Optimal pharmacological treatment and adherence to medication in secondary prevention of cardiovascular events in Spain: Results from the CAPS study.

INTRODUCTION: Despite the large amount of evidence supporting the use of antiplatelet agents, beta-blockers, angiotensin antagonists, and lipid-lowering statins in patients with stable coronary artery disease, several studies have documented underprescription of optimal medical treatment (OMT) in Spain. AIMS: The present study aimed to describe the current trend of pharmacological prescription in secondary prevention treatment for cardiovascular diseases (CVDs) in a Spanish cohort. METHODS: This study was a multicenter, observational, cross-sectional study (CAPS study, FER-CAR-2014-01) in the context of only one visit. Adherence levels to the prescribed medication, the reasons for not prescription of each medication, the existence of possible associations between sociodemographic features, different CVDs, and different drugs with treatment compliance were also analyzed in patients who have suffered cardiovascular effects. RESULTS: Six hundred and twelve patients (68.5±10.7 years old; 78% males) were included. OMT was prescribed in 40.8% of the patients. The main reason for not prescribing was due to the physician's discretion. Adherence to medication, measured by the Morisky-Green questionnaire, was 45.8%, and it was positively related to the presence of coronary events (OR 1.80; 95% CI: 1.05-3.21) but not with any drug type. Moreover, a higher educational background implied a higher percentage of adherence to medication. Finally, nonadherent patients were prescribed more daily medicine intakes. CONCLUSIONS: Low adherence to guideline-oriented treatment as well as low adherence to medication was found by a self-reported questionnaire. Enhancing adherence to guideline-recommended therapy and reducing treatment complexity seem to be reasonable strategies to improve adherence to secondary prevention medications.

Mitochondrial DNA and TFAM gene variation in early-onset myocardial infarction: evidence for an association to haplogroup H.

The main objective of this research was to define the association between common mitochondrial DNA (mtDNA) polymorphisms and mitochondrial transcription A gene (TFAM) variants and myocardial infarction (MI) in patients with atherosclerotic diseased vessels. Ten mitochondrial polymorphisms that defined the nine common European haplogroups were genotyped in 500 male patients with early onset MI (<55 years) and at least one atherosclerotic coronary vessel (angiographically confirmed), and 500 healthy controls. In addition, we searched for DNA variants in the coding region of the TFAM gene and compared patients and controls for the allele and genotype frequencies. Early onset MI was strongly associated with male gender and tobacco smoking in our population. MtDNA haplogroup H (defined by allele 7028 °C) was significantly more frequent in a first group of patients (n = 250) compared to controls (n = 300), and the association was confirmed in a second group of only smokers (250 patients and 200 controls). For total patients and controls, we obtained a p = 0.002 (OR = 1.50; 95% CI = 1.17-1.92) for H vs. the other haplogroups. We found four common TFAM polymorphisms, with allele/genotype frequencies that did not differ between patients and controls. In conclusion, mitochondrial haplogroup H was associated with early onset MI in male smokers. Our work supported a role for the mtDNA variation in the risk for atherosclerosis and ischemic associated events, likely due to differences in mitochondrial function and reactive oxygen production between the different haplogroups.

Sudden death in a patient with multiple left anterior descending coronary artery fistulas to the left ventricle.

Coronary fistulas to cardiac chambers are an infrequent anomaly and usually are found casually. Although the majority of patients are asymptomatic, in rare cases it may cause coronary steal and cardiac ischemia. We present a patient with a left anterior descending coronary artery with multiple small fistulas to the left ventricle that suffered angina and an episode of ventricular fibrillation that required electrical cardioversion and an intracardiac defibrillator.

Enfermedad coronaria en jóvenes y síndrome metabólico / Coronary artery disease in young people and metabolic syndrome

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ABCA1 polymorphisms and prognosis after myocardial infarction in young patients.

