RESUMEN

BACKGROUND: Atrial fibrillation (AF) is a major preventable risk factor for stroke and may be silent in elderly individuals who are at especially high risk. This paper describes the first phase of implementation of a clinical AF detection programme in a community setting. Objectives were (i) to determine the feasibility of using a handheld ECG recording system for AF detection among individuals aged 65 years or more, who have cardiovascular risk factors. (ii) to estimate the yield of previously undiagnosed atrial fibrillation cases, and the proportion of these who would be suitable for oral anticoagulation. METHODS: a handheld ECG monitor was placed in each of 23 primary care practices across Scotland. Eligible patients attending for annual health checks had ECGs recorded, and the ECGs were transmitted and interpreted by two senior cardiologists. ECG quality was rated, and an adjudication made on the rhythm. For patients confirmed with AF, stroke and bleeding risk were estimated using CHA2DS2-VASc and HAS-BLED scoring tools. RESULTS: single lead ECGs were recorded in 1805 patients (703 female and 1102 male), mean (SD) age 74.9 (7.1) years. Rhythm regularity could be assessed in 98.7% of ECGs recorded. 92 patients (5.1%) were found to have AF. Median [range]CHA2DS2-VASc score was 4 ([2-7) and median [range] HAS-BLED score was 2 (1-5). CONCLUSION: handheld ECG recording can be used to identify AF in the primary care setting, with minimal training. The yield was relatively high.

Asunto(s)

Fibrilación Atrial/diagnóstico , Electrocardiografía/métodos , Frecuencia Cardíaca/fisiología , Salud Pública , Medición de Riesgo/métodos , Accidente Cerebrovascular/prevención & control , Telemedicina/métodos , Factores de Edad , Anciano , Fibrilación Atrial/complicaciones , Fibrilación Atrial/fisiopatología , Femenino , Estudios de Seguimiento , Humanos , Masculino , Prevalencia , Estudios Retrospectivos , Factores de Riesgo , Escocia/epidemiología , Accidente Cerebrovascular/epidemiología , Accidente Cerebrovascular/etiología

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INTRODUCTION: Amiodarone is associated with significant long-lasting adverse drug reactions (ADRs). Guidelines recommend laboratory monitoring during long-term use. However, data of compliance with laboratory monitoring are lacking. AIMS: The aim of this study was to assess laboratory monitoring of liver and thyroid function during amiodarone prescribing from 1989 to 2011 in the Tayside, UK, population (approximately 400 000) in relation to National Guidelines recommending laboratory monitoring every 6 months. We also report the population-level incidence of abnormal liver and thyroid function in relation to total exposure of amiodarone. METHODS: Utilizing well-established record-linkage database, a longitudinal retrospective analysis of 1413 patients on long-term amiodarone was carried out, analyzing prescribing, biochemical, and clinical data. RESULTS: Forty-six percent (46%), 28%, and 21% of patients underwent liver, thyroid, and combined testing, respectively, in accordance with guideline recommendations. Thirteen percent and 17% of patients did not have any ALT or TSH testing, respectively. During follow-up, 117 (9.5%) patients had an ALT 3×ULN and 16% patients had an abnormal TSH, (n=125, <0.4 mU/L and n=28, >10 mU/L). One hundred and forty patients (10%) required thyroxine replacement therapy, and 40 (3%) required on hyperthyroid medication. Total amiodarone exposure increased the likelihood of abnormal biochemical testing 2.5-fold after 4 years therapy for liver and thyroid function (P<.0005). CONCLUSION: In this population-based study, adherence to laboratory monitoring guidelines was suboptimal. There was a positive correlation with total amiodarone exposure and biochemical abnormalities and development of thyroid disease compared to the general population, highlighting the need for improvement and continued amiodarone monitoring.

Asunto(s)

Amiodarona/efectos adversos , Antiarrítmicos/efectos adversos , Enfermedad Hepática Inducida por Sustancias y Drogas/epidemiología , Monitoreo de Drogas/normas , Pruebas de Función Hepática/normas , Enfermedades de la Tiroides/epidemiología , Pruebas de Función de la Tiroides/normas , Anciano , Anciano de 80 o más Años , Amiodarona/administración & dosificación , Antiarrítmicos/administración & dosificación , Enfermedad Hepática Inducida por Sustancias y Drogas/diagnóstico , Bases de Datos Factuales , Esquema de Medicación , Femenino , Adhesión a Directriz/normas , Humanos , Incidencia , Estudios Longitudinales , Masculino , Persona de Mediana Edad , Guías de Práctica Clínica como Asunto/normas , Valor Predictivo de las Pruebas , Estudios Retrospectivos , Factores de Riesgo , Escocia/epidemiología , Enfermedades de la Tiroides/inducido químicamente , Enfermedades de la Tiroides/diagnóstico , Enfermedades de la Tiroides/tratamiento farmacológico , Factores de Tiempo

