Sustained-release isosorbide mononitrate as adjuvant treatment in isolated systolic hypertension in the elderly.

Hypertension is one of the main cardiovascular risk factors. In the elderly, the most common form is isolated systolic hypertension, a consequence of the increase in arterial stiffness. None of the antihypertensives currently used affects arterial stiffness, whereas nitrates seem to have an effect. The aim of this work was to assess their effect on elderly patients with uncontrolled isolated systolic hypertension, defined as systolic blood pressure over 140 mmHg and diastolic blood pressure under 90 mmHg. The present study is a phase III, randomized, multicenter, double-blind, placebo-controlled clinical trial, conducted at the University Hospital La Princesa in Madrid. Patients of both sexes, aged 65 years or older, with poorly controlled isolated systolic hypertension, were treated with 40-60 mg of sustained-release isosorbide mononitrate or matching placebo for 12 weeks. The main objective was to assess the effect on clinical pulse pressure (PP); in addition, its effect on vascular function was evaluated. Analysis was performed by intention to treat. The study was registered at the European Union Clinical Trials Register (EUDRACT 2012-002988-10) and was funded by the Spanish Ministry of Health. A total of 58 patients with an average age of 77 years were enrolled, 32 were treated with nitrate, and 26 with placebo. No significant differences were found either in PP decline (5.28 vs 7.49 mmHg, p = 0.79) or in other variables, including parameters of vascular function. There were no differences in adverse events. The results of this study have not confirmed the benefit of nitrate treatment in isolated systolic hypertension or the improvement of vascular function.

Familial hypercholesterolemia: A single-nucleotide variant (SNV) in mosaic at the low density lipoprotein receptor (LDLR).

BACKGROUND AND AIMS: Familial hypercholesterolemia is most frequently caused by genetic variants in the LDLR gene. Most of LDLR pathogenic variants are missense, followed by splicing and deletion/insertions variants. Mosaicism is a genetic condition in which an individual shows more than one clone of cells with different genotypes. The objective of this article was the molecular characterization of a patient with hypercholesterolemia. METHODS AND RESULTS: Genetic analysis of DNA from peripheral blood and saliva was performed by NGS, Sanger sequencing and pyrosequencing technologies. NGS analysis detected the pathogenic variant LDLR:c.1951G > T:p.(Asp651Tyr) in 9%-12% of reads. The presence of the variant was confirmed by pyrosequencing analysis. The variant found was functional characterized using an in vitro model (CHO-ldlA7 cells). Activity and expression of cell surface LDLR were measured by flow cytometry. Colocalization LDLR-Dil-LDL was detected by immunofluorescence. The LDLR activity showed 80% uptake, 50% binding and 53% expression of cell surface LDLR regarding wild type. CONCLUSIONS: Herein, we report the first case of a mosaic single nucleotide variant affecting the LDLR gene in a patient with familial hypercholesterolemia. As it has been described for other pathologies, mosaicism could be underestimated in FH and its detection will improve with the introduction of NGS technologies in the diagnostic routine.

Functional analysis of new variants at the low-density lipoprotein receptor associated with familial hypercholesterolemia.

Familial hypercholesterolemia is an autosomal dominant disease of lipid metabolism caused by defects in the genes LDLR, APOB, and PCSK9. The prevalence of heterozygous familial hypercholesterolemia (HeFH) is estimated between 1/200 and 1/250. Early detection of patients with FH allows initiation of treatment, thus reducing the risk of coronary heart disease. In this study, we performed in vitro characterization of new LDLR variants found in our patients. Genetic analysis was performed by Next Generation Sequencing using a customized panel of 198 genes in DNA samples of 516 subjects with a clinical diagnosis of probable or definitive FH. All new LDLR variants found in our patients were functionally validated in CHO-ldlA7 cells. The LDLR activity was measured by flow cytometry and LDLR expression was detected by immunofluorescence. Seven new variants at LDLR were tested: c.518 G>C;p.(Cys173Ser), c.[684 G>T;694 G>T];p.[Glu228Asp;Ala232Ser], c.926C>A;p.(Pro309His), c.1261A>G;p.(Ser421Gly), c.1594T>A;p.(Tyr532Asn), and c.2138delC;p.(Thr713Lysfs*17). We classified all variants as pathogenic except p.(Ser421Gly) and p.(Ala232Ser). The functional in vitro characterization of rare variants at the LDLR is a useful tool to classify the new variants. This approach allows us to confirm the genetic diagnosis of FH, avoiding the classification as "uncertain significant variants", and therefore, carry out cascade family screening.

