.2) days and median 382 (364.0-430.0) days, mortality rate tended to be higher in hypertensive patients (6.1 versus 3.5%; P=0.16). Cox regression survival analysis identified pathological ABI as the only TOD independently associated with mortality. When assessed globally, the presence of at least one TOD predicted mortality only in patients with hypertension and differences in mortality rate appeared very early in the follow-up. A linear increase in mortality rate was observed with the clustering of TOD: 2.0%, if no TOD was present, 7.6% in one TOD, 11.1% in two TODs and 20.0%, if three TODs were present. An increased risk in the combined end point of ischaemic events was observed in hypertensive patients without TOD (odds ratio (OR): 3.18; 95% confidence interval (CI): 1.31-7.70; P=0.01) and was still higher in patients with hypertension and TOD (OR: 4.61; 95% CI: 1.90-11.80; P<0.01). TOD predicts mortality and ischaemic events of hypertensive patients after ACS.

Consenso de médicos expertos en HTA sobre el uso clínico de la triple terapia antihipertensiva a dosis fija en España / Medical expert consensus in AH on the clinical use of triple fixed-dose antihypertensive therapy in Spain

Introducción: La opinión de expertos (de distintas especialidades) sobre la triple terapia antihipertensiva a dosis fijas en la práctica clínica puede variar. Material y métodos: Encuesta online con aspectos controvertidos del tratamiento triple realizada por un panel de expertos en hipertensión arterial (HTA) empleando un método Delphi modificado en 2 rondas. Resultados: Participaron 158 expertos: Medicina Interna (49) Nefrología (26) y Cardiología (83). Se consensuaron (acuerdo) 27/45 ítems (60%); 7 ítems presentaron diferencias estadísticamente significativas. Se consensuó: los factores predictivos de la necesidad de tratamiento combinado y su eficacia frente al aumento de dosis de un tratamiento previo, y las ventajas de la triple terapia (prescripción/adherencia/costes/control) frente a la combinación libre. Conclusiones: El presente consenso ofrece una visión amplia del uso clínico de la triple terapia en HTA moderada-severa y resistente/de difícil control

Introduction: The opinion of experts (different specialties) on the triple fixed-dose antihypertensive therapy in clinical practice may differ. Materials and methods: Online questionnaire with controversial aspects of the triple therapy answered by panel of experts in hypertension (HT) using two-round modified Delphi method. Results: The questionnaire was completed by 158 experts: Internal Medicine (49), Nephrology (26), Cardiology (83). Consensus was reached (agreement) on 27/45 items (60%); 7 items showed differences statistically significant. Consensus was reached regarding: Predictive factors in the need for combination therapy and its efficacy vs. increasing the dose of a pretreatment, and advantage of triple therapy (prescription/adherence/cost/pressure control) vs. free combination. Conclusions: This consensus provides an overview of the clinical use of triple therapy in moderate-severe and resistant/difficult to control HT

R 56865 delays cellular electrical uncoupling in ischemic rabbit papillary muscle.

The compound R56865 protects the heart from irreversible ischemic damage. The proposed mechanism of its action is a reduction of Ca2+ overload secondary to a reduction of intracellular Na+, caused by blockade of the Na(+)-channel. In addition, cardioprotection is ascribed to blockade of the Na(+)-sensitive K(+)-channel (IK-Na). We tested whether R 56865 delays cellular electrical uncoupling, one aspect of irreversible ischemic damage that is due to Ca2+ overload. Also, we studied whether the Na(+)-channel and IK-Na are involved in cardioprotection by relating delay of the onset of cellular electrical uncoupling to changes of conduction velocity and action potential duration (APD80), respectively. Experiments were performed with isolated perfused rabbit papillary muscles that were treated with 1 microM R 56865 for 45 min prior to ischemia. Uncoupling started at 15.0 +/- 0.8 min (mean +/- S.E.M., n = 12) of ischemia in the control group and at 23.4 +/- 1.7 min in the R 56865 group (n = 9, P < 0.005 vs control). R 56865 tended to decrease conduction velocity and to increase APD80 during pre-treatment, but these changes were not statistically significant. During ischemia, conduction velocity was statistically not different between the R 56865 group and the control group. APD80 was significantly longer in the R 56865 than in the control group during the first 7 min of ischemia and similar after that. We conclude that R 56865 delays the onset of cellular uncoupling during ischemia and that this effect is not related to changes of conduction velocity and at most in part to changes of APD80.