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Background: Chronic obstructive pulmonary disease (COPD) case-finding aims to detect airflow obstruction in symptomatic smokers and ex-smokers. We used a clinical algorithm including smoking, symptoms, and spirometry to classify smokers into COPD risk phenotypes. In addition, we evaluated the acceptability and effectiveness of including smoking cessation advice in the case-finding intervention. Methods: Smoking, symptoms, and spirometry abnormalities (airflow obstruction: forced expiratory volume in 1 second [FEV1] to forced vital capacity [FVC] <0.7 or preserved-ratio spirometry (FEV1<80% of predicted value and FEV1/FVC ratio ≥ 0.7)] were assessed in a group of 864 smokers aged ≥ 30 years. The combination of these parameters allowed the identification of 4 phenotypes: Phenotype A (no symptoms, normal spirometry; reference), Phenotype B (symptoms; normal spirometry; possible COPD), Phenotype C (no symptoms; abnormal spirometry; possible COPD), and Phenotype D (symptoms; abnormal spirometry; probable COPD). We assessed phenotype differences in clinical variables and modeled the trend from phenotype A to phenotype D. Smoking cessation advice based on spirometry was provided. Follow-up was done by telephone 3 months later. Results: Using smokers without symptoms or abnormal spirometry (phenotype A; n=212 [24.5%]) as a reference, smokers were classified into possible COPD (phenotype B;n=332 [38.4%]; and C: n=81 [9.4%]) and probable COPD (phenotype D: n=239 [27.2%]). The trend from baseline phenotype A to probable COPD phenotype D was significant for the number of cigarettes/day and the number of years of smoking (p=0.0001). At follow-up, 58 (7.7%) of the respondents (n=749) reported that they had quit smoking. Conclusions: Our clinical algorithm allowed us to classify smokers into COPD phenotypes whose manifestations were associated with smoking intensity and to significantly increase the number of smokers screened for COPD. Smoking cessation advice was well accepted, resulting in a low but clinically significant quit rate.
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BACKGROUND: Vascular endothelial cells (VECs) are an essential component of each tissue, contribute to multiple pathologies, and are targeted by important drugs. Yet, there is a shortage of biomarkers to assess VEC turnover. METHODS: To develop DNA methylation-based liquid biopsies for VECs, we determined the methylome of VECs isolated from freshly dissociated human tissues. FINDINGS: A comparison with a human cell-type methylome atlas yielded thousands of loci that are uniquely unmethylated in VECs. These sites are typically gene enhancers, often residing adjacent to VEC-specific genes. We also identified hundreds of genomic loci that are differentially methylated in organotypic VECs, indicating that VECs feeding specific organs are distinct cell types with a stable epigenetic identity. We established universal and lung-specific VEC markers and evaluated their presence in circulating cell-free DNA (cfDNA). Nearly 2.5% of cfDNA in the plasma of healthy individuals originates from VECs. Sepsis, graft versus host disease, and cardiac catheterization are associated with elevated levels of VEC-derived cfDNA, indicative of vascular damage. Lung-specific VEC cfDNA is selectively elevated in patients with chronic obstructive pulmonary disease (COPD) or lung cancer, revealing tissue-specific vascular turnover. CONCLUSIONS: VEC cfDNA biomarkers inform vascular dynamics in health and disease, potentially contributing to early diagnosis and monitoring of pathologies, and assessment of drug activity. FUNDING: This work was supported by the Beutler Research Program, Helmsley Charitable Trust, JDRF, Grail and the DON Foundation (to Y.D.). Y.D holds the Walter & Greta Stiel Chair in heart studies. B.G., R.S., J.M., D.N., T.K., and Y.D. filed patents on cfDNA analysis.