Type and doses of oral anticoagulants and adherence to anticoagulant treatment in elderly patients with atrial fibrillation: the ESPARTA study.

AIM: To analyze the use of oral anticoagulants in elderly patients with atrial fibrillation in clinical practice. PATIENTS & METHODS: Cross-sectional and multicenter study performed in atrial fibrillation patients ≥75 years treated with oral anticoagulants ≥3 months. RESULTS: 837 patients (83.0 ± 5.0 years; CHA2DS2-VASc 5.0 ± 1.4; HAS-BLED 2.1 ± 0.9; 70.8% vitamin K antagonists; 29.2% direct oral anticoagulants [DOACs]) were included. Poor adherence was observed in 27.9% of patients. Higher scores in the Pfeiffer's test and FRAIL scale were associated with poorer adherence. Among patients treated with DOACs, 62.3% received the lower doses. Having high CHADS2 score and being older were associated with the use of low doses. CONCLUSION: 28% of patients had a poor adherence to anticoagulant treatment. 62% of patients were treated with the lower doses of DOACs.

Effect of oral nitrates on pulse pressure and arterial elasticity in patients aged over 65 years with refractory isolated systolic hypertension: study protocol for a randomized controlled trial.

BACKGROUND: Isolated systolic hypertension is a highly prevalent disease among the elderly. The little available evidence on the efficacy of nitrates for treating the disease is based on small experimental studies. METHODS/DESIGN: We performed a multicenter, randomized, double-blind, phase III, placebo-controlled trial in 154 patients aged over 65 years with refractory isolated systolic hypertension. Patients were randomized to placebo or 40 mg/day of extended-release isosorbide mononitrate added to standard therapy and titrated to 60 mg/day at week 6 if blood pressure exceeded 140/90 mmHg.The primary objective was to assess the effect on clinical pulse pressure of extended-release isosorbide mononitrate added to standard therapy in patients aged over 65 years with refractory isolated systolic hypertension after 3 months of treatment.The secondary objectives were as follows: to quantify the effect of adding the study drug on central blood pressure and vascular compliance using the augmentation index and pulse wave velocity; to evaluate the safety profile by recording adverse effects (frequency, type, severity) and the percentage of patients who had to withdraw from the trial because of adverse events; to quantify the percentage of patients who reach a clinical systolic blood pressure <140 mmHg or <130 mmHg measured by ambulatory blood pressure monitoring; and to quantify the change in pulse pressure measured by ambulatory blood pressure monitoring. DISCUSSION: Few clinical trials have been carried out to test the effect of oral nitrates on isolated systolic hypertension, even though these agents seem to be effective. Treatment with extended-release isosorbide mononitrate could improve control of systolic blood pressure without severe side effects, thus helping to reduce the morbidity and mortality of the disease. TRIAL REGISTRATION: EUDRACT Number: 2012-002988-10.

A cluster-randomised clinical trial comparing two cardiovascular health education strategies in a child population: the Savinghearts project.

BACKGROUND: This paper describes a methodology for comparing the effects of an eduentertainment strategy involving a music concert, and a participatory class experience involving the description and making of a healthy breakfast, as educational vehicles for delivering obesity-preventing/cardiovascular health messages to children aged 7-8 years. METHODS/DESIGN: This study will involve a cluster-randomised trial with blinded assessment. The study subjects will be children aged 7-8 years of both sexes attending public primary schools in the Madrid Region. The participating schools (n=30) will be randomly assigned to one of two groups: 1) Group MC, in which the children will attend a music concert that delivers obesity-preventing/cardiovascular health messages, or 2) Group HB, in which the children will attend a participatory class providing the same information but involving the description and making of a healthy breakfast. The main outcome measured will be the increase in the number of correct answers scored on a knowledge questionnaire and in an attitudes test administered before and after the above interventions. The secondary outcome recorded will be the reduction in BMI percentile among children deemed overweight/obese prior to the interventions. The required sample size (number of children) was calculated for a comparison of proportions with an α of 0.05 and a ß of 0.20, assuming that the Group MC subjects would show values for the measured variables at least 10% higher than those recorded for the subjects of Group HB. Corrections were made for the design effect and assuming a loss to follow-up of 10%. The maximum sample size required will be 2107 children. Data will be analysed using summary measurements for each cluster, both for making estimates and for hypothesis testing. All analyses will be made on an intention-to-treat basis. DISCUSSION: The intervention providing the best results could be recommended as part of health education for young schoolchildren. TRIAL REGISTRATION: Clinicaltrials.gov: NCT01418872.

