RESUMO
BACKGROUND: International guidelines stipulate that primarily cardiac troponin (cTn) assays with a coefficient of variation (CV) < or = 10% at the 99th percentile cutoff should be used for diagnosing myocardial infarction. Point-of-care (POC) assays usually do not meet these criteria. Here, we sought to confirm the manufacturer-recommended 99th percentile cutoff and CV of the POC assay AQT90 FLEX cTnI. METHODS: 119 healthy persons without cardiac disorders were examined to determine the 99th percentile cutoff and the corresponding CV. This cutoff was validated in a cohort of 80 patients with unstable angina and 71 patients with non-ST-segment elevation myocardial infarction (NSTEMI), who were admitted to a chest pain unit. cTnI concentrations were measured in serial serum samples obtained from these patients at presentation, 3 and 6 hours after admission. RESULTS: A cTnI concentration of 20 ng/L was found as the 99th percentile cutoff (CV 6.7%). cTnI was > or = 20 ng/L in 51 (75%), 59 (87%), and 60 (88%) of the NSTEMI patients 0, 3 and 6 hours after admission, respectively. At admission, sensitivity was 76% and specificity 95%. Three and six hours later, sensitivity and negative predictive values increased to 88% and 98.8%, and to 92% and 97%, respectively. CONCLUSIONS: We confirmed the manufacturer recommended 99th percentile cutoff of 23 ng/L and established a CV of 6.7% at 20 ng/L. These results demonstrated that the POC assay AQT90 FLEX cTnI must be classified as "guideline acceptable".
Assuntos
Infarto do Miocárdio/diagnóstico , Sistemas Automatizados de Assistência Junto ao Leito , Troponina/sangue , Adulto , Idoso , Angina Pectoris/sangue , Angina Pectoris/diagnóstico , Estudos de Coortes , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Infarto do Miocárdio/sangue , Curva ROC , Valores de Referência , Reprodutibilidade dos Testes , Adulto JovemRESUMO
BACKGROUND: Cardiac troponin T is an established prognostic marker in patients with acute coronary syndromes, but not in stable coronary artery disease (CAD) like N-terminal pro-B-type natriuretic peptide (NT-proBNP). We examined the additive prognostic value of a high-sensitivity troponin T (hsTnT) assay to predict adverse clinical outcomes in stable CAD. METHODS: A retrospective nested case-control analysis of 256 patients with stable CAD who participated in the LURIC study: 128 cases who died from cardiovascular causes during a median follow-up of 7.5 years and 128 survivors (controls) matched for age and gender, were included. hsTnT and NT-proBNP were determined in baseline samples using immunoassays (Roche Diagnostics, Germany). RESULTS: Sixty-two percent of the 256 subjects exhibited concentrations of hsTnT≥14 ng/L, the manufacturer recommended cut-off to diagnose myocardial infarction in patients with acute chest pain. hsTnT, NT-proBNP, diabetes mellitus and fasting glucose were associated with cardiovascular mortality in univariate analysis. Logistic regression identified hsTnT and NT-proBNP as independent risk markers. Receiver operator characteristic (ROC) curves analysis identified optimal cut-offs at 15 ng/L and 352 µg/L for hsTnT (AUC 0.728, p<0.05) and NT-proBNP (AUC 0.751, p=0.07), respectively. Patients with one or two positive markers exhibited 5-year cardiovascular mortalities of 40% and 60%, respectively, compared to 10% in patients with negative markers. The addition of hsTnT to NT-proBNP significantly increased c-statistics of proportional hazards calculated from survival times as well as net reclassification indexes. CONCLUSIONS: Many patients with stable CAD exhibited increased concentrations of hsTnT. The combined determination of NT-proBNP and hsTnT was superior for risk stratification compared to determining either marker alone.
Assuntos
Doença da Artéria Coronariana/sangue , Doença da Artéria Coronariana/diagnóstico , Peptídeo Natriurético Encefálico/sangue , Fragmentos de Peptídeos/sangue , Troponina T/sangue , Idoso , Doença da Artéria Coronariana/mortalidade , Feminino , Humanos , Masculino , Prognóstico , Estudos Retrospectivos , RiscoRESUMO
BACKGROUND: Nonresponsiveness to clopidogrel and acetylsalicylic acid (ASA), a frequent result of platelet aggregometry studies, has unclear clinical and prognostic significance. METHODS: We performed impedance aggregometry in 182 patients 12-24 h after percutaneous coronary intervention (PCI) and a 600-mg loading dose of clopidogrel, adding 5 micromol/L ADP and 1 mg/L collagen to diluted whole blood to determine platelet inhibition by clopidogrel and ASA, respectively. Samples from nonresponders were incubated in vitro with methyl-S-adenosine monophosphate or ASA to distinguish between pharmacodynamic and pharmacokinetic types of resistance. We assessed a combined primary endpoint of myocardial infarction, target vessel revascularization, late stent thrombosis, or cardiac death. RESULTS: Nineteen patients (10.4%) were dual nonresponders (nonresponsive to both ASA and clopidogrel), and 163 patients (89.6%) were designated responders. The latter group also included 15 and 14 single nonresponders (responsive to either clopidogrel or ASA, respectively), who exhibited endpoint frequencies comparable to those of full responders (n = 134). Pharmacokinetic resistance was most prevalent. Primary endpoints occurred more frequently in dual nonresponders (n = 6, 31.6%) than in responders (n = 20, 12.3%) (relative risk 2.57; 95% CI 1.18-5.61; log-rank P = 0.03). Multivariate analysis confirmed dual nonresponsiveness (hazard ratio 2.9; 95% CI 1.17-7.2; P = 0.02) as an independent risk factor. CONCLUSIONS: Dual nonresponders carry a high cardiovascular risk after PCI and should obtain intensified antiplatelet therapy and follow-up.