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Ácidos Nucleicos Livres , Epigenoma , Humanos , Endotélio Vascular , Células Endoteliais/metabolismo , Biomarcadores/metabolismo , Biópsia LíquidaRESUMO
Background: Although smoking is the leading cause of chronic obstructive pulmonary disease (COPD), many patients with COPD smoke, highlighting the need for effective smoking cessation interventions in this population. This study examined the efficacy and safety of varenicline in increasing smoking cessation rates through "gradual" versus "abrupt" cessation in COPD patients with low motivation to quit smoking. Methods: A randomized, open label, 30-week, controlled trial (ClinicalTrials.gov identifier: NCT02894957) was conducted between January 2019 and October 2020 at a center in Israel. Smokers with COPD, poorly motivated to quit, were randomized to 6 weeks of varenicline for smoking reduction and a target quit day (TQD) at the end of week 6 (gradual cessation group) or ad libitum smoking for 5 weeks, 1 week of varenicline, and a TQD at the end of week 6 (abrupt cessation group). After the pre-quit phase, both groups received 12-week regular varenicline treatment and 12-week follow-up. Primary outcome was biochemically-validated continuous abstinence for weeks 6-30. Secondary outcomes were: (1) biochemically-confirmed7-day point prevalence abstinence for weeks 4-30, (2) efficient smoking reduction (≥50% in number of cigarettes/day) in the pre-quit phase; and (3) number of cigarettes/day, motivation to quit, and changes in respiratory symptoms and spirometry from baseline through week 30. Results: A drug recall issued by the study sponsor stopped the study after 70/242 (28.9%) patients had been enrolled. The gradual cessation group (n=29) had significantly higher continuous abstinence rates from TQD through week 30 versus the abrupt cessation group (n=41): 20.7% versus 4.9% (odds ratio [OR]=5.09; 95% confidence interval [CI] 0.89-29.17; p=0.048) and higher 7-day point prevalence abstinence levels at all time points but week 18 (p=0.027 at week 6, 0.056 at week 7, and 0.096 at week 9). Motivation to quit increased (p=0.002) and the number of cigarettes/day decreased (p=0.002) over time in both groups. Respiratory symptoms, but not spirometry, improved in both groups at week 30. Treatment was safe and well tolerated. Conclusion: In poorly motivated smokers with COPD, using varenicline for a 6-week gradual smoking cessation before TQD, compared with abrupt cessation, significantly increased quit rates up to 6 months. Results were not affected by the smaller-than-expected sample size. Further studies are needed to confirm these data.
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BACKGROUND: Circulating biomarkers for lung damage are lacking. Lung epithelium-specific DNA methylation patterns can potentially report the presence of lung-derived cell-free DNA (cfDNA) in blood, as an indication of lung cell death. METHODS: We sorted human lung alveolar and bronchial epithelial cells from surgical specimens, and obtained their methylomes using whole-genome bisulfite sequencing. We developed a PCR sequencing assay determining the methylation status of 17 loci with lung-specific methylation patterns, and used it to assess lung-derived cfDNA in the plasma of healthy volunteers and patients with lung disease. RESULTS: Loci that are uniquely unmethylated in alveolar or bronchial epithelial cells are enriched for enhancers controlling lung-specific genes. Methylation markers extracted from these methylomes revealed that normal lung cell turnover probably releases cfDNA into the air spaces, rather than to blood. People with advanced lung cancer show a massive elevation of lung cfDNA concentration in blood. Among individuals undergoing bronchoscopy, lung-derived cfDNA is observed in the plasma of those later diagnosed with lung cancer, and to a lesser extent in those diagnosed with other lung diseases. Lung cfDNA is also elevated in patients with acute exacerbation of COPD compared with patients with stable disease, and is associated with future exacerbation and mortality in these patients. CONCLUSIONS: Universal cfDNA methylation markers of normal lung epithelium allow for mutation-independent, sensitive and specific detection of lung-derived cfDNA, reporting on ongoing lung injury. Such markers can find broad utility in the study of normal and pathologic human lung dynamics.
