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Hypertrophic cardiomyopathy (HCM) is characterized by asymmetric left ventricular hypertrophy, diastolic dysfunction and myocardial disarray. HCM is caused by mutations in sarcomeric genes, but in >40% of patients, the mutation is not yet identified. We hypothesized that FHL1, encoding four-and-a-half-LIM domains 1, could be another disease gene since it has been shown to cause distinct myopathies, sometimes associated with cardiomyopathy. We evaluated 121 HCM patients, devoid of a mutation in known disease genes. We identified three novel variants in FHL1 (c.134delA/K45Sfs, c.459C>A/C153X and c.827G>C/C276S). Whereas the c.459C>A variant was associated with muscle weakness in some patients, the c.134delA and c.827G>C variants were associated with isolated HCM. Gene transfer of the latter variants in C2C12 myoblasts and cardiac myocytes revealed reduced levels of FHL1 mutant proteins, which could be rescued by proteasome inhibition. Contractility measurements after adeno-associated virus transduction in rat-engineered heart tissue (EHT) showed: (i) higher and lower forces of contraction with K45Sfs and C276S, respectively, and (ii) prolonged contraction and relaxation with both mutants. All mutants except one activated the fetal hypertrophic gene program in EHT. In conclusion, this study provides evidence for FHL1 to be a novel gene for isolated HCM. These data, together with previous findings of proteasome impairment in HCM, suggest that FHL1 mutant proteins may act as poison peptides, leading to hypertrophy, diastolic dysfunction and/or altered contractility, all features of HCM.
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Cardiomiopatia Hipertrófica/genética , Peptídeos e Proteínas de Sinalização Intracelular/genética , Proteínas com Domínio LIM/genética , Proteínas Musculares/genética , Adolescente , Adulto , Idoso , Animais , Cardiomiopatia Hipertrófica/metabolismo , Estudos de Casos e Controles , Células Cultivadas , Criança , Humanos , Peptídeos e Proteínas de Sinalização Intracelular/metabolismo , Proteínas com Domínio LIM/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Pessoa de Meia-Idade , Proteínas Musculares/metabolismo , Mutação , Miócitos Cardíacos/metabolismo , Linhagem , Adulto JovemRESUMO
PURPOSE: Digitally planned and manufactured PMMA for full arch implant supported immediate loading interim prosthesis are becoming popular comparing with conventional acrylic prosthesis. Studies on prosthodontic performance and patient related outcomes are scarce but needed. The purpose of this study was to evaluate the clinical survival and impact on oral health related quality of life of immediate loading implant supported full arch CAD-CAM milled PMMA interim rehabilitations. METHODS: This was a practice based prospective cohort study performed in a Portuguese dental clinic. Eleven patients received a total of seventeen CAD CAM full implant-supported, screw-retained, full arch rehabilitation with milled PMMA and were followed up for 1 year. Primary outcome was Prosthesis survival determined with a modification of the California Dental Association score and a Kaplan Meyer survival function analysis. Secondary outcome was patient's quality of life as defined by application of the OHIP 14 PT questionnaire and standardized effect size variation between two visits. Significance was set at 5%. RESULTS: Survival probability at 12 months was 76%, complete fracture of the prosthesis occurred in 17,6 % of the cases and small fractures without lab involvement in 5,9%. There was a significant improvement in oral health related quality of life between visit 1 and 4. Mean difference and effect size for total OHIP-14 PT score were -32.91 (± 3.68 SD) and 3.66 (95% CI -1.83 to -5.80) P < 0.001* Wilcoxon matched paired rank test. CONCLUSIONS: Full arch implant supported CAD-CAM milled PMMA interim prosthesis seems a viable approach with good survival rate and great impact on patient's oral health related quality of life.
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BACKGROUND: Hypertrophic Cardiomyopathy (HCM) is a complex myocardial disorder with a recognized genetic heterogeneity. The elevated number of genes and mutations involved in HCM limits a gene-based diagnosis that should be considered of most importance for basic research and clinical medicine. METHODOLOGY: In this report, we evaluated High Resolution Melting (HRM) robustness, regarding HCM genetic testing, by means of analyzing 28 HCM-associated genes, including the most frequent 4 HCM-associated sarcomere genes, as well as 24 genes with lower reported HCM-phenotype association. We analyzed 80 Portuguese individuals with clinical phenotype of HCM allowing simultaneously a better characterization of this disease in the Portuguese population. RESULTS: HRM technology allowed us to identify 60 mutated alleles in 72 HCM patients: 49 missense mutations, 3 nonsense mutations, one 1-bp deletion, one 5-bp deletion, one in frame 3-bp deletion, one insertion/deletion, 3 splice mutations, one 5'UTR mutation in MYH7, MYBPC3, TNNT2, TNNI3, CSRP3, MYH6 and MYL2 genes. Significantly 22 are novel gene mutations. CONCLUSIONS: HRM was proven to be a technique with high sensitivity and a low false positive ratio allowing a rapid, innovative and low cost genotyping of HCM. In a short return, HRM as a gene scanning technique could be a cost-effective gene-based diagnosis for an accurate HCM genetic diagnosis and hopefully providing new insights into genotype/phenotype correlations.