Assuntos
Aspirina/uso terapêutico , Doenças Cardiovasculares/etiologia , Inibidores da Agregação Plaquetária/uso terapêutico , Ticlopidina/análogos & derivados , Idoso , Clopidogrel , Estudos de Coortes , Resistência a Medicamentos , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Fatores de Risco , Ticlopidina/uso terapêuticoRESUMO
BACKGROUND: Whole-body magnetic resonance angiography (WB-MRA) has shown its potential for the non-invasive assessment of nearly the entire arterial vasculature within one examination. Since the presence of extra-cardiac atherosclerosis is associated with an increased risk of coronary events, our goal was to establish the relationship between WB-MRA findings, including a systemic atherosclerosis score index, and the presence of significant coronary artery disease (CAD). METHODS: WB-MRA was performed on a 1.5T scanner in 50 patients scheduled to undergo elective cardiac catheterization for suspected CAD. In each patient, 40 extra-cardiac vessel segments were evaluated and assigned scores according to their luminal narrowing. The atherosclerosis score index (ASI) was generated as the ratio of summed scores to analyzable segments. RESULTS: ASI was higher in patients with significant (> 50% stenosis) CAD (n = 27) vs. patients without CAD (n = 22; 1.56 vs. 1.28, p = 0.004). ASI correlated with PROCAM (R = 0.57, p < 0.001) and Framingham (R = 0.36, p = 0.01) risk scores as estimates of the 10-year risk of coronary events. A ROC derived ASI of > 1.54 predicted significant CAD with a sensitivity of 59%, specificity of 86% and a positive predictive value of 84%. Logistic regression revealed ASI > 1.54 as the strongest independent predictor for CAD with a 11-fold increase in likelihood to suffer from significant coronary disease. On the contrary, while 15/27 (55%) of patients with CAD exhibited at least one extra-cardiac stenosis > 50%, only 3/22 (14%) of those patients without CAD did (p = 0.003). The likelihood for an extra-cardiac stenosis when CAD is present differed between vascular territories and ranged from 15% for a carotid stenosis to 44% for a stenosis in the lower extremities. CONCLUSION: This study provides important new evidence for the close association of extra-cardiac and coronary atherosclerosis. The novel findings that a WB-MRA derived systemic atherosclerosis score index is not only associated with established cardiovascular risk scores but is also predictive of significant CAD suggest its potential prognostic implications and underline the importance to screen for coronary disease in patients with extra-cardiac manifestations of atherosclerosis.
Assuntos
Aterosclerose/diagnóstico , Doença da Artéria Coronariana/diagnóstico , Angiografia por Ressonância Magnética , Doenças Vasculares Periféricas/diagnóstico , Imagem Corporal Total/métodos , Tornozelo/irrigação sanguínea , Aterosclerose/fisiopatologia , Pressão Sanguínea , Artéria Braquial/fisiopatologia , Cateterismo Cardíaco , Constrição Patológica , Angiografia Coronária , Feminino , Humanos , Interpretação de Imagem Assistida por Computador , Modelos Logísticos , Masculino , Pessoa de Meia-Idade , Razão de Chances , Doenças Vasculares Periféricas/fisiopatologia , Valor Preditivo dos Testes , Curva ROC , Sensibilidade e Especificidade , Índice de Gravidade de Doença , Ultrassonografia DopplerRESUMO
We have identified a family in which several members died of sudden cardiac death or suffer from dilated cardiomyopathy (DCM) and rhythm disturbances. Mutation screening revealed co-segregation of a novel nonsense mutation (pR321X) in the lamin A gene, LMNA, with the disease. Lamin A, and its smaller splice form lamin C are nuclear intermediate filament proteins forming a major part of the lamina, which is underlying the inner nuclear membrane. They are involved in the organization of heterochromatin and both in DNA replication and transcription. Recently, an increasing number of missense mutations in LMNA have been discovered to cause various types of rare diseases. Here, we investigated the causal role of the new nonsense mutation for the disease. Quantification of wild type and mutant lamin A mRNA from explanted myocardial tissue and cultured fibroblasts revealed an up to 30-fold reduction in the relative amount of the mutant transcript indicating that its synthesis was massively down-regulated by nonsense-mediated mRNA decay (NMD). Correspondingly, we did not detect the mutant truncated lamin A by Western blot analysis in extracts of patient fibroblasts and cardiac muscle tissue. Both wild type lamin A and C were present, however, in normal quantities. The immunohistochemical analyses of patient tissues revealed a normal distribution of lamin A/C and of major inner nuclear membrane proteins such as emerin and the lamin B receptor. Moreover, both chromatin distribution and nuclear shape were normal. However, over-expression of truncated lamin A in HeLa cells by transient transfection caused major disturbances of lamin A organization within both the nucleoplasm and the cytoplasm. In addition, after treatment of patient fibroblasts with the proteasome inhibitor epoxomicin, mutant truncated lamin A was detected in relatively high levels by Western blotting demonstrating that it is synthesized in these cells. Therefore, we conclude that NMD is not sufficient to completely prevent the expression of truncated lamin A and that even trace amounts of it may negatively interfere with structural and/or regulatory functions of lamin A/C eventually leading to the development of DCM and rhythm disturbances.