RESUMEN

AIMS: Controversy exists regarding the importance of glycaemic control in patients with type 2 diabetes mellitus (T2DM) and chronic heart failure (CHF) based on conflicting reports using single baseline glycosyated haemoglobin (HbA1c ). Using the time-weighted mean of serial HbA1c measurements has been found to be a better predictor of diabetic complications as it reflects the glycaemic burden for that individual over time. We therefore sought to confirm this in a large cohort of patients with T2DM and incident CHF. METHODS AND RESULTS: A time-weighted mean HbA1c was calculated using all HbA1c measurements following CHF diagnosis. Patients were grouped into five categories of HbA1c (≤6.0%, 6.1-7.0%, 7.1-8.0%, 8.1-9.0%, and >9.0%). The relationship between time-weighted mean HbA1c and all-cause death after CHF diagnosis was assessed. A total of 1447 patients with T2DM met the study criteria. During a median follow-up of 2.8 years, there were 826 (57.1%) deaths, with a crude death rate of 155 deaths per 1000 person-years [95% confidence interval (CI) 144-166]. A Cox regression model, adjusted for all significant predictors, with the middle HbA1c category (7.1-8.0%) as the reference, showed a U-shaped relationship between HbA1c and outcome [HbA1c <6.0%, hazard ratio (HR) 2.5, 95% CI 1.8-3.4; HbA1c 6.1-7.0%, HR 1.4, 95% 1.1-1.7; HbA1c 8.1-9.0%, HR 1.3, 95% CI 1.0-1.6; and HbA1c >9.0%, HR 1.8, 95% CI 1.4-2.3]. Further analysis revealed a protective effect of insulin sensitizers (i.e. metformin) (HR 0.7, 95% CI 0.61-0.93) but not other drug classes. CONCLUSIONS: In patients with T2DM and CHF, our study shows a U-shaped relationship between HbA1c and mortality, with the lowest risk in patients with modest glycaemic control (HbA1c 7.1-8.0%) and those treated with insulin sensitizers.

Asunto(s)

Diabetes Mellitus Tipo 2 , Hemoglobina Glucada/análisis , Insuficiencia Cardíaca , Metformina/uso terapéutico , Monitoreo Fisiológico/métodos , Anciano , Anciano de 80 o más Años , Estudios de Cohortes , Diabetes Mellitus Tipo 2/sangre , Diabetes Mellitus Tipo 2/complicaciones , Diabetes Mellitus Tipo 2/tratamiento farmacológico , Diabetes Mellitus Tipo 2/epidemiología , Femenino , Insuficiencia Cardíaca/sangre , Insuficiencia Cardíaca/complicaciones , Insuficiencia Cardíaca/diagnóstico , Insuficiencia Cardíaca/mortalidad , Humanos , Hipoglucemiantes/uso terapéutico , Masculino , Persona de Mediana Edad , Mortalidad , Evaluación de Resultado en la Atención de Salud , Modelos de Riesgos Proporcionales , Medición de Riesgo/métodos , Reino Unido/epidemiología

RESUMEN

Cancer cells adapt metabolically to proliferate under nutrient limitation. Here we used combined transcriptional-metabolomic network analysis to identify metabolic pathways that support glucose-independent tumor cell proliferation. We found that glucose deprivation stimulated re-wiring of the tricarboxylic acid (TCA) cycle and early steps of gluconeogenesis to promote glucose-independent cell proliferation. Glucose limitation promoted the production of phosphoenolpyruvate (PEP) from glutamine via the activity of mitochondrial PEP-carboxykinase (PCK2). Under these conditions, glutamine-derived PEP was used to fuel biosynthetic pathways normally sustained by glucose, including serine and purine biosynthesis. PCK2 expression was required to maintain tumor cell proliferation under limited-glucose conditions in vitro and tumor growth in vivo. Elevated PCK2 expression is observed in several human tumor types and enriched in tumor tissue from non-small-cell lung cancer (NSCLC) patients. Our results define a role for PCK2 in cancer cell metabolic reprogramming that promotes glucose-independent cell growth and metabolic stress resistance in human tumors.

Asunto(s)

Carcinoma de Pulmón de Células no Pequeñas/metabolismo , Regulación Neoplásica de la Expresión Génica , Gluconeogénesis/genética , Neoplasias Pulmonares/metabolismo , Neoplasias/metabolismo , Fosfoenolpiruvato Carboxiquinasa (ATP)/metabolismo , Adaptación Fisiológica/genética , Animales , Carcinoma de Pulmón de Células no Pequeñas/genética , Carcinoma de Pulmón de Células no Pequeñas/patología , Línea Celular Tumoral , Proliferación Celular , Ciclo del Ácido Cítrico/genética , Glucosa/deficiencia , Glutamina/metabolismo , Humanos , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/patología , Metabolómica , Ratones , Ratones Desnudos , Mitocondrias/metabolismo , Neoplasias/genética , Neoplasias/patología , Fosfoenolpiruvato/metabolismo , Fosfoenolpiruvato Carboxiquinasa (ATP)/genética , Purinas/biosíntesis , Ácido Pirúvico/metabolismo , Serina/biosíntesis

RESUMEN

AIMS: To identify the prevalence and characteristics of recently hospitalized chronic heart failure (CHF) patients in community care who meet the indication for ivabradine. METHODS: A retrospective clinical audit of CHF patients recently hospitalized with acute decompensated heart failure (ADHF) and subsequently referred to the Tayside Heart Failure Nurse Liaison Service (THFNLS), a Scottish nurse-led community heart failure liaison service. Inclusion criteria were previous hospitalization with ADHF, subsequent referral to the THFNLS, data for ≥ 2 nurse visits, and a recorded pulse. The main outcome measure was the proportion of patients who meet the indicated criteria for ivabradine. RESULTS: In the UK, ivabradine is indicated for CHF with systolic dysfunction in patients in sinus rhythm, with a heart rate ≥ 75 bpm, and NYHA class II-class IV. After up-titration of a beta-blocker, 19.0% of patients in the full dataset (158 of 830) met the indication for ivabradine at the last visit. Of these "ivabradine-suitable" patients, 101 of 158 (63.9%) received bisoprolol "at any time" during the study period; 20 of 158 (12.7%) achieved the target dose (10 mg daily); 52 of 158 (32.9%) received 5 mg or 7.5 mg daily; and 93 of 158 (58.9%) received <5 mg daily. CONCLUSIONS: In this group of Scottish patients previously hospitalized with ADHF and under the care of a protocol-driven clinic, 19% met the indication for ivabradine and may benefit from the increased control of CHF that ivabradine can provide. Among these "ivabradine-suitable" patients, <15% achieved the target dose of beta-blockers, illustrating the substantial clinical need for a well-tolerated and effective therapy such as ivabradine.