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Ácidos Nucleicos Livres , Neoplasias Pulmonares , Humanos , Metilação de DNA , Ácidos Nucleicos Livres/genética , Biópsia Líquida , Biomarcadores , Epitélio , Pulmão , Neoplasias Pulmonares/genética , Biomarcadores Tumorais/genéticaRESUMO
Cancer inflicts damage to surrounding normal tissues, which can culminate in fatal organ failure. Here, we demonstrate that cell death in organs affected by cancer can be detected by tissue-specific methylation patterns of circulating cell-free DNA (cfDNA). We detected elevated levels of hepatocyte-derived cfDNA in the plasma of patients with liver metastases originating from different primary tumors, compared with cancer patients without liver metastases. In addition, patients with localized pancreatic or colon cancer showed elevated hepatocyte cfDNA, suggesting liver damage inflicted by micrometastatic disease, by primary pancreatic tumor pressing the bile duct, or by a systemic response to the primary tumor. We also identified elevated neuron-, oligodendrocyte-, and astrocyte-derived cfDNA in a subpopulation of patients with brain metastases compared with cancer patients without brain metastasis. Cell type-specific cfDNA methylation markers enabled the identification of collateral tissue damage in cancer, revealing the presence of metastases in specific locations and potentially assisting in early cancer detection.
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Neoplasias Encefálicas , Ácidos Nucleicos Livres , Metilação de DNA , Biópsia Líquida/métodos , Neoplasias Hepáticas , Metástase Neoplásica , Neoplasias Pancreáticas , Biomarcadores Tumorais/análise , Biomarcadores Tumorais/sangue , Neoplasias Encefálicas/genética , Neoplasias Encefálicas/patologia , Neoplasias Encefálicas/secundário , Ácidos Nucleicos Livres/análise , Ácidos Nucleicos Livres/sangue , Detecção Precoce de Câncer/métodos , Hepatócitos/metabolismo , Hepatócitos/patologia , Humanos , Neoplasias Hepáticas/genética , Neoplasias Hepáticas/patologia , Neoplasias Hepáticas/secundário , Metástase Neoplásica/genética , Metástase Neoplásica/patologia , Neoplasias Pancreáticas/complicações , Neoplasias Pancreáticas/metabolismo , Neoplasias Pancreáticas/patologiaRESUMO
Pulmonary calcifications are usually incidental asymptomatic findings discovered on x-rays or computed tomography scans that can be easily overlooked, and their significance undermined, especially in a seemingly asymptomatic person. Calcifications can be a marker of chronicity or disease severity, and thus have diagnostic value. Rarely, calcification can be the direct cause of morbidity. Calcifications can be either localized or diffuse. Many diseases, in particular infectious diseases, can cause localized calcifications. Diffuse calcifications are less common and usually secondary to a handful of conditions such as dystrophic pulmonary calcifications, metastatic pulmonary calcifications, disseminated pulmonary ossifications and pulmonary alveolar microlithiasis. We describe three cases of diffuse pulmonary calcifications, review the different causes of diffuse pulmonary calcifications and provide some indicators on how to differentiate between them. Differentiating between the different types of pulmonary calcifications has significant implications on the management and prognosis of the patients, and thus it is important to distinguish between them.
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BACKGROUND: Different case finding approaches have been used to identify early COPD. The objective of this study was to assess the feasibility and the yield of opportunistic early COPD case finding in visitors to a large medical centre. PATIENTS AND METHODS: From May 2014 to June 2017, we consecutively recruited adults aged ≥ 18 years visiting the Shaare Zedek Medical Center, in Jerusalem. Our 3-step intervention included: a) pre-screening for symptoms with the 5-item "Could it be COPD?" questionnaire (score= 0-5 pts); b) pre-BD spirometry; and c) referral to a caregiver. Airflow obstruction was defined by a FEV1/FVC < 0.7. Spirometry results were used as an incentive to promote smoking cessation and quit rates were verified by phone survey 3 months after the intervention. RESULTS: A total of 1001 subjects (956 smokers; 45 ex-smokers) were recruited. Mean (SD) age was 48.3 years (13.5). Airflow obstruction was detected in 180 (18%) subjects of whom 142 (78.9%) were unaware of it, including 27 subjects with severe (50% ≥ FEV1 ≤ 30% predicted) (n=25) or very severe (FEV1 < 30% predicted) (n=2) obstruction. Multiple logistic regression analysis found that age, BMI, cigarette smoking (p.y.) and a "Could it be COPD?" questionnaire score ≥ 3 points correctly classified 83.3% of cases of airflow obstruction. At follow-up, 54.5% of participants reported smoking as usual, 30.9% reduced smoking [mean (SD) = 10.1 ± 7.8 cigarettes/day], 7.4% increased smoking [mean (SD) = 9.2 ± 6.3 cigarettes/day] and 7.2% claimed smoking cessation. Among obstructed subjects, 38.7% had visited a physician because of COPD, while 20.7% were taking a new respiratory medication. CONCLUSION: Early COPD case finding was feasible and effective in identifying undiagnosed airflow obstruction among visitors to a medical centre. Smoking cessation counselling based on spirometry promoted a small but clinically meaningful cessation rate.