Assuntos
Cardiomiopatia Dilatada/genética , Códon sem Sentido/genética , Lamina Tipo A/metabolismo , Proteínas Mutantes/metabolismo , Estabilidade de RNA , Taquicardia Ventricular/genética , Adulto , Alelos , Estudos de Casos e Controles , Núcleo Celular/metabolismo , Cromatina/metabolismo , Regulação para Baixo , Feminino , Fibroblastos/metabolismo , Saúde , Humanos , Masculino , Miocárdio/metabolismo , Proteínas Nucleares/metabolismo , Linhagem , Inibidores de Proteassoma , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Pele/metabolismo , Pele/patologiaRESUMO
It was the aim of this study to compare the efficacy of early platelet inhibition by 600 mg clopidogrel and acetylsalicylic acid (ASA) to a triple therapy including a glycoprotein IIb-IIIa receptor blocker. Immediate percutaneous coronary intervention (PCI) is recommended for high-risk acute coronary syndromes. In this setting the efficacy of platelet inhibition is unknown. One hundred patients were randomized to receive ASA and 600 mg clopidogrel, or additional open-label tirofiban (bolus of 10 microg/kg body weight followed by continued infusion of 0.15 microg/kg body weight per minute) as soon as non-ST-segment elevation myocardial infarction was diagnosed. The primary endpoint was the reduction of infarct size determined by post-interventional increases of cardiac troponin T (cTnT). Secondary endpoints included platelet function measured by optical and impedance aggregometry using ADP (5 and 20 microM) and collagen (1 microg/ml) as platelet agonists. Tirofiban maximized platelet inhibition (p < 0.0001) immediately and was associated with significantly lower post-interventional cTnT concentrations (p = 0.0352). In the dual platelet inhibition arm, clopidogrel was not effective in 69% of patients at the time of coronary intervention, and still in 47%, if pre-treatment time was >120 minutes. The frequency of cardiovascular (death, myocardial infarction, revascularization) and bleeding events was comparable. Platelet aggregation is not adequately inhibited in cTnT-positive patients in the setting of immediate PCI with very short pre-treatment times. Only tirofiban provided consistent and effective inhibition of platelet aggregation at the time of immediate or very early invasive therapy.
Assuntos
Plaquetas/efeitos dos fármacos , Doença da Artéria Coronariana/tratamento farmacológico , Trombose Coronária/prevenção & controle , Inibidores da Agregação Plaquetária/administração & dosagem , Tirosina/análogos & derivados , Idoso , Angioplastia Coronária com Balão/estatística & dados numéricos , Aspirina/administração & dosagem , Clopidogrel , Trombose Coronária/epidemiologia , Trombose Coronária/patologia , Quimioterapia Combinada , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Infarto do Miocárdio/epidemiologia , Infarto do Miocárdio/patologia , Infarto do Miocárdio/prevenção & controle , Necrose , Fatores de Risco , Ticlopidina/administração & dosagem , Ticlopidina/análogos & derivados , Tirofibana , Resultado do Tratamento , Tirosina/administração & dosagemRESUMO
BACKGROUND: Mutations in MYBPC3 encoding myosin binding protein C belong to the most frequent causes of hypertrophic cardiomyopathy (HCM) and may also lead to dilated cardiomyopathy (DCM). MYBPC3 mutations initially were considered to cause a benign form of HCM. The aim of this study was to examine the clinical outcome of patients and their relatives with 18 different MYBPC3 mutations. METHODS: 87 patients with HCM and 71 patients with DCM were screened for MYBPC3 mutations by denaturing gradient gel electrophoresis and sequencing. Close relatives of mutation carriers were genotyped for the respective mutation. Relatives with mutation were then evaluated by echocardiography and magnetic resonance imaging. A detailed family history regarding adverse clinical events was recorded. RESULTS: In 16 HCM (18.4%) and two DCM (2.8%) index patients a mutation was detected. Seven mutations were novel. Mutation carriers exhibited no additional mutations in genes MYH7, TNNT2, TNNI3, ACTC and TPM1. Including relatives of twelve families, a total number of 42 mutation carriers was identified of which eleven (26.2%) had at least one adverse event. Considering the twelve families and six single patients with mutations, 45 individuals with cardiomyopathy and nine with borderline phenotype were identified. Among the 45 patients, 23 (51.1%) suffered from an adverse event. In eleven patients of seven families an unexplained sudden death was reported at the age between 13 and 67 years. Stroke or a transient ischemic attack occurred in six patients of five families. At least one adverse event occurred in eleven of twelve families. CONCLUSION: MYBPC3 mutations can be associated with cardiac events such as progressive heart failure, stroke and sudden death even at younger age. Therefore, patients with MYBPC3 mutations require thorough clinical risk assessment.