Asunto(s)

Benzazepinas/uso terapéutico , Fármacos Cardiovasculares/uso terapéutico , Insuficiencia Cardíaca/tratamiento farmacológico , Hospitalización/estadística & datos numéricos , Enfermedad Aguda , Anciano , Anciano de 80 o más Años , Benzazepinas/administración & dosificación , Bisoprolol/uso terapéutico , Enfermedad Crónica , Protocolos Clínicos , Utilización de Medicamentos , Femenino , Humanos , Ivabradina , Masculino , Administración del Tratamiento Farmacológico , Persona de Mediana Edad , Estudios Retrospectivos , Reino Unido

RESUMEN

PURPOSE: Left ventricular hypertrophy (LVH) is a significant cardiac risk factor, associated with increased mortality. The impact of LVH on mortality in chronic obstructive pulmonary disease (COPD) is unknown. We evaluated the impact of LVH on mortality in COPD patients by measurement of left ventricular dimensions by echocardiography. METHODS: Retrospective cohort study utilizing a NHS database of COPD patients (TARDIS), in Tayside, Scotland (2001-2010), linked with databases regarding echocardiograms, pharmacy prescription, and the General Register Office for Scotland death registry. Cox proportional hazard regression was used to determine hazard ratios for mortality and hospital admissions based upon left ventricular mass index (LVMI) and left ventricular internal diastolic diameter after correction for all available influential covariates. Increased LVIDd was defined as >5.3 cm (female) and >5.9 cm (male). LVH was defined as an LVMI of >95 g/m(2) (female) and >115 g/m(2) (male). RESULTS: 617 patients were included for analysis. Mean (SD) age at diagnosis, 70 (9); mean FEV1 % (SD), 60.6 (19.3); mean resting SaO2 % (SD), 92.7 (10). Mean follow-up 4.5 years. Increased LVIDd was not associated with increased mortality, χ (2)= 0.767, p = 0.381. Increased LVMI was associated with a significant increased risk of mortality, χ (2) = 5.447, p = 0.02 with an adjusted HR (95 % CI) of 1.542 (1.068-2.228), p = 0.021. CONCLUSIONS: The presence of LVH, demonstrated by elevated left ventricular mass index is associated with a significantly increased risk of mortality in COPD patients. Therapeutic interventions are required to address this important modifiable risk factor in COPD patients.

Asunto(s)

Hipertrofia Ventricular Izquierda/complicaciones , Enfermedad Pulmonar Obstructiva Crónica/mortalidad , Anciano , Causas de Muerte , Femenino , Ventrículos Cardíacos/diagnóstico por imagen , Ventrículos Cardíacos/patología , Hospitalización/estadística & datos numéricos , Humanos , Hipertrofia Ventricular Izquierda/diagnóstico por imagen , Estimación de Kaplan-Meier , Masculino , Persona de Mediana Edad , Infarto del Miocardio/mortalidad , Tamaño de los Órganos , Modelos de Riesgos Proporcionales , Enfermedad Pulmonar Obstructiva Crónica/complicaciones , Estudios Retrospectivos , Escocia/epidemiología , Ultrasonografía

RESUMEN

BACKGROUND: Type 2 diabetes mellitus is an independent risk factor for heart failure development, but the relationship between incident heart failure and antecedent glycemia has not been evaluated. METHODS AND RESULTS: The Genetics of Diabetes Audit and Research in Tayside Study study holds data for 8683 individuals with type 2 diabetes mellitus. Dispensed prescribing, hospital admission data, and echocardiography reports were linked to extract incident heart failure cases from December 1998 to August 2011. All available HbA1c measures until heart failure development or end of study were used to model HbA1c time-dependently. Individuals were observed from study enrolment until heart failure development or end of study. Proportional hazard regression calculated heart failure development risk associated with specific HbA1c ranges accounting for comorbidities associated with heart failure, including blood pressure, body mass index, and coronary artery disease. Seven hundred and one individuals with type 2 diabetes mellitus (8%) developed heart failure during follow up (mean 5.5 years, ±2.8 years). Time-updated analysis with longitudinal HbA1c showed that both HbA1c <6% (hazard ratio =1.60; 95% confidence interval, 1.38-1.86; P value <0.0001) and HbA1c >10% (hazard ratio =1.80; 95% confidence interval, 1.60-2.16; P value <0.0001) were independently associated with the risk of heart failure. CONCLUSIONS: Both high and low HbA1c predicted heart failure development in our cohort, forming a U-shaped relationship.