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Doença Pulmonar Obstrutiva Crônica , Fumantes , Adulto , Ex-Fumantes , Volume Expiratório Forçado , Humanos , Pessoa de Meia-Idade , Doença Pulmonar Obstrutiva Crônica/diagnóstico , Doença Pulmonar Obstrutiva Crônica/epidemiologia , Fumar/efeitos adversos , EspirometriaAssuntos
Neoplasias Pulmonares/diagnóstico por imagem , Embolia Pulmonar/diagnóstico por imagem , Carcinoma de Pequenas Células do Pulmão/diagnóstico por imagem , Feminino , Humanos , Neoplasias Pulmonares/patologia , Pessoa de Meia-Idade , Carcinoma de Pequenas Células do Pulmão/patologia , Tomografia Computadorizada por Raios XRESUMO
BACKGROUND: Many studies have described asthma-COPD overlap (ACO) among patients diagnosed with asthma or chronic obstructive pulmonary disease (COPD), but less so in broad populations of patients with chronic airway obstruction. OBJECTIVE: This study aimed to (i) examine the prevalence of ACO, asthma, and COPD phenotypes among subjects referred for pulmonary function testing (PFT), who had airway obstruction in spirometry (forced expiratory volume in 1 s [FEV1]/forced vital capacity [FVC] <0.7); and (ii) delineate the therapeutic approach of each group. METHODS: Cross-sectional study of patients who were referred for PFT at the Rokach Institute, in Jerusalem. Working definitions were as follows: (a) COPD: post-bronchodilator (BD) FEV1/FVC <0.70; (b) asthma: physician-diagnosed asthma before age 40 and/or minimum post-BD increase in FEV1 or FVC of 12% and 200 mL; and (c) ACO: the combination of the 2. Demographics, smoking habits, episodes of exacerbation, health-related quality of life (HRQL), and respiratory medication utilization were analyzed. RESULTS: Of 3,669 referrals from January 1 to April 30, 2017, 1,220 had airway obstruction of which 215 were included. Of these, 82 (38.1%) had ACO, 49 (22.8%) asthma, and 84 (39.1%) COPD. ACO subjects tended to (a) be predominantly female; (b) be older than asthmatics, (c) be smokers; (d) have worse HRQL in the activity domain; and (d) have more exacerbations. Treatment of ACO and COPD patients differed from that of asthmatics, but not from each other, in the proportion of subjects on maintenance treatment, use of LABA, LAMA, and ICS, alone or in combination, and in the number of inhaler devices used by patients. CONCLUSION: ACO represented >1/3 of patients referred for PFT. Despite a clearly identifiable phenotype, ACO patients received treatment similar to COPD patients, suggesting poor ACO identification. Our data emphasize the need to raise the awareness of ACO among clinicians, in order to guide better recognition and appropriate treatment in individual patients.