Assuntos
Cardiomiopatia Dilatada/genética , Cardiomiopatia Hipertrófica Familiar/genética , Proteínas de Transporte/genética , Mutação , Adulto , Idoso , Idoso de 80 Anos ou mais , Cardiomiopatia Dilatada/diagnóstico , Cardiomiopatia Hipertrófica Familiar/diagnóstico , Ecocardiografia , Feminino , Humanos , Imageamento por Ressonância Magnética , Masculino , Pessoa de Meia-Idade , Linhagem , Prognóstico , Fatores de RiscoRESUMO
OBJECTIVE: The objective of this study of a case series was to examine the effects of low-level laser therapy (LLLT) in patients with age-related macular degeneration (AMD). BACKGROUND DATA: AMD affects a large proportion of the elderly population; current therapeutic options for AMD are limited, however. PATIENTS AND METHODS: In total, 203 patients (90 men and 113 women; mean age 63.4 +/- 5.3 y) with beginning ("dry") or advanced ("wet") forms of AMD (n = 348 eyes) were included in the study. One hundred ninety-three patients (mean age 64.6 +/- 4.3 y; n = 328 eyes) with cataracts (n = 182 eyes) or without cataracts (n = 146 eyes) were treated using LLLT four times (twice per week). A semiconductor laser diode (780 nm, 7.5 mW, 292 Hz, continuous emission) was used for transconjunctival irradiation of the macula for 40 sec (0.3 J/cm2) resulting in a total dose of 1.2 J/cm2. Ten patients (n = 20 eyes) with AMD received mock treatment and served as controls. Visual acuity was measured at each visit. Data were analyzed retrospectively using a t-test. RESULTS: LLLT significantly improved visual acuity (p < 0.00001 versus baseline) in 162/182 (95%) of eyes with cataracts and 142/146 (97%) of eyes without cataracts. The prevalence of metamorphopsia, scotoma, and dyschromatopsia was reduced. In patients with wet AMD, edema and bleeding improved. The improved vision was maintained for 3-36 mo after treatment. Visual acuity in the control group remained unchanged. No adverse effects were observed in those undergoing therapy. CONCLUSION: In patients with AMD, LLLT significantly improved visual acuity without adverse side effects and may thus help to prevent loss of vision.
Assuntos
Terapia com Luz de Baixa Intensidade , Degeneração Macular/radioterapia , Acuidade Visual/fisiologia , Feminino , Humanos , Degeneração Macular/fisiopatologia , Masculino , Pessoa de Meia-IdadeRESUMO
Anticoagulants and anti-platelet drugs are essential and widely used therapeutic tools in modern cardiovascular medicine. However, the initiation of anti-thrombotic therapies, their termination, or transient discontinuation (e.g. for surgical procedures) are critical steps which have to be managed appropriately. In the near future, several novel irreversibly or reversibly acting anti-thrombotic drugs with direct and indirect mechanisms of action, will be approved. Their prescription will require a deep understanding of their pharmacodynamics and -kinetics. In addition, pharmacogenomic issues will become increasingly important for the optimization of individual therapeutic strategies. This review summarizes clinically relevant principles and discusses them in the light of the assessment of the individual thrombotic and bleeding risks.
Assuntos
Anticoagulantes/administração & dosagem , Inibidores da Agregação Plaquetária/administração & dosagem , Tromboembolia/tratamento farmacológico , Anticoagulantes/efeitos adversos , Anticoagulantes/farmacocinética , Relação Dose-Resposta a Droga , Esquema de Medicação , Interações Medicamentosas , Quimioterapia Combinada , Humanos , Inibidores da Agregação Plaquetária/efeitos adversos , Inibidores da Agregação Plaquetária/farmacocinética , Síndrome de Abstinência a Substâncias/sangue , Síndrome de Abstinência a Substâncias/prevenção & controle , Tromboembolia/sangueRESUMO
Cardiomyopathies are complex myocardial diseases characterized by inappropriate ventricular hypertrophy (HCM) or dilation (DCM). Both disorders may lead to sudden death or progressive heart failure and exhibit familial aggregation with marked genetic heterogeneity. Many candidate genes were identified by linkage analysis, experimental animal studies, and expression analysis. A systematic assessment of the prevalence of different mutations in these genes requires high-throughput analyses. In this paper, we present a simple and reliable protocol for mutation screening by heteroduplex analysis which reduced costs and workload of sequencing. Employing denaturing gradient gel electrophoresis (DGGE), 11 known and 14 potential candidate genes for HCM and DCM were analyzed. DGGE assays allowed analysis of 286 of the 312 protein coding exons, performing only four alternative polymerase chain reaction protocols and only two different DGGE analysis conditions. Sensitivity for the detection of heteroduplexes proved excellent, even for GC-rich DNA fragments, which were analyzed by a combination of DGGE and constant denaturant gel electrophoresis. To confirm DGGE sensitivity in cases where no variants in our human DNA samples could be observed, we generated heteroduplexes from homologous human and chimpanzee DNA. The platform proved a valuable contribution to elucidating the genetic causes of DCM and HCM as demonstrated by the identification of 17 different known and novel mutations and 98 different polymorphisms in our setting.