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Cardiomiopatia Hipertrófica/diagnóstico , Cardiomiopatia Hipertrófica/genética , Desnaturação de Ácido Nucleico/genética , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Biometria , Miosinas Cardíacas/genética , Proteínas de Transporte/genética , Estudos de Coortes , Biologia Computacional , Éxons/genética , Feminino , Variação Genética , Genoma Humano/genética , Humanos , Masculino , Pessoa de Meia-Idade , Mutação/genética , Cadeias Pesadas de Miosina/genética , Reação em Cadeia da Polimerase , Portugal , Troponina T/genética , Adulto JovemRESUMO
AIMS: Dilated cardiomyopathy (DCM) is a major cause of heart failure with a high familial recurrence risk. So far, the genetics of DCM remains largely unresolved. We conducted the first genome-wide association study (GWAS) to identify loci contributing to sporadic DCM. METHODS AND RESULTS: One thousand one hundred and seventy-nine DCM patients and 1108 controls contributed to the discovery phase. Pools of DNA stratified on disease status, population, age, and gender were constituted and used for testing association of DCM with 517 382 single nucleotide polymorphisms (SNPs). Three DCM-associated SNPs were confirmed by individual genotyping (P < 5.0 10(-7)), and two of them, rs10927875 and rs2234962, were replicated in independent samples (1165 DCM patients and 1302 controls), with P-values of 0.002 and 0.009, respectively. rs10927875 maps to a region on chromosome 1p36.13 which encompasses several genes among which HSPB7 has been formerly suggested to be implicated in DCM. The second identified locus involves rs2234962, a non-synonymous SNP (c.T757C, p. C151R) located within the sequence of BAG3 on chromosome 10q26. To assess whether coding mutations of BAG3 might cause monogenic forms of the disease, we sequenced BAG3 exons in 168 independent index cases diagnosed with familial DCM and identified four truncating and two missense mutations. Each mutation was heterozygous, present in all genotyped relatives affected by the disease and absent in a control group of 347 healthy individuals, strongly suggesting that these mutations are causing the disease. CONCLUSION: This GWAS identified two loci involved in sporadic DCM, one of them probably implicates BAG3. Our results show that rare mutations in BAG3 contribute to monogenic forms of the disease, while common variant(s) in the same gene are implicated in sporadic DCM.
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Proteínas Adaptadoras de Transdução de Sinal/genética , Cardiomiopatia Dilatada/genética , Cromossomos Humanos Par 10/genética , Cromossomos Humanos Par 1/genética , Loci Gênicos/genética , Insuficiência Cardíaca/genética , Adulto , Proteínas Reguladoras de Apoptose , Canais de Cloreto/genética , Feminino , Estudo de Associação Genômica Ampla , Proteínas de Choque Térmico HSP27/genética , Heterozigoto , Humanos , Masculino , Pessoa de Meia-Idade , Mutação de Sentido Incorreto/genética , Polimorfismo de Nucleotídeo Único/genéticaRESUMO
Constrictive pericarditis is a rare clinical entity that can pose diagnostic problems. The gold standard for diagnosis is cardiac catheterization with analysis of intracavitary pressure curves, which are high and, in end-diastole, equal in all chambers. The diastolic profile in both ventricles presents the classic dip-and-plateau pattern and the difference between the diastolic pressures of both ventricles should not exceed 3-5mmHg. Unfortunately, these traditional criteria are not always present and in fact the sensitivity and specificity of equalization of diastolic pressures are relatively low and of limited value in individual patients. This highlights the need to use new cardiac imaging techniques to resolve any doubts. The case described here is a good example.