Asunto(s)

Diabetes Mellitus Tipo 2/sangre , Diabetes Mellitus Tipo 2/epidemiología , Hemoglobina Glucada/análisis , Insuficiencia Cardíaca/sangre , Insuficiencia Cardíaca/epidemiología , Anciano , Comorbilidad , Enfermedad de la Arteria Coronaria/epidemiología , Femenino , Humanos , Masculino , Persona de Mediana Edad , Medición de Riesgo , Factores de Riesgo

RESUMEN

BACKGROUND: The use of oral anticoagulation in patients with heart failure in sinus rhythm remains controversial as previous large randomized controlled trials (RCTs) have not shown a survival benefit. However, heterogeneity exists among heart failure patients and it is possible that high-risk subgroups may benefit from anticoagulation (warfarin). We hypothesize that one such subgroup are patients with heart failure and pulmonary hypertension (PH), conditions associated with coagulation abnormalities. METHODS: We conducted a retrospective, population-based, longitudinal cohort study in patients with left ventricular systolic dysfunction (LVSD) and PH [defined as a right ventricular systolic pressure (RVSP) >35 mmHg] identified from echocardiograms performed between January 1994 to May 2011. This data was linked using a unique patient-specific identifier to community-dispensed prescriptions, hospital admissions, and mortality data. For comparison, we included patients with LVSD and no PH. RESULTS: A total of 2619 subjects with LVSD and a measurable RVSP were identified (mean ± SD age of 73 ± 12 years); 1606 out of 2619 had PH and 1013 out of 2619 had no PH. The overall mean follow-up period was 2.56 ± 3.0 years. In patients with LVSD and PH, the use of warfarin was associated with an improved survival [hazard ratio (HR) = 0.72 95% confidence interval (CI) 0.58-0.90, P = 0.0003], fewer non-cardiovascular disease-related deaths (HR = 0.65, 95%CI 0.49-0.87, P = 0.0033 and showed a trend towards reduced cardiovascular disease-associated mortality (HR = 0.72, 95%CI 0.51-1.02). Warfarin did not improve survival in those with LVSD with no PH. CONCLUSIONS: In patients with both LVSD and PH, the use of warfarin is associated with a 28% reduction in mortality. Further prospective trials are required to confirm our findings.

Asunto(s)

Anticoagulantes/uso terapéutico , Insuficiencia Cardíaca/tratamiento farmacológico , Hipertensión Pulmonar/tratamiento farmacológico , Disfunción Ventricular Izquierda/tratamiento farmacológico , Warfarina/uso terapéutico , Anciano , Anciano de 80 o más Años , Estudios de Casos y Controles , Estudios de Cohortes , Femenino , Insuficiencia Cardíaca/complicaciones , Insuficiencia Cardíaca/mortalidad , Humanos , Hipertensión Pulmonar/complicaciones , Hipertensión Pulmonar/mortalidad , Estudios Longitudinales , Masculino , Persona de Mediana Edad , Modelos de Riesgos Proporcionales , Estudios Retrospectivos , Sístole , Disfunción Ventricular Izquierda/complicaciones , Disfunción Ventricular Izquierda/mortalidad

RESUMEN

BACKGROUND: Glycogen synthase kinase 3 (GSK3) is a central regulator of cellular metabolism, development and growth. GSK3 activity was thought to oppose tumourigenesis, yet recent studies indicate that it may support tumour growth in some cancer types including in non-small cell lung carcinoma (NSCLC). We examined the undefined role of GSK3 protein kinase activity in tissue from human NSCLC. METHODS: The expression and protein kinase activity of GSK3 was determined in 29 fresh frozen samples of human NSCLC and patient-matched normal lung tissue by quantitative immunoassay and western blotting for the phosphorylation of three distinct GSK3 substrates in situ (glycogen synthase, RelA and CRMP-2). The proliferation and sensitivity to the small-molecule GSK3 inhibitor; CHIR99021, of NSCLC cell lines (Hcc193, H1975, PC9 and A549) and non-neoplastic type II pneumocytes was further assessed in adherent culture. RESULTS: Expression and protein kinase activity of GSK3 was elevated in 41% of human NSCLC samples when compared to patient-matched control tissue. Phosphorylation of GSK3α/ß at the inhibitory S21/9 residue was a poor biomarker for activity in tumour samples. The GSK3 inhibitor, CHIR99021 dose-dependently reduced the proliferation of three NSCLC cell lines yet was ineffective against type II pneumocytes. CONCLUSION: NSCLC tumours with elevated GSK3 protein kinase activity may have evolved dependence on the kinase for sustained growth. Our results provide further important rationale for exploring the use of GSK3 inhibitors in treating NSCLC.

Asunto(s)

Carcinoma de Pulmón de Células no Pequeñas/enzimología , Carcinoma de Pulmón de Células no Pequeñas/patología , Proliferación Celular , Glucógeno Sintasa Quinasa 3/metabolismo , Neoplasias Pulmonares/enzimología , Neoplasias Pulmonares/patología , Apoptosis , Western Blotting , Estudios de Casos y Controles , Humanos , Técnicas para Inmunoenzimas , Pulmón/enzimología , Fosforilación , Transducción de Señal , Células Tumorales Cultivadas

RESUMEN

OBJECTIVE: To determine all-cause mortality in patients with a first myocardial infarct who were treated with simvastatin compared with high-potency statin and simvastatin/ezetimibe combination. BACKGROUND: Despite statin use, residual cardiovascular risk remains. Therapeutic options include more potent statins or addition of ezetimibe. There is no clinical outcome data on the use of ezetimibe in such patients. METHODS: Retrospective longitudinal study using the United Kingdom General Practice Research Database. Patients who had survived 30 days after their first acute myocardial infarct (AMI), had not received prior statin or ezetimibe therapy and were started on a statin within 30 days of AMI were included. Three groups were identified according to their follow-up: (i) simvastatin monotherapy; (ii) high-potency statin group (patients who started on simvastatin and switched to atorvastatin or rosuvastatin); and (iii) ezetimibe/statin combination group (patients who received ezetimibe in addition to statin). RESULTS: 9597 patients (57% male, mean age of 65 ± 13 years) matched study criteria: simvastatin (n=6990 (72.8%)); high-potency statin (n=1883, (19.6%)); and ezetimibe/statin combination (n=724 (7.5%)). During a mean follow-up of 3.2 years, there were 1134 (12%) deaths. In the multivariate proportional hazards model, the adjusted HR for high-potency statin and ezetimibe group were 0.72 (95% CI 0.59 to 0.88, p<0.001) and 0.96 (95% CI 0.64 to 1.43, p=0.85), respectively. A similar result was also obtained in the propensity score analysis that took into account covariates that predicted drug treatment groups. CONCLUSIONS: Patients switched to a high-potency statin had a significantly reduced mortality compared with simvastatin monotherapy. There was no observed mortality benefit in the ezetimibe group.