Assuntos
Cardiomiopatia Dilatada/genética , Cardiomiopatia Hipertrófica Familiar/genética , Adolescente , Adulto , Sequência de Bases , Criança , Pré-Escolar , Eletroforese em Gel de Poliacrilamida , Feminino , Perfilação da Expressão Gênica , Humanos , Lactente , Masculino , Pessoa de Meia-Idade , Dados de Sequência Molecular , Mutação , Linhagem , Projetos PilotoRESUMO
Biomarkers are not established for cardiovascular phenotyping in mice. We compared the use of echocardiography with the determination of N-terminal propeptide of the atrial natriuretic peptide (Nt-proANP) and osteopontin (Opn). We measured plasma Nt-proANP and Opn levels in (1) the inbred strains C57BL/6, BALB/c, C3H/He, DBA/2, FVB/N, 129S1/Sv; (2) a surgical model of nonischemic myocardial infarction; and (3) delta-sarcoglycan (Sgcd) and calsarcin 1 [also known as myozenin 2 (Myoz2)] knockout models of cardiomyopathy. Left ventricular function was assessed as fractional shortening (FS) by echocardiography in conscious mice. Plasma Nt-proANP exhibited marked variability and ranged from 0.31 +/- 0.19 (C57BL/6 male mice) to 1.34 +/- 0.43 nmol/l (DBA/2 female mice), depending on sex, age, and genetic background. Opn was less variable than Nt-proANP and was decreased significantly in C3H/He and DBA/2 throughout the 16 wk of study. Nt-proANP increased temporarily in mice with myocardial injury. In contrast, Opn increased in both operated and sham-treated mice. Nt-proANP was inversely correlated with FS and distinguished controls from Sgcd and Myoz2 mutants with 100% sensitivity and 71% specificity. Opn was increased in Sgcd mutants, which exhibited only mildly reduced FS but marked myocardial degeneration and fibrosis. Both of these histologic features were absent in Myoz2 mutants. Nt-proANP is an early marker of cardiac disease and is suitable for age- and sex-matched comparisons between groups of transgenic and matched control mice. Opn is useful to detect inflammatory and degenerative myocardial disorders that may be missed by echocardiography.
Assuntos
Fator Natriurético Atrial/sangue , Cardiopatias/sangue , Osteopontina/sangue , Envelhecimento/sangue , Animais , Biomarcadores/sangue , Cardiomiopatias/sangue , Cardiomiopatias/genética , Cardiomiopatias/patologia , Proteínas de Transporte/genética , Modelos Animais de Doenças , Feminino , Cardiopatias/genética , Cardiopatias/patologia , Masculino , Camundongos , Camundongos Endogâmicos , Camundongos Knockout , Proteínas dos Microfilamentos , Proteínas Musculares/deficiência , Proteínas Musculares/genética , Fenótipo , Sarcoglicanas/deficiência , Sarcoglicanas/genética , Especificidade da Espécie , Remodelação VentricularRESUMO
Calcification of severely dystrophic muscle is occasionally observed in targeted mouse models of muscular dystrophy and cardiomyopathy. Intracellular calcium deposition occurs in necrotic myocytes in the absence of plasma calcium and phosphate imbalances. In the heart, this recessive trait is referred to as dystrophic cardiac calcinosis (DCC). We identified previously Dyscalc1, a major genetic determinant of DCC, in a 15.2-Mbp region on proximal chromosome 7. We report now further steps toward the identification of the Dyscalc1 gene by reverse genetics. Transferring the Dyscalc1 locus from susceptible mouse strain C3H/He onto a resistant C57BL/6 strain background, we generated congenic inbred strains B6.C3-(D7Mit56-D7Mit230) and B6.C3-(D7Nds5-D7Mit230). Three days after myocardial freeze-thaw injury, both strains exhibited calcification of necrotic lesions, confirming the pathogenetic relevance of Dyscalc1. Analysis of two (129S1 x C57BL/6) x 129S1 backcrosses allowed mapping of Dyscalc1 more precisely to a region spanning 0.76 Mbp between genes Fgf21 (39.70 Mbp) and Myod1 (40.46 Mbp). This interval contains 31 known and putative genes in three large, ancestral haplotypes shared by susceptible strains C3H/He, 129S1, and DBA/2. Thus we were able to exclude previously proposed candidate genes Bax and Hrc. Instead, a potential candidate may be the gene encoding the ATP-binding cassette C6. Mutations in the orthologous human ABCC6 gene cause pseudoxanthoma elasticum, or Gronblad-Strandberg syndrome, an elastic tissue disorder with cardiovascular calcifications.