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Pericardite Constritiva/diagnóstico , Idoso , Humanos , MasculinoRESUMO
BACKGROUND: Sarcomeric hypertrophic cardiomyopathy has heterogeneous phenotypic expressions, of which sudden cardiac death is the most feared. A genetic diagnosis is essential to identify subjects at risk in each family. The spectrum of disease-causing mutations in the Portuguese population is unknown. METHODS: Seventy-seven unrelated probands with hypertrophic cardiomyopathy were systematically screened for mutations by PCR and sequencing of five sarcomeric genes: MYBPC3, MYH7, TNNT2, TNNI3 and MYL2. Familial cosegregation analysis was performed in most patients. RESULTS: Thirty-four different mutations were identified in 41 (53%) index patients, 71% with familial hypertrophic cardiomyopathy. The most frequently involved gene was MYBPC3 (66%) with 22 different mutations (8 novel) in 27 patients, followed by MYH7 (22%), TNNT2 (12%) and TNNI3 (2.6%). In three patients (7%), two mutations were found in MYBPC3 and/or MYH7. Additionally, 276 relatives were screened, leading to the identification of a mean of three other affected relatives for each pedigree with the familial form of the disease. CONCLUSIONS: Disease-associated mutations were identified mostly in familial hypertrophic cardiomyopathy, corroborating the idea that rarely studied genes may be implicated in sporadic forms. Private mutations are the rule, MYBPC3 being the most commonly involved gene. Mutations in MYBPC3 and MYH7 accounted for most cases of sarcomere-related disease. Multiple mutations in these genes may occur, which highlights the importance of screening both. The detection of novel mutations strongly suggests that all coding regions should be systematically screened. Genotyping in hypertrophic cardiomyopathy enables a more precise diagnosis of the disease, with implications for risk stratification and genetic counseling.
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Cardiomiopatia Hipertrófica/genética , Adulto , Idoso , Idoso de 80 Anos ou mais , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Mutação , Portugal , Sarcômeros/genética , Adulto JovemRESUMO
INTRODUCTION: Hypertrophic cardiomyopathy (HCM), a complex myocardial disorder with an autosomal dominant genetic pattern and prevalence of 1:500, is the most frequent cause of sudden death in apparently healthy young people. The benefits of gene-based diagnosis of HCME for both basic research and clinical medicine are limited by the considerable costs of current genetic testing due to the large number of genes and mutations involved in this pathology. However, coupling two high-throughput techniques--mass spectrometry genotyping (MSG) and high resolution melting (HRM)--is an encouraging new strategy for HCM diagnosis. Our aim was to evaluate the diagnostic efficacy of both techniques in this pathology by studying 13 individuals with a clinical phenotype of HCM. METHODS: Peripheral blood samples were collected from: (i) seven subjects with a clinical diagnosis of HCM, all bearing known mutations previously identified by dideoxy sequencing and thus being used as blinded samples (sample type 1); (ii) one individual with a clinical diagnosis of HCM negative for mutations after dideoxy sequencing of the five most common HCM genes, MYH7, MYBPC3, TNNI3, TNNT2 and MYL2 (sample type 2); and (iii) five individuals individual with a clinical diagnosis of HCM who had not previously been genetically studied (sample type 3). RESULTS: The 13 samples were analyzed by MSG for 534 known mutations in 32 genes associated with HCM phenotypes and for all coding regions and exon-intron boundaries of the same HCM genes by HRM. The 32 studied genes include the most frequent HCM-associated sarcomere genes, as well as 27 genes with lower reported HCM phenotype association. This coupled genotyping strategy enabled us to identify a c.128delC (p.A43Vfs165) frame-shift mutation in the CSRP3 gene, a gene not usually studied in current HCM genetics. The heterozygous CSRP3 mutation was found in two patients (sample types 2 and 3) aged 50 and 52 years, respectively, both with diffuse left ventricular hypertrophy. Furthermore, this coupled strategy enabled us to find a novel mutation, c.817C >T (p.Arg273Cys), in MYBPC3 in an individual from sample type 3, subsequently confirmed by dideoxy sequencing. This novel mutation in MYBPC3, not present in 200 chromosomes from 200 healthy individuals, affects a codon known to harbor an HCM-causing mutation--p.Arg253His. CONCLUSION: In conclusion, in the cohort used in this work coupling two technologies, MSG and HRM, with high sensitivity and low false positive results, enabled rapid, innovative and low-cost genotyping of HCM patients, which may in the short-term be suitable for accurate genetic diagnosis of HCM.
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Cardiomiopatia Hipertrófica/diagnóstico , Cardiomiopatia Hipertrófica/genética , Espectrometria de Massas/métodos , Mutação/genética , Análise de Sequência com Séries de Oligonucleotídeos/métodos , Adulto , Miosinas Cardíacas/genética , Cardiomiopatia Hipertrófica/complicações , Proteínas de Transporte/genética , Estudos de Casos e Controles , Morte Súbita Cardíaca/etiologia , Feminino , Testes Genéticos , Humanos , MAP Quinase Quinase Quinases/genética , Masculino , Pessoa de Meia-Idade , Cadeias Pesadas de Miosina/genética , Cadeias Leves de Miosina/genética , Fenótipo , Proteínas Serina-Treonina Quinases , Troponina T/genéticaRESUMO
Left ventricular non-compaction (LVNC) is a rare disorder of endomyocardial morphogenesis that results in multiple trabeculations and deep intertrabecular recesses filled with direct blood flow from the left ventricular cavity. LVNC is attracting increasing interest as a model for the study of cardiomyopathies, since it is a genetically heterogeneous disorder which varies greatly in clinical presentation and age of onset. The authors present the case of a young black male with progressive congestive heart failure of 2-3 years' evolution. The investigation, which included transthoracic echocardiography (contrast and 3D), transesophageal echocardiography and cardiac magnetic resonance imaging, showed LVNC and severe aortic regurgitation, with severe left ventricular systolic dysfunction. The family history was suggestive of genetically transmitted disease and genetic study of the TAZ gene at locus Xq28 identified the mutation p.Phe128Ser (c.383T>C), the first description of this mutation in a patient with LVNC. The patient underwent aortic valve replacement, with excellent clinical evolution, regression of left ventricular dimensions and global systolic functio Aortic regurgitation (not related to LVNC) was the determining factor in the clinical expression. However, the excellent reverse remodeling that occurred after surgery highlights the heterogeneity of myocardial behavior in LVNC patients.