Influence of multiple blood pressure measurements on the estimation of the ankle-brachial index and the consequent diagnosis of peripheral artery disease.

OBJECTIVE: The ankle-brachial index (ABI) is the most useful and efficient tool for assessing the presence of peripheral artery disease (PAD). The aim of this study was to evaluate the effect of multiple sequential blood pressure (BP) measurements on the estimation of the ABI and the consequent diagnosis of PAD in a high vascular risk population. METHODS: This is a cross-sectional study of 71 patients admitted to the Cardiology Department or evaluated as outpatients in the Internal Medicine Department at our institution. The ABI was calculated with the first blood pressure (BP) measurement in the arm with the higher BP (dominant arm; method A) and with the average of the second and third measurements in that same arm (method B). The results of both methods were compared. RESULTS: No statistically significant difference was found for the numerical value of ABI between the methods. The κ correlation index for agreement in the diagnosis of PAD between the methods was 0.87 (95% confidence interval: 0.74-0.99). CONCLUSION: Multiple BP measurements had no impact on the final ABI or on the subsequent diagnosis of PAD.

A Study on the Relationship between Serum Beta 2-Microglobulin Levels, Underlying Chronic Kidney Disease, and Peripheral Arterial Disease in High-Vascular-Risk Patients.

BACKGROUND: Serum beta 2-microglobulin (B2M) levels have been found to be increased in patients with peripheral arterial disease (PAD), yet it is still unknown whether B2M correlates with PAD intensity. OBJECTIVES: We aim to evaluate the correlation between B2M and the ankle-brachial index (ABI) values in high-vascular-risk patients. METHODS: This is a cross-sectional study of 63 high-vascular-risk patients admitted to the Cardiology Department or evaluated as outpatients in the Internal Medicine Department of our institution. Patients were classified into two groups according to their ABI: patients without PAD (n = 44, ABI values between 0.9 and 1.4) and patients with PAD (n = 19, ABI values lower than 0.9 or higher than 1.4). We performed univariate and multivariate analysis based on a multiple linear regression model. RESULTS: Serum B2M levels were higher in patients with pathological ABI values than in those without PAD (2.36 ± 1.13 vs. 1.80 ± 0.65 mg/L; P<0.05). We found no correlation between B2M and ABI in our total population (r = -0.12) or in patients with PAD (r = -0.09; NS for both comparisons). Age, gender, arterial hypertension, estimated glomerular filtration rate (eGFR), uric acid, total cholesterol, and LDL-cholesterol correlated with B2M in the univariate analysis. In the final linear regression model, eGFR, uric acid and total cholesterol correlated independently with B2M (P<0.01). CONCLUSION: We found no correlation between B2M levels and ABI values in high-vascular-risk patients that could usefully help in the subsequent diagnosis of PAD. However, we observed a significant correlation between B2M and eGFR, even when renal function was only slightly impaired.

Datos al año de seguimiento del registro REACH en España / One-year data from the REACH registry in Spain