Asunto(s)

Azetidinas/uso terapéutico , Lípidos/sangre , Infarto del Miocardio/tratamiento farmacológico , Vigilancia de la Población , Simvastatina/uso terapéutico , Sobrevivientes/estadística & datos numéricos , Anciano , Combinación de Medicamentos , Quimioterapia Combinada , Combinación Ezetimiba y Simvastatina , Femenino , Estudios de Seguimiento , Humanos , Masculino , Persona de Mediana Edad , Infarto del Miocardio/sangre , Infarto del Miocardio/mortalidad , Estudios Retrospectivos , Tasa de Supervivencia/tendencias , Factores de Tiempo , Resultado del Tratamiento , Reino Unido/epidemiología

RESUMEN

BACKGROUND: Left ventricular hypertrophy has multiple aetiologies including diabetes and genetic factors. We aimed to identify genetic variants predicting left ventricular hypertrophy in diabetic individuals. METHODS: Demographic, echocardiographic, prescribing, morbidity, mortality and genotyping databases connected with the Genetics of Diabetes Audit and Research in Tayside, Scotland project were accurately linked using a patient-specific identifier. Left ventricular hypertrophy cases were identified using echocardiographic data.Genotyping data from 973 cases and 1443 non-left ventricular hypertrophy controls were analysed, investigating whether single nucleotide polymorphisms associated with left ventricular hypertrophy in previous Genome Wide Association Studies predicted left ventricular hypertrophy in our population of individuals with type 2 diabetes. Meta-analysis assessed overall significance of these single nucleotide polymorphisms, which were also used to create gene scores. Logistic regression assessed whether these scores predicted left ventricular hypertrophy. RESULTS: Two single nucleotide polymorphisms previously associated with left ventricular hypertrophy were significant: rs17132261: OR 2.03, 95% CI 1.10-3.73, p-value 0.02 and rs2292462: OR 0.82, 95% CI 0.73-0.93 and p-value 2.26x10-3. Meta-analysis confirmed rs17132261 and rs2292462 were associated with left ventricular hypertrophy (p=1.03x10-8 and p=5.86x10-10 respectively) and one single nucleotide polymorphisms in IGF1R (rs4966014) became genome wide significant upon meta-analysis although was not significant in our study. Gene scoring based on published single nucleotide polymorphisms also predicted left ventricular hypertrophy in our study.Rs17132261, within SLC25A46, encodes a mitochondrial phosphate transporter, implying abnormal myocardial energetics contribute to left ventricular hypertrophy development. Rs2292462 lies within the obesity-implicated neuromedin B gene. Rs4966014 lies within the IGF1R1 gene. IGF1 signalling is an established factor in cardiac hypertrophy. CONCLUSIONS: We created a resource to study genetics of left ventricular hypertrophy in diabetes and validated our left ventricular hypertrophy phenotype in replicating single nucleotide polymorphisms identified by previous genome wide association studies investigating left ventricular hypertrophy.

Asunto(s)

Diabetes Mellitus Tipo 2/complicaciones , Hipertrofia Ventricular Izquierda/genética , Proteínas Mitocondriales/genética , Neuroquinina B/análogos & derivados , Proteínas de Transporte de Fosfato/genética , Anciano , Estudios de Casos y Controles , Femenino , Predisposición Genética a la Enfermedad , Estudio de Asociación del Genoma Completo , Humanos , Hipertrofia Ventricular Izquierda/complicaciones , Hipertrofia Ventricular Izquierda/diagnóstico por imagen , Masculino , Persona de Mediana Edad , Neuroquinina B/genética , Polimorfismo de Nucleótido Simple , Receptor IGF Tipo 1/genética , Ultrasonografía

RESUMEN

Phase III trials of the anti-insulin-like growth factor-1 receptor (IGF1R) antibody figitumumab in non-small cell lung cancer (NSCLC) patients have been discontinued owing to lack of survival benefit. We investigated whether inhibition of the highly homologous insulin receptor (IR) in addition to the IGF1R would be more effective than inhibition of the IGF1R alone at preventing the proliferation of NSCLC cells. Signalling through IGF1R and IR in the NSCLC cell lines A549 and Hcc193 was stimulated by a combination of IGF1, IGF2 and insulin. It was inhibited by antibodies that block ligand binding, αIR3 (IGF1R) and IR47-9 (IR), and by the ATP-competitive small molecule tyrosine kinase inhibitors AZ12253801 and NVPAWD742 which inhibit both IGF1R and IR tyrosine kinases. The effect of inhibitors was determined by an anchorage-independent proliferation assay and by analysis of Akt phosphorylation. In Hcc193 cells the reduction in cell proliferation and Akt phosphorylation due to anti-IGF1R antibody was enhanced by antibody-mediated inhibition of the IR whereas in A549 cells, with a relatively low IR:IGF1R expression ratio, it was not. In each cell line proliferation and Akt phosphorylation were more effectively inhibited by AZ12253801 and NVPAWD742 than by combined αIR3 and IR47-9. When the IGF1R alone is inhibited, unencumbered signalling through the IR can contribute to continued NSCLC cell proliferation. We conclude that small molecule inhibitors targeting both the IR and IGF1R more effectively reduce NSCLC cell proliferation in a manner independent of the IR:IGF1R expression ratio, providing a therapeutic rationale for the treatment of this disease.