High-density cholesterol (HDL) levels are affected by genetic influences and certain behaviors. Low levels of HDL-C are considered as an independent risk factor for premature coronary heart disease. In patients with Tangier disease, characterised by low HDL levels, mutations in the ATP binding cassette transporter have been described. We have analysed three polymorphisms of the ABCA1 gene (-477C/T, R219 K, and I883M) in a cohort of young male survivors of myocardial infarction in order to know their influence in long-term prognosis. In premature heart disease, knowing prognosis factors is specially relevant.

Hypertrophic cardiomyopathy linked to homozygosity for a new mutation in the myosin-binding protein C gene (A627V) suggests a dosage effect.

Mutations in the cardiac myosin-binding protein C gene (MYBPC3) are responsible for up to 50% of familial cases with hypertrophic cardiomyopathy (HC). Compared to patients with mutations in other sarcomeric genes, patients with MYBPC3 mutations would have a milder form of the disease, with a lower incidence of sudden cardiac death. Because most of the mutations have been found in only one family, it is currently difficult to establish a correlation between a particular mutation and the HC phenotype. The aim of our study was to contribute to understanding of the role of MYBPC3 mutations in HC. We analysed the MYBPC3 exons and intron flanking regions in 10 patients from 10 families with at least two HC cases. After direct sequencing of polymerase chain reaction (PCR) fragments, we found three new mutations in three families (V771M, V342D, and A627V). These changes affected evolutionary conserved amino acids and were not found in 100 healthy controls. The Ala 627>Val was found homozygous in a 47-year-old patient with a severe form of HC, while his mother and a nephew were heterozygous carriers and asymptomatic. This fact suggests a dosage effect for mutations at the MYPBC3 gene.

A single-nucleotide polymorphism in the human p27kip1 gene (-838C>A) affects basal promoter activity and the risk of myocardial infarction.

BACKGROUND: Excessive proliferation of vascular smooth muscle cells and leukocytes within the artery wall is a major event in the development of atherosclerosis. The growth suppressor p27kip1 associates with several cyclin-dependent kinase/cyclin complexes, thereby abrogating their capacity to induce progression through the cell cycle. Recent studies have implicated p27kip1 in the control of neointimal hyperplasia. For instance, p27kip1 ablation in apolipoprotein-E-null mice enhanced arterial cell proliferation and accelerated atherogenesis induced by dietary cholesterol. Therefore, p27kip1 is a candidate gene to modify the risk of developing atherosclerosis and associated ischaemic events (i.e., myocardial infarction and stroke). RESULTS: In this study we found three common single-nucleotide polymorphisms in the human p27kip1 gene (+326T>G [V109G], -79C>T, and -838C>A). The frequency of -838A carriers was significantly increased in myocardial infarction patients compared to healthy controls (odds ratio [OR] = 1.73, 95% confidence interval [95%CI] = 1.12-2.70). In addition, luciferase reporter constructs driven by the human p27kip1 gene promoter containing A at position -838 had decreased basal transcriptional activity when transiently transfected in Jurkat cells, compared with constructs bearing C in -838 (P = 0.04). CONCLUSIONS: These data suggest that -838A is associated with reduced p27kip1 promoter activity and increased risk of myocardial infarction.

[Direct detection of malignant mutations in patients with hypertrophic cardiomyopathy]. / Detección directa de mutaciones malignas en pacientes con miocardiopatía hipertrófica.

We determined the prevalence of mutations considered malignant in the genes for beta-myosin heavy chain (MYH7, 11 mutations) and troponin T (TNNT2, 5 mutations) in 30 patients with hypertrophic cardiomyopathy aged 18 to 60 years, 83% of whom had familial antecedents of hypertrophic myocardiopathy or sudden death. Mutations were identified with polymerase chain reaction followed by restriction enzyme digestion and agarose gel electrophoresis. Direct analysis identified 16 mutations in 2 of the 30 patients (7%): one women diagnosed at the age of 25 years as carrying the MYH7453cysteine mutation, and a 60-year-old women with the TNNT2278 cysteine mutation. These cases illustrate the considerable clinical heterogeneity that characterizes carriers of these mutations. Clinical manifestations can range from severe hypertrophy or early sudden death to the absence of symptoms up to advanced age.

