Novel genes for airway wall thickness identified with combined genome-wide association and expression analyses.

RATIONALE: Airway wall thickness (AWT) is affected by both environmental and genetic factors and is strongly associated with airflow limitation in smaller airways. OBJECTIVES: To investigate the genetic component of AWT. METHODS: AWT was measured on low-dose computed tomography scans in male heavy smokers participating in a lung cancer screening study (n = 2,640). Genome-wide association studies on AWT were performed under an additive model using linear regression (adjusted for pack-years, lung volume), followed by metaanalysis. An independent cohort was used for validation of the most strongly associated single-nucleotide polymorphisms (SNPs). The functional relevance of significant SNPs was evaluated. MEASUREMENTS AND MAIN RESULTS: Three significant loci on chromosomes 2q (rs734556; P = 6.2 × 10(-7)) and 10q (rs10794108, P = 8.6 × 10(-8); rs7078439, P = 2.3 × 10(-7)) were associated with AWT and confirmed in the metaanalysis in cohorts with comparable lung function: P values = 4.6 × 10(-8), 7.4 × 10(-8), and 7.5 × 10(-8), respectively. SNP rs734556 was associated with decreased lung tissue expression of SERPINE2, a susceptibility gene for emphysema. Two nominally significant SNPs showed effects with similar direction: rs10251504 in MAGI2 (P = 5.8 × 10(-7)) and rs4796712 in NT5C3B (P = 3.1 × 10(-6)). Higher MAGI2 expression in bronchial biopsies of patients with chronic obstructive pulmonary disease was significantly associated with fewer inflammatory cells. The presence of the NT5C3B risk allele was associated with higher lung tissue expression (P = 1.09 × 10(-41)). CONCLUSIONS: Genetic variants contribute to AWT. Among others, the identified genes are also involved in emphysema, airway obstruction, and bronchial inflammation.

The diagnostic value of physical examination and additional testing in primary care patients with suspected heart failure.

BACKGROUND: Early diagnosis of nonacute heart failure is crucial because prompt initiation of evidence-based treatment can prevent or slow down further progression. To diagnose new-onset heart failure in primary care is challenging. METHODS AND RESULTS: This is a cross-sectional diagnostic accuracy study with external validation. Seven hundred twenty-one consecutive patients suspected of new-onset heart failure underwent standardized diagnostic work-up including chest x-ray, spirometry, ECG, N-terminal pro-B-type natriuretic peptide (NT-proBNP) measurement, and echocardiography in specially equipped outpatient diagnostic heart failure clinics. The presence of heart failure was determined by an outcome panel using the initial clinical data and 6-month follow-up data, blinded to biomarker data. Of the 721 patients, 207 (28.7%) had heart failure. The combination of 3 items from history (age, coronary artery disease, and loop diuretic use) plus 6 from physical examination (pulse rate and regularity, displaced apex beat, rales, heart murmur, and increased jugular vein pressure) showed independent diagnostic value (c-statistic 0.83). NT-proBNP was the most powerful supplementary diagnostic test, increasing the c-statistic to 0.86 and resulting in net reclassification improvement of 69% (P<0.0001). A simplified diagnostic rule was applied to 2 external validation datasets, resulting in c- statistics of 0.95 and 0.88, confirming the results. CONCLUSIONS: In this study, we estimated the quantitative diagnostic contribution of elements of the history and physical examination in the diagnosis of heart failure in primary care outpatients, which may help to improve clinical decision making. The largest additional quantitative diagnostic contribution to those elements was provided by measurement of NT-proBNP. For daily practice, a diagnostic rule was derived that may be useful to quantify the probability of heart failure in patients with new symptoms suggestive of heart failure.

The importance of cardiovascular disease for mortality in patients with COPD: a prognostic cohort study.

BACKGROUND: Cardiovascular diseases are the major cause of mortality in patients with chronic obstructive pulmonary disease (COPD), however, are rarely considered in prediction models in patients with COPD. OBJECTIVE: To quantify the effect of cardiovascular determinants on mortality in patients with a GP's diagnosis of COPD. METHODS: Four hundred and five patients aged ≥65 years with a diagnosis of COPD (244 with COPD by spirometry) were followed up for an average period of 4.2 (SD 1.4) years. Cox proportional hazard regression analyses with bootstrapping techniques were performed to identify independent predictors of all-cause mortality. RESULTS: In multivariable analysis, all-cause mortality was best predicted by age [hazard ratio (HR) 1.05 [95% confidence interval (CI): 1.01-1.10] per year of age], angina pectoris on history taking [HR 2.32 (95% CI: 1.50-3.58)], airflow obstruction [HR 1.02 (95% CI: 1.01-1.03) per percentage decrease in level of forced expiratory volume in one second (FEV(1)) as % predicted] and C-reactive protein [HR 1.04 (95% CI: 1.02-1.05] per milligram per millilitre increase), respectively. The final model had a C statistic of 0.78 (95% CI: 0.72-0.83) after bootstrapping, and the calibration of the model was very good. The model performed similarly in the subgroup of 244 patients with COPD according to the GOLD criteria (post-dilatory FEV(1)/forced vital capacity < 0.70). CONCLUSIONS: Physicians should consider ischaemic heart disease in the clinical evaluation of any patient with a GP's diagnosis of COPD. Angina pectoris on history taking is a strong predictor of all-cause mortality in these patients and should be treated adequately to improve prognosis.

Cardiovascular magnetic resonance imaging to identify left-sided chronic heart failure in stable patients with chronic obstructive pulmonary disease.