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Síndrome de Sobreposição da Doença Pulmonar Obstrutiva Crônica e Asma/epidemiologia , Asma/epidemiologia , Doença Pulmonar Obstrutiva Crônica/epidemiologia , Fumar/epidemiologia , Administração por Inalação , Agonistas Adrenérgicos beta/uso terapêutico , Adulto , Distribuição por Idade , Idoso , Asma/tratamento farmacológico , Asma/fisiopatologia , Síndrome de Sobreposição da Doença Pulmonar Obstrutiva Crônica e Asma/tratamento farmacológico , Síndrome de Sobreposição da Doença Pulmonar Obstrutiva Crônica e Asma/fisiopatologia , Estudos Transversais , Progressão da Doença , Feminino , Volume Expiratório Forçado , Glucocorticoides/uso terapêutico , Hospitalização/estatística & dados numéricos , Humanos , Pneumopatias Obstrutivas/classificação , Masculino , Pessoa de Meia-Idade , Antagonistas Muscarínicos/uso terapêutico , Fenótipo , Doença Pulmonar Obstrutiva Crônica/tratamento farmacológico , Doença Pulmonar Obstrutiva Crônica/fisiopatologia , Qualidade de Vida , Testes de Função Respiratória , Distribuição por Sexo , Capacidade VitalRESUMO
BACKGROUND: Pulmonary rehabilitation has shown significant benefit for patients with chronic obstructive pulmonary disease (COPD). The effect on non-COPD pulmonary patients is less well established. OBJECTIVES: To determine whether pulmonary rehabilitation is also beneficial for non-COPD pulmonary patients. METHODS: Clinical and demographic data on non-COPD pulmonary patients who participated in our institutional pulmonary rehabilitation program between January 2009 and December 2016 were collected. Participants engaged in a 60-minute, twice-weekly, ambulatory hospital-based program lasting 12 to 24 sessions. Sessions included both endurance and muscle training as well as healthy lifestyle educational activities. The six-minute walk test (6MWT) and the St. George's Respiratory Questionnaire (SGRQ) were conducted before and after the rehabilitation program. RESULTS: We recruited 214 non-COPD patients, of whom 153 completed at least 12 sessions. Of these, 59 presented with interstitial lung disease (ILD), 18 with non-ILD restrictive lung defects, 25 with asthma, 30 with lung cancer, and 21 with other conditions (e.g., pulmonary hypertension, bronchiectasis) The groups demonstrated significant improvement in 6MWT and in SGRQ scores. Non-COPD patients gained a 61.9 meter (19%) improvement in the 6MWT (P < 0.0001) and 8.3 point reduction in their SGRQ score (P < 0.0001). CONCLUSIONS: Pulmonary rehabilitation is effective in non-COPD pulmonary patients. As such, it should be an integral part of the treatment armament provided to the vast majority of those suffering from chronic respiratory disease.
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Dispneia , Terapia por Exercício/métodos , Pneumopatias , Qualidade de Vida , Idoso , Dispneia/etiologia , Dispneia/fisiopatologia , Dispneia/psicologia , Dispneia/reabilitação , Treino Aeróbico/métodos , Feminino , Humanos , Pneumopatias/classificação , Pneumopatias/diagnóstico , Pneumopatias/psicologia , Pneumopatias/reabilitação , Masculino , Pessoa de Meia-Idade , Exercícios de Alongamento Muscular/métodos , Inquéritos e Questionários , Resultado do Tratamento , Teste de Caminhada/métodosRESUMO
BACKGROUND: Fiberoptic bronchoscopy (FOB) with transbronchial biopsy (TBB) is complicated by a pneumothorax in 1-4% of cases. Performance of routine post-TBB chest radiography (CXR) results in an extremely low diagnostic yield but nevertheless is the common clinical practice prevailing today. It has previously been suggested that routine post-TBB CXR could be avoided in asymptomatic patients. OBJECTIVE: The objective of this study was to prospectively assess the feasibility and safety of this approach. METHODS: The study group included 201 consecutive patients who underwent FOB with TBB at our institution between January 2009 and September 2014. All subjects completed a preprocedural, a 2-hour postprocedural, and a 24- to 48-hour postprocedural symptom questionnaire (chest pain, dyspnea, and cough). Post-TBB CXR was ordered by the treating physician only if indicated. All cases of pneumothorax were documented. Additionally, the following information was recorded: sex, age, immune status, indication for FOB, total number of biopsies done, lobe sampled, and pulse oxygen saturation. RESULTS: Sixteen CXRs were ordered by the treating physician due to suspected pneumothorax (8%). Early-onset pneumothorax (i.e. within 2 h of TBB) was diagnosed radiologically in 6 patients (3%). Two late-onset pneumothoraxes (1%) were diagnosed more than 24 h after TBB. No pneumothoraxes of clinical significance were diagnosed among asymptomatic patients without significant oxygen desaturation events. CONCLUSIONS: Among asymptomatic patients without significant desaturation events, pneumothorax is rare and usually of negligible clinical significance. Therefore, performance of routine CXR after TBB is not necessary and can be safely avoided in this category of patients.