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Cardiomiopatias/genética , Ventrículos do Coração , Mutação , Remodelação Ventricular/genética , Adolescente , Predisposição Genética para Doença , Humanos , Masculino , LinhagemRESUMO
BACKGROUND: Hypertrophic cardiomyopathy (HCM) is a genetic disease associated with mutations in genes encoding cardiac sarcomere proteins. A mutation is identified in two-thirds of cases, and more frequently in familial forms. Doubts remain concerning the true identity of the sporadic form. OBJECTIVE: To compare, in a genotyped population, the phenotypic expression of the disease over time in patients with familial and sporadic HCM. METHODS: 79 patients with HCM, aged 39 +/- 17.8 years at diagnosis, were followed for 12 +/- 9.5 (1-30) years and divided into two groups: G1 (familial)--68 patients (24 unrelated index patients, 44 relatives), follow-up time (FUP) 12 +/- 9.8 (1-30) years; G2 (sporadic)1 index patients (no phenotypic disease in first-degree relatives), FUP 10.8 +/- 8 (2-24) years. Fabry disease was excluded in G2. The two groups were compared regarding clinical, ECG and echocardiographic (echo) features at diagnosis and after FUP. Five sarcomere genes (MYH7, MYBPC3, TNNT2, MYL2 and TNNI3) were screened for mutations by direct sequencing, after PCR amplification with intronic sets of oligonucleotide primers designed according to the published genomic sequence of the genes. RESULTS: A) Thirteen different mutations (in 3 genes) were identified in 14 index patients in G1; only in one patient in G2 was a mutation found. B) The two groups differed clinically in age at diagnosis (G1: 37.18 (4-79) years; G2: 51 +/- 14 (19-67) years; p = 0.02), and family history of sudden cardiac death (G1: 12/24 families; G2: 1/11 families; p = 0.04). Age, gender, FUP, symptoms, need for medical treatment, cardiovascular (CV) hospitalization and mortality (CV or any cause) were similar. C) ECG patterns did not differ, although significant (but similar) changes occurred in 45% (G1) and 36% (G2) of patients (p = 0.75). These changes were in the same direction, with a trend in both groups toward the development of atrial fibrillation and/or advanced conduction disease. D) Echo features (only considered in adults) were similar despite significant changes during FUP (in 68% of G1, and 82% of G2; p = 0.48). These changes also followed the same tendency: progression to a more diffuse pattern of ventricular hypertrophy (G1: 52%; G2: 73%; p = 0.33) and development of left atrial dilatation (G1: 37%; G2: 45%; p = 0.52). CONCLUSIONS: The similar phenotypic expression and behavior over time in familial and sporadic forms of HCM strongly indicate that the disease is one and the same. Differences in genetic findings, age at diagnosis and family history of sudden death suggest that sporadic forms may be caused by low penetrance de novo mutations in sarcomeric genes other than those associated with familial disease.
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Cardiomiopatia Hipertrófica Familiar/genética , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Criança , Pré-Escolar , Feminino , Seguimentos , Genótipo , Humanos , Masculino , Pessoa de Meia-Idade , Fatores de TempoRESUMO
Dilated cardiomyopathy (DCM) is a myocardial disease, characterized by ventricular dilatation and impaired systolic function, that in more than 30% of cases has a familial or genetic origin. Given its age-dependent penetrance, DCM frequently manifests in adults by signs or symptoms of heart failure, arrhythmias or sudden death. The predominant mode of inheritance is autosomal dominant, and in these cases mutations are identified in genes coding for cytoskeletal, sarcomeric or nuclear envelope proteins. To date, most studies aimed at molecular diagnosis of DCM have been in selected families, or in larger groups of patients, but screening for mutations in a limited number of genes. Consequently, the epidemiology of mutations in familial DCM remains unknown. There is thus a need for multicenter studies, involving screening for a wide range of mutations in several families and in cases of idiopathic DCM. The present article describes the methodology of a multicenter study, aimed at clinical and molecular characterization of familial DCM patients in the Portuguese population.