BACKGROUND: Although cardiovascular magnetic resonance imaging (CMR) is well established, its diagnostic accuracy in identifying chronic heart failure (CHF) in patients with chronic obstructive pulmonary disease (COPD) has not yet been quantified. METHODS: Participants were recruited from a cohort of 405 patients aged >or=65 years, with mild to moderate and stable COPD. In this population, 83 (20.5%) patients had a new diagnosis of CHF, all left-sided, established by an expert panel using all available diagnostic information, including echocardiography. In a nested case-control study design, 37 consecutive COPD patients with newly detected CHF (cases) and a random sample of 41 of the remaining COPD patients (controls) received additional CMR measurements. The value of CMR in diagnosing heart failure was quantified using univariable and multivariable logistic modeling in combination with area under the receiver operating characteristic curves (ROC-area). RESULTS: Combination of CMR measurements of left ventricular ejection fraction, indexed left and right atrial volume, and left ventricular end-systolic dimensions provided high added diagnostic value beyond clinical items (ROC-area 0.91) for identifying CHF. Left-sided measurements of CMR and echocardiography correlated well, including ejection fraction. Right ventricular mass divided by right ventricular end-diastolic volume was higher in COPD patients with CHF than in those without concomitant CHF. CONCLUSIONS: Easily assessable morphologic and volume-based CMR measurements have excellent capacities to identify previously unknown left-sided chronic heart failure in mild to moderate COPD patients. There seems to be an adaptive tendency to concentric right ventricular hypertrophy in COPD patients with left-sided CHF.

Genetic loci associated with chronic obstructive pulmonary disease overlap with loci for lung function and pulmonary fibrosis.

Chronic obstructive pulmonary disease (COPD) is a leading cause of mortality worldwide. We performed a genetic association study in 15,256 cases and 47,936 controls, with replication of select top results (P < 5 × 10-6) in 9,498 cases and 9,748 controls. In the combined meta-analysis, we identified 22 loci associated at genome-wide significance, including 13 new associations with COPD. Nine of these 13 loci have been associated with lung function in general population samples, while 4 (EEFSEC, DSP, MTCL1, and SFTPD) are new. We noted two loci shared with pulmonary fibrosis (FAM13A and DSP) but that had opposite risk alleles for COPD. None of our loci overlapped with genome-wide associations for asthma, although one locus has been implicated in joint susceptibility to asthma and obesity. We also identified genetic correlation between COPD and asthma. Our findings highlight new loci associated with COPD, demonstrate the importance of specific loci associated with lung function to COPD, and identify potential regions of genetic overlap between COPD and other respiratory diseases.

Embolotherapy of pulmonary arteriovenous malformations: long-term results in 112 patients.

PURPOSE: To evaluate the long-term results of embolotherapy of pulmonary arteriovenous malformations (PAVMs) in a large group of patients. MATERIALS AND METHODS: Between July 1988 and August 2001, 134 consecutive patients underwent embolotherapy of PAVMs with feeding arteries larger than 3 mm or that had previously caused bleeding or systemic complications. The mean follow-up was 62.2 months. The primary endpoints of the study were the efficacy of embolotherapy, decrease in right-to-left shunt, and increase in partial arterial oxygen pressure (PaO(2)); the secondary endpoint was the prevalence of complications. Standard follow-up consisted of yearly history, chest radiography, and arterial blood gas measurement. RESULTS: Follow-up was available in 112 patients. Initially, 296 PAVMs were embolized in these patients. Nineteen patients (17%) underwent a second procedure and four patients underwent a third procedure because of recanalization of originally occluded feeding arteries (25 PAVMs, 8%) or interval enlargement of untreated PAVMs (53 PAVMs). In total, 349 PAVMs were embolized in 157 sessions. The mean diameter of occluded vessels was 4.7 mm. The long-term outcomes of embolotherapy were successful in 83% of patients overall and in 96% of patients in whom all angiographically visible PAVMs were embolized. Recanalization occurred in 12 of 16 patients who underwent repeat treatment because of enlargement of nonembolized PAVMs. Postprocedural pleurisy occurred after 14 of 157 sessions (9%). Periprocedural complications occurred in 12 sessions (8%) and included migration of an embolic device, transient ischemic attack (TIA), angina pectoris, and early cerebral infarction after embolization. Three patients experienced TIA and two patients experienced a cerebral abscess during follow-up after embolotherapy. CONCLUSIONS: Embolotherapy of PAVMs is efficacious and durable in the majority of patients. Patients should remain under regular review because recanalization of PAVMs or enlargement of untreated PAVMs can occur years after treatment.

p53 mutation analysis for definite diagnosis of multiple primary lung carcinoma.

BACKGROUND: The detection of a second tumor in patients with lung carcinoma raises the question whether this lesion is a metastasis or a second primary lung carcinoma. Patients cannot always be categorized satisfactorily according the criteria of multiple lung carcinoma proposed by Martini and Melamed. This may result in an inadequate treatment schedule in individual patients. Because p53 mutations can be used as clonal marker, the authors investigated whether p53 mutation analysis can differentiate between primary lung carcinomas and metastatic disease. METHODS: Sixty-four tumors in 31 patients with synchronous and metachronous lung tumors were investigated by p53 mutation analysis. RESULTS: In 21 patients, the tumors showed different p53 mutations, and therefore a definite diagnosis of multiple primary lung carcinoma was made. One of these patients did not meet the criteria of Martini and Melamed. In two other patients not matching these criteria, identical mutations were demonstrated in both tumors, indicating the presence of metastatic disease. In eight patients, analysis was not conclusive or possible. CONCLUSIONS: p53 mutation analysis can be a useful tool to confirm or rule out multiple primary lung carcinoma, and the results confirm the criteria of Martini and Melamed. However, in patients not meeting these criteria, the diagnosis of multiple lung carcinoma still has to be considered, and metastatic disease has to be ruled out. P53 mutation analysis can be helpful for this purpose.