Asunto(s)

Carcinoma de Pulmón de Células no Pequeñas/metabolismo , Neoplasias Pulmonares/metabolismo , Terapia Molecular Dirigida , Receptor IGF Tipo 1/antagonistas & inhibidores , Receptor de Insulina/antagonistas & inhibidores , Anticuerpos Monoclonales/farmacología , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Supervivencia Celular/efectos de los fármacos , Humanos , Isoxazoles/farmacología , Inhibidores de Proteínas Quinasas/farmacología , Pirimidinas/farmacología , Receptor IGF Tipo 1/metabolismo , Receptor de Insulina/metabolismo , Transducción de Señal/efectos de los fármacos

Asunto(s)

Marcapaso Artificial , Adolescente , Mama , Estética , Femenino , Humanos , Implantación de Prótesis/métodos , Adulto Joven

RESUMEN

Aortic valve disease (AVD) is the most common form of valvular heart disease in the western world. The only proven therapy for severe AVD is open aortic valve replacement, with trans-catheter aortic valve implantation emerging as a promising modality to treat severe aortic stenosis in a selected group of patients. AVD has a long asymptomatic phase with symptoms occurring late in the disease and once symptoms develop, prognosis is poor. There is a growing appreciation that aortic valvular heart disease incorporates a disease process that extends beyond the valve itself leading to an aortic valvular 'heart' disease. The renin-angiotensin system is known to modulate adverse left ventricular remodeling and myocardial fibrosis, which could be caused by increased load caused by the AVD. In this review, the authors explore evidence that suggest that drugs that target the renin-angiotensin system may have a potential therapeutic role in AVD.

Asunto(s)

Inhibidores de la Enzima Convertidora de Angiotensina/uso terapéutico , Cardiotónicos/uso terapéutico , Cardiopatías Congénitas/tratamiento farmacológico , Enfermedades de las Válvulas Cardíacas/tratamiento farmacológico , Inhibidores de la Enzima Convertidora de Angiotensina/efectos adversos , Animales , Válvula Aórtica/metabolismo , Válvula Aórtica/fisiopatología , Estenosis de la Válvula Aórtica/etiología , Estenosis de la Válvula Aórtica/prevención & control , Enfermedad de la Válvula Aórtica Bicúspide , Cardiotónicos/efectos adversos , Medicina Basada en la Evidencia , Cardiopatías Congénitas/metabolismo , Cardiopatías Congénitas/fisiopatología , Enfermedades de las Válvulas Cardíacas/metabolismo , Enfermedades de las Válvulas Cardíacas/fisiopatología , Humanos , Sistema Renina-Angiotensina/efectos de los fármacos , Remodelación Ventricular/efectos de los fármacos

RESUMEN

BNP (B-type natriuretic peptide) has been reported to be elevated in preclinical states of vascular damage. To elucidate the relationship between plasma BNP and endothelial function, we have investigated the relationship between BNP and endothelial function in a cohort of subjects comprising healthy subjects as well as at-risk subjects with cardiovascular risk factors. To also clarify the relative contribution of different biological pathways to the individual variation in endothelial function, we have examined the relationship between a panel of multiple biomarkers and endothelial function. A total of 70 subjects were studied (mean age, 58.1±4.6 years; 27% had a history of hypertension and 18% had a history of hypercholesterolaemia). Endothelium-dependent vasodilatation was evaluated by the invasive ACH (acetylcholine)-induced forearm vasodilatation technique. A panel of biomarkers of biological pathways was measured: BNP, haemostatic factors PAI-1 (plasminogen-activator inhibitor 1) and tPA (tissue plasminogen activator), inflammatory markers, including cytokines [hs-CRP (high sensitive C-reactive protein), IL (interleukin)-6, IL-8, IL-18, TNFα (tumour necrosis factor α) and MPO (myeloperoxidase] and soluble adhesion molecules [E-selectin and sCD40 (soluble CD40)]. The median BNP level in the study population was 26.9 pg/ml. Multivariate regression analyses show that age, the total cholesterol/HDL (high-density lipoprotein) ratio, glucose and BNP were independent predictors of endothelial function, and BNP remained an independent predictor (P=0.009) in a binary logistic regression analysis using FBF (forearm blood flow) as a dichotomous variable based on the median value. None of the other plasma biomarkers was independently related to ACH-mediated vasodilatation. In a strategy using several biomarkers to relate to endothelial function, plasma BNP was found to be an independent predictor of endothelial function as assessed by endothelium-dependent vasodilatation in response to ACH.