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Cardiomiopatia Dilatada , Adulto , Cardiomiopatia Dilatada/diagnóstico , Cardiomiopatia Dilatada/epidemiologia , Cardiomiopatia Dilatada/genética , Seguimentos , Humanos , PortugalRESUMO
INTRODUCTION: In adults, unexplained left ventricular hypertrophy is usually due to sarcomeric hypertrophic cardiomyopathy (HCM). Fabry disease (FD) is rare but may mimic sarcomeric HCM, and has an adverse prognosis in the absence of specific treatment. We aimed to assess cardiologists' awareness of FD based on data from the Portuguese Registry of Hypertrophic Cardiomyopathy. METHODS: A total of 811 index patients, aged 55 ± 16 years, 486 (59.9%) male, were included. Three groups were characterized: A - 128 patients, 74 (57.8%) male, with pathogenic or likely pathogenic mutation(s) in sarcomeric genes; B - 234 patients, 146 (62.4%) male, with negative genetic testing; and C - 449 patients, 266 (59.2%) male, no genetic testing performed. The groups were compared in terms of whether FD was excluded in the registry. Potential red flags for FD were also analyzed and compared between groups. RESULTS: Patients in group A were younger and more frequently had familial HCM (A - 53.9% vs. B - 20.1% vs. C - 18.3%; p <0.001). FD was recorded as excluded in 217 (26.8%), similar in all groups; GLA gene testing was performed in only 50/217 patients (A - 48.6%, B - 25.7%, p = 0.019; C - 13.4%, p = 0.036 for B vs. C), mostly in women (p <0.001) in groups B and C. Alpha-galactosidase A (α-Gal A) activity was assessed in 39/217 (18%) patients, with no difference between groups, but more often in men (p = 0.005). Among patients with potential red flags for FD, only 46.7% underwent specific tests (GLA gene testing and/or α-Gal A activity). When GLA genotyping was performed no mutations were identified. CONCLUSIONS: There is a need to improve cardiologists' alertness for the identification of FD among the Portuguese HCM population.
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Doença de Fabry/diagnóstico , Hipertrofia Ventricular Esquerda/diagnóstico , Cardiologia , Diagnóstico Diferencial , Feminino , Humanos , Masculino , Pessoa de Meia-IdadeRESUMO
INTRODUCTION: We report the results of the Portuguese Registry of Hypertrophic Cardiomyopathy, an initiative that reflects the current spectrum of cardiology centers throughout the territory of Portugal. METHODS: A direct invitation to participate was sent to cardiology departments. Baseline and outcome data were collected. RESULTS: A total of 29 centers participated and 1042 patients were recruited. Four centers recruited 49% of the patients, of whom 59% were male, and mean age at diagnosis was 53±16 years. Hypertrophic cardiomyopathy (HCM) was identified as familial in 33%. The major reason for diagnosis was symptoms (53%). HCM was obstructive in 35% of cases and genetic testing was performed in 51%. Invasive septal reduction therapy was offered to 8% (23% of obstructive patients). Most patients (84%) had an estimated five-year risk of sudden death of <6%. Thirteen percent received an implantable cardioverter-defibrillator. After a median follow-up of 3.3 years (interquartile range [P25-P75] 1.3-6.5 years), 31% were asymptomatic. All-cause mortality was 1.19%/year and cardiovascular mortality 0.65%/year. The incidence of heart failure-related death was 0.25%/year, of sudden cardiac death 0.22%/year and of stroke-related death 0.04%/year. Heart failure-related death plus heart transplantation occurred in 0.27%/year and sudden cardiac death plus equivalents occurred in 0.53%/year. CONCLUSIONS: Contemporary HCM in Portugal is characterized by relatively advanced age at diagnosis, and a high proportion of invasive treatment of obstructive forms. Long-term mortality is low; heart failure is the most common cause of death followed by sudden cardiac death. However, the burden of morbidity remains considerable, emphasizing the need for disease-specific treatments that impact the natural history of the disease.