La aterotrombosis es una de las principales causas de mortalidad en todo el mundo. Constituye un importante problema para la salud pública en España, al igual que en el resto de los países, y constituye una prioridad asistencial. El objetivo del registro REACH (REduction of Atherothrombosis for Continued Health) es analizar el riesgo a largo plazo de los episodios aterotrombóticos en la población de riesgo, evaluar la importancia del riesgo cruzado y definir los factores pronósticos de los episodios aterotrombóticos. En el registro REACH se han inscrito más de 68.000 pacientes en más de 5.000 centros distribuidos en 44 países, de los cuales 2.252 se encuentran en España. Como en los resultados a escala mundial, en los pacientes españoles la tasa de complicaciones, solamente al año de seguimiento, fue alta. La tasa anual de mortalidad global en los pacientes con enfermedad vascular establecida (EV) o en prevención primaria pero con alto riesgo aterotrombótico, representado por los pacientes con sólo factores de riesgo, fue del 3,57 y del 1,98%, respectivamente, la de mortalidad cardiovascular del 2,69 y del 0,62%. Las tasas según el territorio afectado fueron, en los subgrupos de enfermedad coronaria, enfermedad cerebrovascular y en el de enfermedad arterial periférica, del 3,47, del 2,78 y del 1,46%, respectivamente. La afección de más de un territorio es claramente un factor de mal pronóstico, de forma que la tasa anual de complicaciones se incrementó según tuvieran 0, 1, 2 o 3 territorios vasculares afectados, respectivamente, para la mortalidad cardiovascular (0,62, 2,46, 3,55 y 4,32%; p < 0,05) y para el conjunto de mortalidad cardiovascular más infarto, más ictus y más hospitalización cardiovascular (5,50, 4,18, 20,59 y 19,40%). Es importante resaltar el mal pronóstico de estos pacientes, incluso a corto plazo, especialmente en aquellos con enfermedad vascular establecida y tanto peor cuanto más extensa sea la afectación vascular. Por ello es necesario mejorar esta situación, identificando más precozmente a los sujetos de alto riesgo y optimizando las medidas preventivas, tanto en prevención primaria como secundaria (AU)

Atherothrombosis is one of the main causes of death worldwide. In Spain, as in other countries, this disease is a major public health problem, constituting a healthcare priority. The aim of the REduction of Atherothrombosis for Continued Health (REACH) registry is to analyze the long-term risk of atherothrombotic episodes in the at-risk population, evaluate the importance of cross risk, and define the prognostic factors of atherothrombotic episodes. More than 68,000 patients in more than 5,000 centers in 44 countries have been included in the REACH registry, of which 2,252 live in Spain. As observed internationally, in Spanish patients the complication rate at only 1-year of follow-up was high. The annual overall mortality rate in patients with established vascular disease or under primary prevention but with high atherothrombotic risk, represented by patients with risk factors only, was 3.57% and 1.98%, respectively, while that of cardiovascular mortality was 2.69% and 0.62%. In the subgroups of coronary artery disease (CAD), cerebral vascular disease (CVD) and peripheral artery disease (PAD) rates according to the affected territory were 3.47%, 2.78% and 1.46%, respectively. Involvement of more than one territory was clearly a poor prognostic factor: the annual complications rate increased according to whether 0, 1, 2, or 3 vascular beds were diseased for cardiovascular mortality (0.62%, 2.46%, 3.55% and 4.32%, respectively, p < 0.05) and for cardiovascular mortality, plus myocardial infarction, plus stroke, plus hospitalization for cardiovascular reasons these rates were 5.50%, 4.18%, 20.59% and 19.40%. Importantly, these patients have a poor prognosis even in the short-term, especially those with established vascular disease; furthermore, the greater the number of diseased vascular beds, the poorer the prognosis. This situation must therefore be improved by earlier identification of at-risk individuals and by optimizing both primary and secondary preventive measures (AU)

Abordaje multidisciplinar de la enfermedad aterotrombótica / Multidisciplinary approach to atherothrombotic disease

La aterotrombosis es una enfermedad sistémica que puede expresarse por la afectación de diferentes territorios vasculares, siendo más frecuentemente el coronario, vasculocerebral o el arterial periférico el que lleva a su diagnóstico. La ateromatosis aórtica o de sus ramas puede ser asintomática o manifestarse clínicamente en forma de isquemia meséntérica o nefropatía isquémica. Es, por ello, una patología que afecta a diferentes especialidades médicas y ámbitos asistenciales, como la cardiología, la neurología, la nefrología, la endocrinología, la cirugía vascular, la medicina interna y la atención primaria. La afectación simultánea de diferentes territorios, de forma sintomática o asintomática, hace necesario un abordaje global, multidisciplinar y coordinado. Adicionalmente, la actuación médica no debe limitarse al tratamiento del accidente agudo, y el pilar clave lo constituye la prevención, tanto primaria como secundaria. Es aquí donde, especialmente, las especialidades con visión global, como la medicina interna o los médicos de atención primaria, deben tener un papel coordinador y prioritario. Esta intervención multidisciplinar afecta no solamente al personal facultativo, sino también a otro tipo de personal sanitario, como dietistas, especialistas en ejercicio físico y, muy especialmente, a la enfermería, que debe desempeñar un papel clave en el control de los factores de riesgo, en la educación sanitaria y en la monitorización de adherencia al tratamiento (AU)