Assuntos
Calcinose/genética , Cardiomiopatias/genética , Transportadores de Cassetes de Ligação de ATP/genética , Animais , Calcinose/patologia , Cardiomiopatias/patologia , Mapeamento Cromossômico , Cruzamentos Genéticos , Predisposição Genética para Doença , Humanos , Camundongos , Camundongos Endogâmicos C3H , Camundongos Endogâmicos C57BL , Camundongos Endogâmicos CBA , Proteínas Associadas à Resistência a Múltiplos Medicamentos/genética , Mutação , Pseudoxantoma Elástico/genética , Locos de Características QuantitativasRESUMO
OBJECTIVE: The purpose of this work was to study the safety of photobiomodulation therapy in patients with primary open angle glaucoma (POAG). BACKGROUND DATA: Therapeutic options for POAG focus on lowering the intraocular pressure (IOP) but cannot stop disease progression to irreversible damages. METHODS: The study was designed as a controlled, single-blinded, interventional case series (38 patients; 63 eyes). Low-level laser therapy was performed once or twice per week using a continuous wave (CW) diode laser (780 nm; 10 mW; 292 Hz modulation; 3 mm(2) beam spot). The limbus area was circularly irradiated for 30 sec (0.3 W/cm(2); 10 J/cm(2)) at a 1 cm distance. Additional parts of the bulbus were irradiated for 90 sec (30 J/cm(2)) pointing the beam toward retinal areas corresponding to defective visual fields. A control group of 10 patients (20 eyes) received mock treatment. Visual acuity was assessed using Snellen projection optotypes. IOP was determined by applanation tonometry. Visual fields were determined by kinetic Goldmann perimetry. Multifocal visual evoked potential (M-VEP) was recorded in 15 patients (30 eyes). RESULTS: Poor visual acuity (≤ 20/25), initially found in 24 of 63 eyes (38.1%), improved in 17 (70.8%) eyes and did not change in 7 eyes (29.2%). Mean IOP dropped from 24.9 ± 14.9 to 15.0 ± 6.5 mm Hg (-39.7%, p < 0.001). Visual fields were either fully restored, improved by at least 10 degrees, or remained unchanged in 32, 29, and 2 of 63 eyes (51%, 46%, and 3%), respectively. Mean M-VEP latency was reduced by 13.5 msec (-8%, p < 0.001); mean amplitude increased by +677 nV (+14%, p < 0.001). Adverse effects were not observed. No changes were noted in control eyes. CONCLUSIONS: This first small series of cases indicated that photobiomodulation might be a safe approach to lower IOP and to improve visual acuity and fields in eyes with POAG.
RESUMO
OBJECTIVE: This case report describes the effects of low-level laser therapy (LLLT) in a single patient with retinitis pigmentosa (RP). BACKGROUND DATA: RP is a heritable disorder of the retina, which eventually leads to blindness. No therapy is currently available. METHODS: LLLT was applied using a continuous wave laser diode (780 nm, 10 mW average output at 292 Hz, 50% pulse modulation). The complete retina of eyes was irradiated through the conjunctiva for 40 sec (0.4 J, 0.333 W/cm2) two times per week for 2 weeks (1.6 J). A 55-year-old male patient with advanced RP was treated and followed for 7 years. RESULTS: The patient had complained of nyctalopia and decreasing vision. At first presentation, best visual acuity was 20/50 in each eye. Visual fields were reduced to a central residual of 5 degrees. Tritan-dyschromatopsy was found. Retinal potential was absent in electroretinography. Biomicroscopy showed optic nerve atrophy, and narrow retinal vessels with a typical pattern of retinal pigmentation. After four initial treatments of LLLT, visual acuity increased to 20/20 in each eye. Visual fields normalized except for a mid-peripheral absolute concentric scotoma. Five years after discontinuation of LLLT, a relapse was observed. LLLT was repeated (another four treatments) and restored the initial success. During the next 2 years, 17 additional treatments were performed on an "as needed" basis, to maintain the result. CONCLUSIONS: LLLT was shown to improve and maintain vision in a patient with RP, and may thereby have contributed to slowing down blindness.
Assuntos
Terapia com Luz de Baixa Intensidade , Retinose Pigmentar/terapia , Humanos , Terapia com Luz de Baixa Intensidade/métodos , Masculino , Pessoa de Meia-Idade , Resultado do Tratamento , Visão OcularRESUMO
OBJECTIVE: The purpose of this study was to examine the effects of low-level laser therapy (LLLT) on visual acuity in adolescent and adult patients with amblyopia. BACKGROUND DATA: Currently, amblyopia can be treated successfully only in children. METHODS: In this single-blinded, placebo-controlled study, 178 patients (mean age 46.8 years) with amblyopia caused by ametropia (110 eyes) or strabismus (121 eyes) were included. For LLLT, the area of the macula was irradiated through the conjunctiva from 1 cm distance for 30 sec with laser light (780 nm, 292 Hz, 1:1 duty cycle; average power 7.5 mW; spot area 3 mm(2)). The treatment was repeated on average 3.5 times, resulting in a mean total dose of 0.77 J/cm(2). No occlusion was applied, and no additional medication was administered. Best corrected distant visual acuity was determined using Snellen projection optotypes. In 12 patients (12 eyes), the multifocal visual evoked potential (M-VEP) was recorded. A control group of 20 patients (20 eyes) received mock treatment. RESULTS: Visual acuity improved in â¼90% of the eyes treated with LLLT (p<0.001), increasing by three or more lines in 56.2% and 53.6% of the eyes with amblyopia caused by ametropia and strabismus, respectively. The treatment effect was maintained for at least 6 months. The mean M-VEP amplitude increased by 1207 nV (p<0.001) and mean latency was reduced by 7 msec (p=0.14). No changes were noted in the control group. CONCLUSIONS: LLLT led to a significant improvement in visual acuity in adolescent and adult patients with amblyopia caused by ametropia or strabismus.