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Biópsia/efeitos adversos , Broncoscopia/efeitos adversos , Pneumotórax/diagnóstico por imagem , Complicações Pós-Operatórias/diagnóstico por imagem , Adulto , Idoso , Doenças Assintomáticas , Dor no Peito/epidemiologia , Dor no Peito/etiologia , Tosse/epidemiologia , Tosse/etiologia , Dispneia/epidemiologia , Dispneia/etiologia , Feminino , Humanos , Modelos Logísticos , Masculino , Pessoa de Meia-Idade , Pneumotórax/epidemiologia , Pneumotórax/etiologia , Complicações Pós-Operatórias/epidemiologia , Complicações Pós-Operatórias/etiologia , Radiografia Torácica , Inquéritos e QuestionáriosRESUMO
Ectopic pancreas in the mediastinum is extremely rare. We are reporting on a case of a twenty two year old woman who presented to our clinic with a large cervical mass. The CT scan revealed a cystic lesion in the anterior mediastinum. The patient underwent surgical resection by cervical approach. A Cystic mass with pseudocysts, cysts and complete pancreatic tissue were found in pathology. There were no signs of pancreatitis or malignancy. No recurrence was observed after a follow up of four years. We reviewed the case reports describing this rare condition in the medical literature.We conclude that the possibility of ectopic pancreatic tissue should be included in the differential diagnosis of anterior mediastinal cystic mass, though as a remote possibility. Surgery is probably needed for the diagnosis and treatment. Posterior mediastinal pseudocyst is a different entity associated with acute pancreatitis. In those cases surgery is not recommended. Our third conclusion is that pancreatic tissue should be actively sought, if a structure resembling a pseudocyst is found in an unexpected location. VIRTUAL SLIDES: The virtual slide(s) for this article can be found here: http://www.diagnosticpathology.diagnomx.eu/vs/1849369005957671.
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Coristoma/diagnóstico , Neoplasias do Mediastino/diagnóstico , Cisto Pancreático/diagnóstico , Pseudocisto Pancreático/diagnóstico , Neoplasias do Colo do Útero/diagnóstico , Adulto , Coristoma/cirurgia , Diagnóstico Diferencial , Feminino , Seguimentos , Humanos , Cisto Pancreático/cirurgia , Pseudocisto Pancreático/cirurgia , Tomografia Computadorizada por Raios X , Resultado do TratamentoAssuntos
Broncoscopia/efeitos adversos , Avaliação Geriátrica , Pneumopatias/diagnóstico , Pneumopatias/terapia , Adulto , Fatores Etários , Idoso , Idoso de 80 Anos ou mais , Broncoscopia/métodos , Hemorragia/epidemiologia , Humanos , Hipóxia/epidemiologia , Pessoa de Meia-Idade , Fibras Ópticas , Pneumotórax/epidemiologia , Estudos Retrospectivos , Fatores de RiscoRESUMO
BACKGROUND: The development of left ventricular hypertrophy (LVH) is influenced by gender and by sex hormones including estrogens. This study hypothesized that genetic variation in the TA repeat regulatory region of the estrogen receptor alpha gene (ESR1) is related to left ventricular mass. METHODS: Consecutive patients undergoing coronary angiography with echocardiographic studies were studied. The length of the dinucleotide repeat thymine and adenine (TA) upstream of exon 1 in the ESR1 gene was determined. The mean number of TA repeats (n = 18) categorized the subjects into long, short and mixed allele genotypes. RESULTS: Ninety-two patients (mean age 60.3+/-12.6 years, 63 males, 29 females) were entered into the study. When LV mass indexed to body surface area was examined in the three genotype groups, a significant difference between the groups was noted with lower LV mass in the short allele group (p < 0.03). When the short allele group was compared with subjects with at least one long allele, a highly significant difference in left ventricular mass index was noted (86.9 g/m2 vs 101.3 g/m2, p < 0.009). CONCLUSION. The ESR1 TA repeat polymorphism may influence left ventricular mass. Patients with at least one long allele exhibit a tendency to higher LV mass.