Asunto(s)

Arteria Braquial/fisiología , Endotelio Vascular/fisiología , Péptido Natriurético Encefálico/sangre , Vasodilatación , Biomarcadores/sangre , Enfermedades Cardiovasculares/sangre , Enfermedades Cardiovasculares/etiología , Estudios de Cohortes , Femenino , Humanos , Modelos Lineales , Modelos Logísticos , Masculino , Persona de Mediana Edad , Análisis Multivariante , Factores de Riesgo

RESUMEN

BACKGROUND: Tiotropium has been shown to improve lung function, quality of life, and exacerbations and reduce mortality when compared with placebo in COPD. It remains unclear whether benefits are seen when tiotropium is used in conjunction with inhaled corticosteroids (ICSs) plus long-acting ß-agonists (LABAs). METHODS: We performed a retrospective cohort study using a National Health Service database of patients with COPD in Tayside, Scotland, between 2001 and 2010 that is linked with databases regarding hospital admissions, pharmacy prescriptions, and death registries. The impact of the addition of tiotropium (Tio) to ICS + LABA therapy on all-cause mortality, hospital admissions for respiratory disease, and emergency oral corticosteroid bursts was evaluated. Adjusted hazard ratios (HRs) were calculated by Cox regression after inclusion of the following covariates: cardiovascular and respiratory disease, diabetes, smoking, age, sex, and deprivation index. RESULTS: A total of 1,857 patients were given ICS + LABA + Tio, and 996 were given ICS + LABA. Mean follow-up was 4.65 years. The adjusted HR for all-cause mortality for ICS + LABA + Tio vs ICS + LABA was 0.65 (95% CI, 0.57-0.75; P < .001). Adjusted HRs for hospital admissions and oral corticosteroid bursts were 0.85 (95% CI, 0.73-0.99; P = .04) and 0.71 (95% CI, 0.63-0.80; P < .001), respectively. CONCLUSIONS: The study suggests that the addition of tiotropium to ICSs and LABA therapy may confer benefits in reducing all-cause mortality, hospital admissions, and oral corticosteroid bursts in patients with COPD. Triple therapy is widely used in the real-life management of COPD, with only limited scientific support. The study supports the use of triple therapy in COPD and provides a platform for randomized controlled trials specifically addressing this topic.

Asunto(s)

Agonistas Adrenérgicos beta/administración & dosificación , Glucocorticoides/administración & dosificación , Enfermedad Pulmonar Obstructiva Crónica/tratamiento farmacológico , Derivados de Escopolamina/administración & dosificación , Administración por Inhalación , Anciano , Causas de Muerte/tendencias , Antagonistas Colinérgicos/administración & dosificación , Preparaciones de Acción Retardada/administración & dosificación , Relación Dosis-Respuesta a Droga , Quimioterapia Combinada , Femenino , Estudios de Seguimiento , Volumen Espiratorio Forzado/efectos de los fármacos , Mortalidad Hospitalaria/tendencias , Humanos , Masculino , Modelos de Riesgos Proporcionales , Enfermedad Pulmonar Obstructiva Crónica/mortalidad , Enfermedad Pulmonar Obstructiva Crónica/fisiopatología , Recurrencia , Estudios Retrospectivos , Escocia/epidemiología , Tasa de Supervivencia/tendencias , Factores de Tiempo , Bromuro de Tiotropio , Resultado del Tratamiento , Capacidad Vital/efectos de los fármacos

RESUMEN

AIMS: The presence of pulmonary hypertension (PH) in left ventricular systolic dysfunction (LVSD) and symptomatic heart failure is an ominous sign. There are insufficient data regarding the risk conferred by increasing severity of PH in patients with heart failure. METHODS AND RESULTS: We performed a record linkage study in Tayside, Scotland (population ∼400,000) utilizing the Tayside echocardiogram database (>50,000 echocardiograms) maintained by the Health Informatics Centre (HIC). Data sets from the HIC include mortality data, cardiovascular medications, and other healthcare activities linked anonymously by the community health index (CHI) number. Patients were included in the analysis if they had LVSD, had a valid right ventricular systolic pressure (RVSP) measurement, and had a loop diuretic prescription (provided not more than 1 year prior to echocardiogram). A Cox proportional hazard model was used to examine the effects of RVSP on all-cause mortality. A total of 1612 patients [mean age, 75.2 ± 10.9 (SD) years; 57.4% male] met the entry criteria. Mean RVSP for the cohort was 44.9 ± 13.1 mmHg and mean follow-up was 2.8 ± 2.5 years. For each 5 mmHg stepwise increase in RVSP, after adjustment for confounding factors including the degree of LVSD and the presence of chronic obstructive pulmonary disease, the hazard ratio (HR) for all-cause mortality was 1.06 (1.03-1.08, P < 0.001). CONCLUSIONS: Pulmonary hypertension predicted all-cause mortality in a heterogeneous group of patients with heart failure. Each 5 mmHg rise in RVSP was associated with a 6% increased risk of death.

Asunto(s)

Insuficiencia Cardíaca/mortalidad , Hipertensión Pulmonar/complicaciones , Disfunción Ventricular Izquierda/complicaciones , Anciano , Anciano de 80 o más Años , Estudios de Cohortes , Ecocardiografía , Femenino , Insuficiencia Cardíaca/complicaciones , Insuficiencia Cardíaca/diagnóstico por imagen , Humanos , Masculino , Persona de Mediana Edad , Modelos de Riesgos Proporcionales , Estudios Retrospectivos , Sístole , Disfunción Ventricular Izquierda/diagnóstico por imagen , Presión Ventricular