Detección directa de mutaciones malignas en pacientes con miocardiopatía hipertrófica / Direct detection of malignant mutations in patients with hypertrophic cardiomyopathy

Hemos determinado la prevalencia de mutaciones consideradas malignas en los genes de la cadena pesada de la betamiosina (MYH7, 11 mutaciones) y la troponina T (TNNT2, 5 mutaciones) en 30 pacientes con miocardiopatía hipertrófica (MCH) menores de 60 años, de los que el 83 por ciento tenía antecedentes familiares de MCH y/o muerte súbita. Empleamos la reacción en cadena de la polimerasa (PCR) seguida de digestión con una enzima de restricción y electroforesis en geles de agarosa. El análisis directo nos permitió identificar alguna de las 16 mutaciones en 2 de los 30 pacientes (7 por ciento): una mujer diagnosticada a los 25 años era portadora de la mutación MYH7-453 cisteína, y otra mujer, de 60 años, era portadora de la mutación TNNT2-278 cisteína. Estos casos ilustran la gran heterogeneidad clínica que caracteriza a los portadores, que van desde la hipertrofia grave o la muerte súbita temprana hasta la ausencia de síntomas en edades avanzadas de la vida (AU)

Association between genetic variation in the Y chromosome and hypertension in myocardial infarction patients.

A single nucleotide polymorphism (SNP) in chromosome Y has been associated with blood pressure. In men, the risk of suffering from cardiovascular diseases, including coronary artery disease, could be influenced by one or more loci on chromosome Y. We genotyped 208 men who had suffered an early episode of myocardial infarction (MI) (< or =55 years) and 178 healthy control men for two Y-polymorphisms (a HindIII polymorphism in an alphoid satellite in the centromeric non-recombining region and the -2627 T/C in the SRY gene). Frequencies were compared through a chi(2)-test. Frequencies for the two polymorphisms did not differ between patients and controls. The alphoid-HindIII polymorphism was not related to blood pressures in our population (HindIII+: diastolic, 80 +/- 2; systolic, 129 +/- 5. HindIII-: diastolic, 80 +/- 2; systolic, 128 +/- 3). Seventy-six patients (37%) were hypertensives and had a significantly higher frequency of the HindIII+ allele compared to the normotensive patients (46 and 26%, respectively; P = 0.028). According to our data, the alphoid-HindIII polymorphism in chromosome Y was not associated with differences in blood pressure in men from Asturias (Northern Spain). However, the HindIII+ allele increased the risk of suffering an early episode of MI among hypertensives.

Hypertrophic cardiomyopathy: low frequency of mutations in the beta-myosin heavy chain (MYH7) and cardiac troponin T (TNNT2) genes among Spanish patients.

BACKGROUND: Mutations in the cardiac beta-myosin heavy chain (MYH7) and cardiac troponin T (TNNT2) genes are reportedly responsible for up to 40% of familial cases with hypertrophic cardiomyopathy (HC). Although there are no mutational hotspots, most of the mutations are located in specific exons of the MYH7 and TNNT2 genes. Currently it is not possible to predict the phenotype in carriers of mutations in these genes, although it is widely accepted that mutations in the MYH7 gene predispose to severe HC, whereas TNNT2 mutations are frequently linked to sudden cardiac death (SCD) in spite of minimal hypertrophy. METHODS: We sequenced exons 8, 9, 13-16, 19, 20, 22-24, and 30 of the MYH7 gene and exons 8, 9, 11, and 14-16 of the TNNT2 gene in 30 HC patients (18-60 years of age) from the region of Asturias (Northern Spain); 25 cases (80%) had a family history of the disease. Genomic DNA was amplified, and fragments were directly sequenced. Each DNA variant found in the patients was also analyzed in 200 healthy controls through single-strand conformation analysis. RESULTS: Four of the probands had nucleotide changes absent in the healthy controls. Two cases had mutations previously described in the MYH7 gene (exon 14, Arg453Cys) or the TNNT2 gene (exon 16, Arg278Cys). Two cases had new mutations (MYH7 exon 22, Met822Val; TNNT2 exon 14, Lys247Arg) not found among the healthy controls. We found MYH7 Met822Val in a woman with a severe form of HC; the mutation was absent in her parents, indicating a de novo mutation. MYH7 R453C was present in a woman with mild HC, mother of a son who died from SCD. TNNT2 R278C was present in a woman with severe HC, but a sister and a daughter were mutation carriers and did not have hypertrophy. A patient with severe HC was carrier of TNNT2 247Arg. CONCLUSIONS: Mutations in the MYH7 and TNNT2 genes can be found in patients without a family history of HC. However, compared with other populations MYH7 or TNNT2 mutations were rare among our HC patients. This study illustrates the extreme phenotypic heterogeneity in carriers of MYH7 or TNNT2 mutations.