Atherothrombosis is a systemic disease that can manifest as involvement of distinct vascular territories; those most frequently leading to diagnosis being coronary, cerebrovascular and peripheral arterial vascular territories. Atheromatosis of the aorta or its branches can be asymptomatic or manifest clinically in the form of mesenteric ischemia or ischemic nephropathy. Atherothrombosis therefore involves distinct medical specialities and healthcare levels such as cardiology, neurology, nephrology, endocrinology, vascular surgery, internal medicine, and primary care. Simultaneous involvement of more than one vascular territory, whether symptomatic or asymptomatic, requires a global, multidisciplinary and coordinated approach. Additionally, medical intervention should not be limited to treatment of the acute accident as prevention, both primary and secondary, is a key factor in the management of this disease. It is here that specialties with an overall view such as internal medicine or primary care are especially well placed to play a fundamental and coordinating role. This multidisciplinary intervention involves not only physicians but also other health professionals such as dieticians, physical exercise specialists and, especially, nurses, who should play a key role in controlling risk factors, in health education and in monitoring treatment adherence (AU)

Thyroid hormone resistance and pituitary enlargement after thyroid ablation in a woman on levothyroxine treatment.

We report a patient with inappropriate secretion of thyrotropin (TSH) and a pituitary mass. Although she had been treated for biochemical hyperthyroidism with thyroid surgery and radioiodine ablation, she had never complained of specific symptoms or demonstrated signs of overt thyroid dysfunction. On evaluation, she had increased free thyroxine and TSH levels, normal serum glycoprotein alpha-subunit levels, and a significant TSH over-response to exogenous thyrotropin-releasing hormone stimulation. Magnetic resonance imaging with gadolinium enhancement showed a pituitary enlargement with suprasellar extension. An indium In 111 pentetreotide scan showed an abnormal focus of radionuclide accumulation in the pituitary area. Sequencing of the TRbeta gene showed that the patient was heterozygous for a new single nucleotide substitution resulting in the replacement of the normal arginine with a serine at amino acid 320 (R320S). We review the difficulties encountered in establishing a correct diagnosis in patients with inappropriate secretion of TSH in combination with pituitary enlargement. Due to its possible false-negative results, we do not recommend the use of indium In 111 pentetreotide as a tool in the differential diagnosis of inappropriate secretion of TSH.

Ambulatory blood pressure monitoring: is the daytime period enough for making clinical decisions?

AIM: To assess the agreement between the clinical information provided by the ambulatory daytime average and 24 h average blood pressure value for diagnosing hypertension and assessing the effects of antihypertensive treatment. METHODS: We analysed 261 24 h ambulatory monitoring records (SpaceLabs 90207, SpaceLabs, Redmond, Washington, USA) obtained from hypertensives over 18 years of age (mean age 55.8 years) in order to make a diagnosis of hypertension or assess its control in response to treatment. Recording was programmed to occur every 20 min during waking periods and every 30 min during sleep, daily activity also being registered. The criteria compared in the diagnosis of hypertension were: (1) the evaluation criterion: an average blood pressure for the activity period of less than 135/85 mmHg (Joint National Committee VI); (2) the gold standard: an average blood pressure over 24 h of less than 125/80 mmHg (World Health Organization-International Society of Hypertension, 1999). RESULTS: In 90% of the records, there was agreement between both criteria. In 7.2%, the awake blood pressure average was normal and the 24 h average high. Values obtained were: sensitivity, 89% (95% confidence interval 84-89%); specificity, 92% (95% CI 88-95%); positive predictive value, 95.6% (95% CI 93-98%); negative predictive value, 81% (95% CI 75-85%); pretest probability, 66% (95% CI 60-72%); positive likelihood ratio, 11; and negative likelihood ratio, 0.3. There were no significant differences in age, gender or percentage of treated subjects between the groups with and without agreement. CONCLUSIONS: Daytime and 24 h average blood pressure may indeed carry similar information for diagnosing hypertension and assessing the effects of antihypertensive treatment in clinical practice. Ambulatory blood pressure monitoring used only during the daytime period could be better tolerated and agreed to by patients than 24 h monitoring.