RESUMEN

BACKGROUND: Right ventricular apical pacing can cause dyssynchronous activation of the ventricles, increase sympathetic activation, cause abnormalities in myocardial perfusion, worsen cardiac output and endothelial function, and may be associated with adverse cardiovascular effects. The use of rennin-angiotensin system blockers (RASBs) may be beneficial in counteracting these potentially harmful effects of right ventricular pacing. OBJECTIVE: To explore the impact of RASB use on the outcome in patients with right ventricular pacemakers implanted for complete atrioventricular (AV) block. METHODS: Patients implanted with right ventricular pacemakers for complete AV block between 1994 and 2009 were identified from the Tayside Pacing Registry. Cox proportional hazards model was used to assess differences in all-cause mortality and congestive heart failure hospitalizations for those receiving RASB during follow-up, adjusted for confounding variables. We also performed 2 sensitivity analyses--a propensity score-matched analysis and time-dependent analyses--to minimize bias. RESULTS: Eight hundred twenty patients (57% men; median age 73 years; range 22-103 years) received pacemakers for complete AV block between 1994 and 2008 (54% dual-chamber pacemaker and 46% ventricular demand pacemaker). Two hundred seventy-eight (34%) patients had received RASBs. Mean follow-up was 4.9 ± 4.6 years, with 540 (65%) deaths. RASB use was independently associated with significantly reduced mortality (adjusted hazard ratio 0.67; 95% confidence interval 0.47-0.94; P = .017) and reduced heart failure hospitalization (adjusted hazard ratio 0.42; 95% confidence interval 0.17-0.92; P <.001). CONCLUSIONS: This study suggests that RASBs may confer outcome benefits in patients with right ventricular pacemakers implanted for complete AV block.

Asunto(s)

Bloqueo Atrioventricular/terapia , Estimulación Cardíaca Artificial/métodos , Insuficiencia Cardíaca/mortalidad , Hospitalización , Sistema Renina-Angiotensina/efectos de los fármacos , Adulto , Anciano , Anciano de 80 o más Años , Bloqueadores del Receptor Tipo 1 de Angiotensina II/uso terapéutico , Inhibidores de la Enzima Convertidora de Angiotensina/uso terapéutico , Antihipertensivos/uso terapéutico , Distribución de Chi-Cuadrado , Intervalos de Confianza , Femenino , Insuficiencia Cardíaca/tratamiento farmacológico , Insuficiencia Cardíaca/terapia , Humanos , Masculino , Persona de Mediana Edad , Puntaje de Propensión , Modelos de Riesgos Proporcionales , Sistema de Registros , Factores de Riesgo , Estadísticas no Paramétricas , Resultado del Tratamiento , Reino Unido , Adulto Joven

RESUMEN

OBJECTIVES: The aim of this study was to investigate the effect of renin-angiotensin system blockade on outcomes in patients with aortic regurgitation (AR). BACKGROUND: Angiotensin-converting enzyme (ACE) inhibitors have the potential to reduce afterload, blunt left ventricular wall stress, and limit left ventricular dilation and hypertrophy. However, long-term studies have yielded inconsistent results, and very few have assessed clinical outcomes. METHODS: The Health Informatics Centre dispensed prescription and morbidity and mortality database for the population of Tayside, Scotland, was linked through a unique patient identifier to the Tayside echocardiography database. Patients diagnosed with at least moderate AR from 1993 to 2008 were identified. Cox regression analysis was used to assess differences in all-cause mortality and cardiovascular (CV) and AR events (heart failure hospitalizations, heart failure deaths, or aortic valve replacement) between those treated with and without ACE inhibitors or angiotensin receptor blockers (ARBs). RESULTS: A total of 2,266 subjects with AR (median age 74 years; interquartile range: 64 to 81 years) were studied, with a mean follow-up period of 4.4 ± 3.7 years. Seven hundred and five patients (31%) received ACE inhibitor or ARB therapy. There were 582 all-cause deaths (25.7%). Patients treated with ACE inhibitors or ARBs had significantly lower all-cause mortality and fewer CV and AR events, with adjusted hazard ratios of 0.56 (95% confidence interval [CI]: 0.64 to 0.89; p < 0.01) for all-cause mortality, 0.77 (95% CI: 0.67 to 0.89; p < 0.01) for CV events, and 0.68 (95% CI: 0.54 to 0.87; p < 0.01) for AR events. CONCLUSIONS: This large retrospective study shows that the prescription of ACE inhibitors or ARBs in patients with moderate to severe AR was associated with significantly reduced all-cause mortality and CV and AR events. These data need to be confirmed by a prospective randomized controlled outcome trial.

Asunto(s)

Antagonistas de Receptores de Angiotensina/uso terapéutico , Inhibidores de la Enzima Convertidora de Angiotensina/uso terapéutico , Insuficiencia de la Válvula Aórtica/tratamiento farmacológico , Anciano , Anciano de 80 o más Años , Insuficiencia de la Válvula Aórtica/complicaciones , Insuficiencia de la Válvula Aórtica/diagnóstico por imagen , Insuficiencia de la Válvula Aórtica/mortalidad , Ecocardiografía , Femenino , Insuficiencia Cardíaca/etiología , Insuficiencia Cardíaca/mortalidad , Insuficiencia Cardíaca/prevención & control , Humanos , Estudios Longitudinales , Masculino , Persona de Mediana Edad , Estudios Retrospectivos , Escocia/epidemiología

RESUMEN

Pacemaker implantation remains the only therapeutic option that improves morbidity and mortality for patients with symptomatic bradycardia. However, pacing from the right ventricular apex can induce dyssynchronous activation of the ventricles, increase sympathetic activation, cause abnormalities in myocardial perfusion, worsen cardiac output and endothelial function and may be associated with adverse cardiovascular outcomes. This article reviews the current knowledge on the pathophysiology of pacing-induced cardiovascular disease and current strategies to avoid and mitigate the adverse effects of right ventricular pacing.

Asunto(s)

Bradicardia/terapia , Estimulación Cardíaca Artificial/efectos adversos , Cardiopatías/etiología , Animales , Gasto Cardíaco , Estimulación Cardíaca Artificial/métodos , Cardiopatías/fisiopatología , Ventrículos Cardíacos/fisiopatología , Humanos , Marcapaso Artificial , Disfunción Ventricular/etiología , Disfunción Ventricular/fisiopatología