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Cardiomiopatia Hipertrófica , Sistema de Registros , Cardiomiopatia Hipertrófica/diagnóstico , Cardiomiopatia Hipertrófica/epidemiologia , Cardiomiopatia Hipertrófica/terapia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Portugal/epidemiologiaRESUMO
INTRODUCTION: Levosimendan is an inodilatory drug with hemodynamic effects in patients with decompensated chronic heart failure. AIM: Short-term (one month) evaluation of clinical, hemodynamic and neurohormonal changes in patients with decompensated chronic heart failure undergoing levosimendan therapy. METHODS: Twenty-six (21 male) consecutive patients were studied, corresponding to 32 levosimendan administrations (bolus + 24h infusion), aged 56.7+/-13.0 years, with decompensated chronic heart failure, in NYHA functional class III-IV (78.1% in class IV), and cardiac index (CI) <2.5 l/min/m2. Clinical (NYHA class), non-invasive hemodynamic (echocardiography) and neurohormonal (Elecsys ECLIA NT-ProBNP) evaluations were performed before levosimendan administration and on days 1, 4, 10 and 30. RESULTS: 1) Until day 10, there was a progressive decrease in NT-ProBNP values and weight (p<0.001), with an increase in CI (p<0.001); 2) NYHA functional class improved progressively, with 76% of the patients in NYHA class II at day 30; 3) NT-ProBNP values at day 1 correlated inversely (r=-0.414; p=0.024) with CI at day 4; and 4) the absolute decrease in NT-ProBNP values at day 4 (relative to baseline values) correlated with weight loss at day 4 (r=0.495, p=0.005), day 10 (r=0.424, p=0.031) and day 30 (r=0.486, p=0.030). CONCLUSION: Levosimendan therapy in patients with decompensated chronic heart failure contributes to progressive NYHA class improvement. The variations seen in NYHA class and hemodynamics was reflected in changes in NT-ProBNP.
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Cardiotônicos/administração & dosagem , Insuficiência Cardíaca/tratamento farmacológico , Hidrazonas/administração & dosagem , Piridazinas/administração & dosagem , Biomarcadores/sangue , Pressão Sanguínea/fisiologia , Ecocardiografia Doppler , Feminino , Seguimentos , Insuficiência Cardíaca/sangue , Insuficiência Cardíaca/fisiopatologia , Frequência Cardíaca/fisiologia , Humanos , Masculino , Pessoa de Meia-Idade , Peptídeo Natriurético Encefálico/sangue , Fragmentos de Peptídeos/sangue , SimendanaRESUMO
OBJECTIVE: There is a well known association between mitral valve prolapse (MVP) and low blood pressure (BP), although patients often have high levels of catecholamines and high heart rate (HR). The main objective of our study was to evaluate the effects of long-term adrenergic beta-blockade on these parameters. METHODS: The study population consisted of 46 patients with MVP and the control group consisted of 20 normal individuals. The study had two phases: in the first phase, patients were free of medications. In the second phase, patients were under treatment with propranolol for 10 to 12 months. The tests were performed in normal individuals and patients in the first phase. Only patients underwent the same tests in the second phase. Measurement of urinary epinephrine and norepinephrine levels, by high performance liquid chromatography, was done. Rest HR was determined by electrocardiogram (ECG), and ambulatory blood pressure and HR were evaluated by 24 hours ambulatory blood pressure monitoring (ABPM) using the auscultatory method. RESULTS: The levels of epinephrine and norepinephrine were significantly higher in patients than in normal controls and decreased under propranolol. Rest and ambulatory HR were higher in patients and decreased under propranolol. The 24 hours systolic and diastolic BPs were lower in patients, and their values increased under propranolol. Heart rate decreasing and epinephrine levels reduction were positively correlated. No correlation was found between BP increase and catecholamine levels. CONCLUSION: The study results show divergent effects of propranolol on blood pressure, which increased, and on heart rate, that decreased, in patients with MVP. Heart rate decrease was an expected result and depends, namely, on b1 receptors blockade. Increase in BP is an unusual response to adrenergic beta-blockade in normal conditions, and this finding supports the preponderance of b2 receptors on the BP control in patients with MVP.
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Antiarrítmicos/uso terapêutico , Prolapso da Valva Mitral/tratamento farmacológico , Propranolol/uso terapêutico , Adulto , Antiarrítmicos/administração & dosagem , Pressão Sanguínea , Monitorização Ambulatorial da Pressão Arterial , Eletrocardiografia , Epinefrina/urina , Feminino , Frequência Cardíaca , Humanos , Masculino , Pessoa de Meia-Idade , Prolapso da Valva Mitral/fisiopatologia , Prolapso da Valva Mitral/urina , Norepinefrina/urina , Propranolol/administração & dosagemRESUMO
Hypertrophic cardiomyopathy (HCM) is a relatively common genetic disease, generally with a benign prognosis. However sudden cardiac death may occur, sometimes as the first manifestation of the disease. More than two hundred different mutations have been described in HCM, in 12 different genes encoding sarcomere proteins. This genetic diversity is accompanied by considerable clinical variability and it is likely that phenotype is partially determined by genotype. In recent years it has been suggested that genetic defects could be the major markers of prognosis. Thus, some mutations would carry a good prognosis whereas others, so-called 'malignant' mutations, would be associated with premature sudden death. In a Portuguese population of 35 index patients with HCM the authors found considerable genetic heterogeneity: seven of the 12 mutations identified were de novo, each family having its own 'private' mutation. Moreover, in two unrelated families with the same mutation (I263T--exon 9, missense) in the beta-myosin heavy chain gene (MYH7), penetrance, clinical expression and prognosis were quite different, particularly regarding the occurrence of sudden cardiac death. In two other also unrelated families, in each index patient a different mutation was identified in the troponin I gene (TNNI3): A157V (missense), exon 7 and S199N (missense), exon 8. Phenotypic expression was different but both patients suffered sudden cardiac death (one survived). This suggests that mutations in this gene carry an adverse prognosis. In conclusion, the considerable genetic and clinical variability found in HCM hinders the interpretation of genotype-phenotype correlations, particularly since all the published data is based on small numbers of families.