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Regiões 5' não Traduzidas/genética , Alelos , Repetições de Dinucleotídeos/genética , Receptor alfa de Estrogênio/genética , Hipertrofia Ventricular Esquerda/genética , Polimorfismo Genético , Idoso , Feminino , Ventrículos do Coração/patologia , Humanos , Hipertrofia Ventricular Esquerda/patologia , Masculino , Pessoa de Meia-Idade , Tamanho do Órgão/genética , Fatores SexuaisRESUMO
CONTEXT: Sequence variants in the estrogen receptor alpha gene (ESR1) may alter the atheroprotective effects of estrogens, and be associated with the severity of coronary artery disease (CAD). OBJECTIVE: This study seeks to investigate the association between the ESR1 haplotype created by the c.454-397 T>C and c.454-351 A>G polymorphisms, the length of the (TA)n repeats, and the angiographic extent of CAD. DESIGN: Consecutive subjects with age younger than or equal to 55 yr who had undergone coronary angiography between November 2003 and January 2004 were included in the study. SETTING: The study was conducted in a referral center. PATIENTS: One hundred five subjects with age younger than or equal to 55 yr (87 males, 18 females) participated in the study. MAIN OUTCOME MEASURES: The angiographic extent of CAD was graded by number of: 1) major coronary vessels with more than 50% narrowing (NMCV); 2) narrowed major coronary vessels and/or their second-order branch (NCV); and 3) coronary segments with any narrowing (NN). Analysis of covariance was used to test the effect of haplotype and (TA)n length on the angiographic extent of CAD with gender and number of CAD risk factors (hyperlipidemia, diabetes, hypertension, obesity, smoking, and family history of CAD) as covariates. RESULTS: The ESR1 haplotype c.454-397C and c.454-351G was associated with NCV and NN (P = 0.008 and 0.02, respectively). Carriers of two copies of haplotype C-G had a higher number of NCV compared with subjects with one or no copies combined (3.5 +/- 2.2 vs. 2.3 +/- 1.9, P = 0.012, respectively). A longer (TA)n repeat was associated with NCV (P = 0.04). CONCLUSIONS: The ESR1 c.454-397C and c.454-351G haplotype and longer (TA)n repeats are associated with the extent of CAD in young subjects, independent of the known CAD risk factors.
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Angiografia Coronária , Doença da Artéria Coronariana/diagnóstico por imagem , Doença da Artéria Coronariana/genética , Receptor alfa de Estrogênio/genética , Polimorfismo Genético , Adulto , Feminino , Dosagem de Genes , Frequência do Gene , Haplótipos , Heterozigoto , Humanos , Masculino , Pessoa de Meia-IdadeRESUMO
AIMS: To investigate the association between sequence variants in the promoter region of the oestrogen receptor-alpha (ER-alpha) gene and the angiographic severity of coronary artery disease (CAD). METHODS AND RESULTS: We studied 503 subjects undergoing coronary angiography (mean age 63+/-12 years, 72% men, 28% women). Coronary artery disease extent was assessed by the number of: (1) major coronary vessels with >50% narrowing (NMCV); (2) coronary vessels with any narrowing (NCV); (3) narrowed coronary segments (NCS). The number of thymine and adenine dinucleotide repeats [(TA)(n)], 1174 base-pairs upstream exon 1, was determined by PCR. The median number of (TA)(n)(18) was used to categorize subjects into long, short and mixed allele genotypes. Poisson regression was used to analyse the association between genotypes and CAD extent, with age category (age #10877;55 vs >55), sex, risk factors and age at onset of CAD as covariates. In young subjects, (TA)(n)length had a significant effect on NCS (P=0.047) and a borderline significant effect on NCV (P=0.066). Young subjects homozygous for long alleles had higher NCV and NCS compared to those homozygous for short alleles (NCV 3.7+/-2.4 vs 2.4+/-1.8, NCS 4.4+/-2.7 vs 3.1+/-2.3, respectively, P#10877;0.034). CONCLUSION: The (TA)(n)length in the ER-alpha gene promoter region is associated with the angiographic severity of CAD in young patients.