5-Hydroxytryptamine 5-HT2A receptor and 5-hydroxytryptamine transporter polymorphisms in acute myocardial infarction.

This study was designed to analyse possible associations between DNA polymorphisms in the 5-hydroxytryptamine (5-HT; serotonin) 5-HT(2A) receptor and the 5-HT transporter (5-HTT) genes, and myocardial infarction (MI). 5-HT has been shown to be involved in cardiovascular pathophysiology. In addition to platelet aggregation and vascular contraction, 5-HT induces hyperplasia of artery smooth muscle cells. Recently, a 5-HT transporter gene polymorphism has been associated with MI. To determine the influence of genetic variation at the 5-HT(2A) receptor (T102C polymorphism) and the 5-HTT (insertion/deletion polymorphism) on the risk of developing early MI, we genotyped 210 MI patients of < 55 years old and 238 healthy control subjects for DNA polymorphisms in these genes. In addition, we genotyped 95 patients with late-onset MI (> 60 years old) to analyse the effects of these polymorphisms on the age at which the first MI episode occurred. The 5-HT(2A) receptor polymorphism was not associated with MI in our population. In addition, since the 5-HT(2A) receptor gene and genotype frequencies did not differ between patients with early and late onset of MI, this polymorphism does not appear to have an effect on age at the first MI episode. Gene and genotype frequencies for the 5-HTT promoter did not differ between patients < 55 years old and healthy controls (independent of smoking status). However, homozygotes for the deletion (the ss genotype, where s denotes the short allele) were present at a significantly higher frequency in patients >60 years old compared with patients < 55 years old (P = 0.009; P = 0.004 when only smokers were compared). According to our data, the ss genotype would seem to have a protective role against MI, delaying the age of onset of the first episode, especially among smokers. This could be a consequence of the lower 5-HTT levels linked to the s allele, so that individuals homozygous for the ss genotype may have lower 5-HT re-uptake by platelets.

Variation in the lipoprotein receptor-related protein, alpha2-macroglobulin and lipoprotein receptor-associated protein genes in relation to plasma lipid levels and risk of early myocardial infarction.

BACKGROUND: The lipoprotein receptor-related protein (LRP) is an endocytic receptor for several ligands, such as alpha2-macroglobulin (alpha2 M) and apolipoprotein E. LRP is involved in the clearance of lipids from the bloodstream and is expressed in the atherosclerotic plaque. The LRP-associated protein (LRPAP in humans, RAP in mice) acts as a chaperone protein, stabilizing the nascent LRP peptide in the endoplasmic reticulum and Golgi complex. In mice, the amount of LRP activity was modulated by RAP, and RAP-null mice showed higher levels of total cholesterol. OBJECTIVE: To evaluate the association between DNA polymorphisms at the LRP, LRPAP and alpha2 M genes and early myocardial infarction (MI). METHODS: We genotyped 210 patients with early MI (<55 years) and 200 healthy control participants for three polymorphisms in the LRP, LRPAP and alpha2 M genes. RESULTS: No association was found between these polymorphisms and plasma lipid levels in patients and control participants. Only the LRPAP-intron 1 polymorphism (a 21 bp insertion/deletion) was associated with MI (P = 0.0065; odds ratio = 2.18, 95% confidence intervals = 1.22-3.90). CONCLUSIONS: According to our data, the variation at the LRPAP1 gene could contribute to the risk of developing an early episode of MI.