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Cardiomiopatia Hipertrófica/genética , Morte Súbita Cardíaca , Mutação , Adulto , Cardiomiopatia Hipertrófica/complicações , Feminino , Seguimentos , Humanos , Masculino , Pessoa de Meia-IdadeRESUMO
The prevalence of heart failure is increasing all over the world. It is a common and growing public health problem in Portugal as in many other European countries. This article provides a review of health service organization and current heart failure management in Portugal, discusses primary care and ward practices in different hospitals and reports on the use of proven standard therapies for the treatment of heart failure in the community. Despite major advances in diagnosis and treatment, heart failure is only satisfactorily managed. Furthermore efforts are necessary before the beneficial effects observed in trials have a real impact in clinical practice. A broader view and priority for the management of this syndrome on a national level are needed to improve the quality of heart failure care in Portugal.
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Insuficiência Cardíaca/terapia , Programas Nacionais de Saúde , Cardiotônicos/uso terapêutico , Estudos Transversais , Acessibilidade aos Serviços de Saúde , Insuficiência Cardíaca/diagnóstico , Insuficiência Cardíaca/mortalidade , Transplante de Coração , Humanos , Admissão do Paciente , Portugal , Atenção Primária à Saúde , Taxa de SobrevidaRESUMO
BACKGROUND: Management guidelines for heart failure recommend ACE-I and beta-blockers. The perception of difficult up-titration might have added to the slow uptake of beta-blockers despite their mortality and morbidity benefits. AIMS: CARMEN offered a possibility to study safety and tolerability of enalapril against carvedilol and their combination. METHODS: Five hundred and seventy-two patients were blindly up-titrated on carvedilol (target 25 mg bid) and/or enalapril (target 10 mg bid), and continued for 18 months. In the combination arm, carvedilol was up-titrated before enalapril. RESULTS: There was no group related difference in adverse events during up-titration. Withdrawal rates were 31, 30 and 30%, and serious adverse events 28, 29 and 34% in the combination, carvedilol and enalapril arms. Mortality was similar in all groups (all-cause N=14, 14 and 14; cardiovascular N=9, 13 and 14). All-cause and cardiovascular hospitalizations occurred in 26, 27 and 32%, and in 12, 16 and 22% in the combination, carvedilol and enalapril arms, respectively. CONCLUSION: The safety profile was similar in all treatment arms. In contrast to common perception, there was no difference in tolerability between the ACE-I and carvedilol. This result is even more remarkable as the high prestudy use of ACE-I (65%) might have introduced a bias by selecting ACE-I tolerant patients, who were only switched from their former ACE-I to enalapril.
Assuntos
Antagonistas Adrenérgicos beta/uso terapêutico , Inibidores da Enzima Conversora de Angiotensina/uso terapêutico , Carbazóis/uso terapêutico , Insuficiência Cardíaca/tratamento farmacológico , Insuficiência Cardíaca/fisiopatologia , Propanolaminas/uso terapêutico , Remodelação Ventricular/efeitos dos fármacos , Adolescente , Antagonistas Adrenérgicos beta/administração & dosagem , Antagonistas Adrenérgicos beta/efeitos adversos , Adulto , Idoso , Idoso de 80 Anos ou mais , Inibidores da Enzima Conversora de Angiotensina/administração & dosagem , Inibidores da Enzima Conversora de Angiotensina/efeitos adversos , Biomarcadores/sangue , Pressão Sanguínea/efeitos dos fármacos , Carbazóis/administração & dosagem , Carbazóis/efeitos adversos , Carvedilol , Creatinina/sangue , Relação Dose-Resposta a Droga , Método Duplo-Cego , Quimioterapia Combinada , Enalapril/administração & dosagem , Enalapril/efeitos adversos , Enalapril/uso terapêutico , Feminino , Seguimentos , Insuficiência Cardíaca/mortalidade , Frequência Cardíaca/efeitos dos fármacos , Hospitalização , Humanos , Rim/efeitos dos fármacos , Rim/metabolismo , Masculino , Pessoa de Meia-Idade , Propanolaminas/administração & dosagem , Propanolaminas/efeitos adversos , Índice de Gravidade de Doença , Análise de Sobrevida , Fatores de Tempo , Resultado do Tratamento , Disfunção Ventricular Esquerda/tratamento farmacológico , Disfunção Ventricular Esquerda/mortalidade , Disfunção Ventricular Esquerda/fisiopatologia , Suspensão de TratamentoRESUMO
In Europe the management of heart failure is largely conducted by primary care physicians and several reports have revealed differences between guidelines and actual practice. The IMPROVEMENT of Heart Failure project was designed to assess how patients with heart failure are managed by those physicians. Two surveys, the "perception survey" and the "actual practice survey" addressed to 1363 physicians, included questions on diagnosis, functional assessment and treatment. The major discrepancies found were: the lack of awareness about the concept of heart failure with preserved systolic function; the low number of echocardiograms requested; the low rate of prescription of beta-blocking agents and spironolactone; and the inappropriately low of angiotensine-converting enzyme inhibitors prescribed.