Assuntos
Ambliopia/radioterapia , Potenciais Evocados Visuais/fisiologia , Terapia com Luz de Baixa Intensidade/métodos , Acuidade Visual , Adolescente , Adulto , Fatores Etários , Idoso , Ambliopia/diagnóstico , Relação Dose-Resposta à Radiação , Feminino , Seguimentos , Humanos , Masculino , Pessoa de Meia-Idade , Oftalmoscopia/métodos , Satisfação do Paciente/estatística & dados numéricos , Doses de Radiação , Erros de Refração/diagnóstico , Erros de Refração/radioterapia , Fatores Sexuais , Método Simples-Cego , Estrabismo/diagnóstico , Estrabismo/radioterapia , Fatores de Tempo , Resultado do Tratamento , Adulto JovemRESUMO
AIMS: Penetrance and phenotypic expressivity of cardiomyopathies are modulated by modifier genes both in model systems and patients. We aimed to dissect the disease-modifying mechanisms by examining genome-wide gene expression in a new set of mouse (Mus musculus) congenic strains. METHODS AND RESULTS: Mutant alleles of the genes calsarcin-1 (Myoz2), sarcoglycan-delta (Sgcd), and muscle LIM protein (Csrp2) were each transferred onto inbred strain backgrounds C57BL/6, C3H/He, 129S1/Sv, and FVB/N, respectively. At 9-10 weeks of age, left ventricular pump function (fractional shortening, FS) was determined by echocardiography in non-sedated congenic animals. Gene expression was then analysed in myocardial tissue using the Affymetrix Mouse 430.2 microarray platform. Variance stabilization, linear mixed-effects modelling, correlations, gene functional classification, and pathway analysis were conducted using the standard software. Strain background FVB/N appeared to protect against the consequences of gene inactivation. Sgcd-deficient congenics showed normal FS, which was consistent with their hypertrophic cardiomyopathy phenotype. Animals with other allele/background combinations developed an impaired ventricular pump function (FS <65%). Gender did not influence FS significantly, yet it determined the sets of genes that were differentially expressed in mice with low FS. In particular, genes encoding the elements of the ubiquitin-proteasome system (UPS) were strongly correlated with the cardiac impairment (absolute Spearman r ≥ 0.7) in both males and females. CONCLUSION: Gene expression profiling in a novel set of congenic strains revealed an association between the UPS and myocardial contractile function, indicating that the UPS may be an important modifier of phenotypic variability in cardiomyopathies.
Assuntos
Cardiomiopatias/genética , Contração Miocárdica/genética , Complexo de Endopeptidases do Proteassoma/genética , Ubiquitinas/genética , Função Ventricular Esquerda/genética , Fatores Etários , Animais , Cardiomiopatias/diagnóstico por imagem , Cardiomiopatias/enzimologia , Cardiomiopatias/fisiopatologia , Proteínas de Transporte/genética , Proteínas de Transporte/metabolismo , Biologia Computacional , Feminino , Perfilação da Expressão Gênica/métodos , Regulação da Expressão Gênica , Predisposição Genética para Doença , Estudo de Associação Genômica Ampla , Proteínas com Domínio LIM/genética , Proteínas com Domínio LIM/metabolismo , Masculino , Camundongos , Camundongos da Linhagem 129 , Camundongos Congênicos , Camundongos Endogâmicos C3H , Camundongos Endogâmicos C57BL , Camundongos Knockout , Camundongos Transgênicos , Proteínas dos Microfilamentos , Proteínas Musculares/genética , Proteínas Musculares/metabolismo , Mutação , Proteínas Nucleares/genética , Proteínas Nucleares/metabolismo , Análise de Sequência com Séries de Oligonucleotídeos , Fenótipo , Complexo de Endopeptidases do Proteassoma/metabolismo , Sarcoglicanas/genética , Sarcoglicanas/metabolismo , Ubiquitinação , Ubiquitinas/metabolismo , UltrassonografiaRESUMO
AIMS: Left ventricular non-compaction (LVNC) is caused by mutations in multiple genes. It is still unclear whether LVNC is the primary determinant of cardiomyopathy or rather a secondary phenomenon with intrinsic cardiomyocyte dysfunction being the actual cause of the disease. Here, we describe a family with LVNC due to a novel missense mutation, pE96K, in the cardiac troponin T gene (TNNT2). METHODS AND RESULTS: The novel mutation was identified in the index patient and all affected relatives, but not in 430 healthy control individuals. Mutations in known LVNC-associated genes were excluded. To investigate the pathophysiological implications of the mutation, we generated transgenic mice expressing human wild-type cTNT (hcTNT) or a human troponin T harbouring the pE96K mutation (mut cTNT). Animals were characterized by echocardiography, histology, and gene expression analysis. Mut cTNT mice displayed an impaired left ventricular function and induction of marker genes of heart failure. Remarkably, left ventricular non-compaction was not observed. CONCLUSION: Familial co-segregation and the cardiomyopathy phenotype of mut cTNT mice strongly support a causal relationship of the pE96K mutation and disease in our index patient. In addition, our data suggest that a non-compaction phenotype is not required for the development of cardiomyopathy in this specific TNNT2 mutation leading to LVNC.