Assuntos
Insuficiência Cardíaca/diagnóstico , Insuficiência Cardíaca/tratamento farmacológico , Europa (Continente) , Humanos , Guias de Prática Clínica como AssuntoRESUMO
The gene encoding the beta-myosin heavy chain is one of the most frequently implicated in familial hypertrophic cardiomyopathy. Several mutations have been identified and some genotype-phenotype relationships have been assumed, particularly with regard to prognosis. Nevertheless, phenotypic expression is variable even in affected members of the same family carrying the same mutation. We identified the Ile263Thr mutation in several members of two unrelated Portuguese families. Penetrance, clinical behavior and prognosis were quite different between the two families, particularly concerning the occurrence of sudden death. Additional factors probably exist which account for the differences found. The complexity of hypertrophic cardiomyopathy makes it difficult to accurately determine genotype-phenotype relationships, and the screening and comparison of large affected families carrying the same mutation is warranted.
Assuntos
Cardiomiopatia Hipertrófica/genética , Mutação , Adolescente , Adulto , Idoso , Criança , Pré-Escolar , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Cadeias Pesadas de Miosina/genética , Fenótipo , Portugal , Prognóstico , Isoformas de ProteínasRESUMO
BACKGROUND: B-type natriuretic peptide is secreted mainly in the left ventricle in response to elevated wall tension. Plasma levels of the peptide correlate positively with cardiac filling pressures, making it an excellent marker for the presence of left ventricular dysfunction. In hypertrophic cardiomyopathy, enhanced production of B-type natriuretic peptide is observed. However, the relationship of the various structural and functional features present in the disease with the high plasma levels described is not yet fully clarified. In the present study, we prospectively assessed in hypertrophic cardiomyopathy the relationship of plasma NT-proBNP levels with the extent of left ventricular hypertrophy, presence of left ventricular outflow obstruction and echocardiographic parameters of left ventricular diastolic function. METHODS: The study population included 190 individuals: 53 patients with hypertrophic cardiomyopathy and well-preserved left ventricular systolic function (group A), 92 healthy relatives with no disease expression (group B), and an additional group of 46 healthy volunteers (group C) as controls for NT-proBNP levels. Groups A and B were characterized clinically and by echocardiography and compared with each other. Plasma NT-proBNP levels were measured (ECLIA-Elecsys proBNP) and compared in the 3 groups of individuals included in the study. In hypertrophic cardiomyopathy patients, correlation was sought between NT-proBNP levels, NYHA functional class and echocardiographic data. RESULTS: Groups A and B differed (p < 0.001) in septal thickness, maximal wall thickness, left ventricular hypertrophy score, left atrial size, left atrial fractional shortening, derived transmitral filling indices and plasma NT-proBNP levels (group A: 909.9 +/- 1554.2 pg/ml; group B: 40.7 +/- 45.1 pg/ml). Left ventricular diastolic size and pulmonary venous flow velocity-derived indices were similar in the 2 groups. NT-proBNP levels in group B and C (39.4 +/- 34.5 pg/ml) were similar (p = NS). In hypertrophic cardiomyopathy patients, NT-proBNP levels correlate directly with NYHA functional class (r = 0.56, p < 0.001), septal thickness (r = 0.53, p < 0.001), maximal wall thickness (r = 0.59, p < 0.001), left ventricular hypertrophy score (r = 0.63, p < 0.001), left atrial size (r = 0.32, p = 0.023) and mitral deceleration time (r = 0.46, p = 0.001) and inversely with left atrial fractional shortening (r = -0.41, p = 0.005). Functional class also correlates directly with left ventricular hypertrophy score (r = 0.39, p = 0.006), with the most symptomatic patients having the highest scores. CONCLUSIONS: In hypertrophic cardiomyopathy, plasma NT-proBNP levels depend mainly on the severity of left ventricular hypertrophy rather than on the presence of obstruction. Measurement of the peptide may help in the clinical characterization and follow-up of patients with this disease.