Assuntos
Miocárdio Ventricular não Compactado Isolado/genética , Mutação de Sentido Incorreto , Troponina T/genética , Animais , Biópsia , Estudos de Casos e Controles , Análise Mutacional de DNA , Ecocardiografia Doppler em Cores , Éxons , Feminino , Predisposição Genética para Doença , Humanos , Lactente , Miocárdio Ventricular não Compactado Isolado/diagnóstico , Miocárdio Ventricular não Compactado Isolado/fisiopatologia , Imagem Cinética por Ressonância Magnética , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Pessoa de Meia-Idade , Contração Miocárdica/genética , Linhagem , Fenótipo , Índice de Gravidade de Doença , Volume Sistólico/genética , Disfunção Ventricular Esquerda/genética , Disfunção Ventricular Esquerda/fisiopatologia , Adulto JovemRESUMO
OBJECTIVE: We investigated the potential use of low-intensity laser irradiation (LILI) as a diagnostic tool for identifying hypertensive eyes at risk of glaucoma. BACKGROUND DATA: The diagnosis of early-stage ocular hypertension is particularly difficult to establish. METHODS: This study of a case series included 123 healthy subjects with normal vision. The intraocular pressure (IOP) was determined before (baseline) and 30 min after a 30-sec irradiation of the limbus area with laser light (780 nm; 7.5 mW; 292 Hz modulation). RESULTS: Baseline IOP was >21 mm Hg in 44 of 211 eyes (20.9%), consistent with ocular hypertension. LILI decreased the mean IOP by 6.2 mm Hg (-25.7%; p < 0.001; paired t test) in these eyes. The remaining 167 eyes (79.1%) exhibited a normotensive IOP Assuntos
Pressão Intraocular/efeitos da radiação
, Limbo da Córnea/efeitos da radiação
, Terapia com Luz de Baixa Intensidade
, Hipertensão Ocular/diagnóstico
, Idoso
, Diagnóstico Precoce
, Feminino
, Humanos
, Lasers Semicondutores
, Masculino
, Pessoa de Meia-Idade
RESUMO
BACKGROUND: Platelet hyperreactivity was reported in clopidogrel-naiotave carriers of the H2 haplotype of the P2Y(12) platelet ADP receptor. Here, we studied the influence of this genetic variant on clopidogrel responsiveness. METHODS: ADP-mediated (5 micromol/L) platelet aggregation was determined by impedance (Omega) aggregometry in 43 clopidogrel-naïve blood donors and 557 patients treated with aspirin and clopidogrel after percutaneous coronary stent implantation. A cut-off of 5 Omega was used to classify the aggregation response. Haplotype tagging single nucleotide polymorphism G52T was genotyped using a TaqMan assay. RESULTS: The number of H2 alleles correlated with aggregation in clopidogrel-naïve subjects in healthy subjects (p=0.041): impedance results were 8.4+/-3.6, 10.5+/-1.6 and 12.5+/-2.1 Omega in carriers of the H1/H1 (n=30), H1/H2 (n=11) and H2/H2 (n=2) haplotypes, respectively. 87.1% (n=485) and 12.9% (n=72) of clopidogrel treated patients were responders and nonresponders, respectively. Women were more likely to be nonresponders (O.R. 3.90 [95% CI 2.34-6.50]). Carriers of a H2/H2 haplotype (n=14) exhibited stronger aggregation than patients with at least one H1 allele (6.3+/-7.5 vs. 1.8+/-3.3 Omega, p=0.0212) and were more frequently nonresponders (p=0.004). Consequently, the H2/H2 haplotype was associated with clopidogrel resistance (O.R. 5.42 [95% CI 1.82-16.11]). This risk factor was independent of the gender effect. CONCLUSIONS: This is the first large study in clopidogrel treated patients suggesting that a homozygote H2 genotype contributes to clopidogrel resistance. The clinical significance of this finding remains to be demonstrated.
Assuntos
Resistência a Medicamentos/genética , Haplótipos/genética , Agregação Plaquetária/efeitos dos fármacos , Agregação Plaquetária/genética , Receptores Purinérgicos P2/genética , Ticlopidina/análogos & derivados , Adulto , Idoso , Idoso de 80 Anos ou mais , Alelos , Clopidogrel , Feminino , Humanos , Masculino , Inibidores da Agregação Plaquetária/farmacologia , Valor Preditivo dos Testes , Receptores Purinérgicos P2Y12 , Fatores de Risco , Ticlopidina/farmacologia , Adulto JovemRESUMO
BACKGROUND: Troponin elevation in patients with stable coronary heart disease is associated with adverse outcome and prognosis. However, the mechanism is not yet clearly understood. Our objectives were to examine the prevalence and range of cardiac troponin T (cTnT) in stable patients, 6 months after acute myocardial infarction (AMI) using a new high sensitive cTnT assay and to investigate the association of minor cTnT elevation in these patients to clinical variables, NT-proBNP and cardiac MRI-findings. STUDY DESIGN AND METHODS: cTnT was measured in 98 patients 6 months after AMI with a precommercial assay by electrochemiluminescence methods (Roche Diagnostics, Mannheim, Germany). cTnT values were correlated with clinical and angiographic variables, NT-proBNP concentrations and with cardiac MRI-findings. RESULTS: Minor cTnT concentrations were detectable in 90% of the entire cohort, of whom 16% had cTnT values above the 99th percentile (>12 ng/L). These patients were also significantly older, suffered more frequently from hypertension, had a higher New York Heart Association class and received more often diuretics at follow up. Patients with cTnT elevation had a more impaired left ventricular ejection fraction (P = 0.02) but did not have an increased infarct size (P = 0.73). CONCLUSIONS: Elevated minor cTnT levels are frequently detectable in patients 6 months after AMI. Increased cTnT level were associated with clinical parameter for heart failure, impaired ejection fraction and higher NT-proBNP levels suggesting that myocardial dysfunction is a main cause for cTnT elevation in these patient group.