Citations

Abstract Background: Patients with lung cancer with mutations in EGF receptor (EGFR) tyrosine kinase have improved prognosis when treated with EGFR inhibitors. We hypothesized that EGFR mutations may be related to residential radon or passive tobacco smoke. Methods: This hypothesis was investigated by analyzing EGFR mutations in 70 lung tumors from a population of never and long-term former female smokers from Missouri with detailed exposure assessments. The relationship with passive smoking was also examined in never-smoking female lung cancer cases from the Mayo clinic. Results: Overall, the frequency of EGFR mutation was 41% [95% confidence interval (CI), 32%–49%]. Neither radon nor passive-smoking exposure was consistently associated with EGFR mutations in lung tumors. Conclusions: The results suggest that EGFR mutations are common in female, never-smoking lung cancer cases from the United States, and EGFR mutations are unlikely due to exposure to radon or passive smoking. Cancer Epidemiol Biomarkers Prev; 21(6); 988–92. ©2012 AACR.

Background Conventional cardiac catheterization criteria for the diagnosis of constrictive pericarditis (CP) rely on equalization of intracardiac pressures and have many recognized limitations. Recently, Doppler echocardiographic methods have been used to examine dynamic respiratory changes of increased ventricular interdependence and dissociation of intrathoracic and intracardiac pressures for the diagnosis of CP. These pathophysiological features may be best delineated by cardiac catheterization. Therefore, we studied the accuracy of these dynamic respiratory changes in left ventricular and right ventricular pressure for the diagnosis of CP at cardiac catheterization. Methods and Results High-fidelity manometric catheters and respirometry were used to study 36 patients: 15 patients with surgically proven CP (group 1) and 21 patients with other causes of heart failure (group 2). Conventional cardiac catheterization variables used to establish the diagnosis of CP lacked sensitivity and specificity and failed to distinguish between these groups. However, the finding of discordance between right ventricular and left ventricular pressures during inspiration, a sign of increased ventricular interdependence, accurately distinguished patients in group 1 from those in group 2 ( P <.05). Conclusions Examination of dynamic respiratory changes indicating increased ventricular interdependence may be helpful in the diagnosis of CP in the cardiac catheterization laboratory.

Background Hypertrophic cardiomyopathy is a disease entity characterized by marked heterogeneity in morphology and natural history. Most of our knowledge of the natural history of this disorder derives from the study of hospital-based populations and is influenced by referral bias. Therefore, this population-based study was undertaken to examine the natural history of hypertrophic cardiomyopathy among unselected residents of Olmsted County, Minnesota. Methods and Results Patients with hypertrophic cardiomyopathy, confirmed by echocardiography, were identified by use of the resources of the Rochester Epidemiology Project. Patients with the echocardiographic features of hypertrophic cardiomyopathy but with long-standing hypertension requiring drug therapy were categorized as having hypertensive hypertrophic cardiomyopathy. Baseline clinical details and follow-up events were obtained by retrospective chart review. Thirty-seven patients were diagnosed with hypertrophic cardiomyopathy and 24 with hypertensive hypertrophic cardiomyopathy. Eight additional patients were first diagnosed at autopsy. The mean age of the 37 patients with hypertrophic cardiomyopathy was 59±20 years (range, 1 week to 92 years); the mean ventricular septal thickness was 17.5±3 mm. Follow-up was obtained for a median of 7.7 years (range, 45 days to 17.2 years). The 1- and 5-year survival rates were 95% and 92%, respectively; these rates did not differ from those of an age- and sex-matched population ( P =NS). The annual risk of cardiac death was 0.7%. The mean age of patients with hypertensive hypertrophic cardiomyopathy was 79±8 years (range, 62 to 91 years), and the mean ventricular septal thickness was 19±2.5 mm. Follow-up was obtained for a median of 2.8 years (range, 4 days to 16.7 years). The 1- and 5-year survival rates were 75% and 43%, respectively, which differed sharply from the expected rates of 94% and 70% ( P =.0028). The annual risk of cardiac death was 5%. Atrial fibrillation and evidence for myocardial infarction on ECG, use of digoxin and diuretics, and a high New York Heart Association functional class at presentation were all associated with decreased survival by multivariate analysis for both groups combined. A history of myocardial infarction, atrial fibrillation, and mitral annular calcification at presentation were associated with cardiac death. Conclusions Hypertrophic cardiomyopathy is a more benign disease than previously reported from tertiary referral centers. Patients assessed as having hypertensive hypertrophic cardiomyopathy represent a subset at higher risk for cardiac and noncardiac death, with an overall decreased survival rate.

Background Coronary calcium identified by electron-beam computed tomography (EBCT) correlates poorly with luminal atherosclerotic narrowing, but calcium, an intimate part of coronary plaque, may be more directly related to atheromatous plaque area. Methods and Results Thirty-eight coronary arteries from 13 autopsy hearts were dissected, straightened, and scanned with EBCT in 3-mm contiguous increments. Coronary calcium area was defined as one or more pixels with a density >130 Hounsfield units (0.18 mm 2 /pixel). Each artery was divided into corresponding 3-mm segments, representative histological sections were stained, and atherosclerotic plaque area per segment (mm 2 ) was quantified. Coronary artery calcium and coronary artery plaque areas were correlated for the hearts as a whole, for individual coronary arteries, and for individual coronary artery segments. The sums of histological plaque areas versus the sums of calcium areas were highly correlated for each heart and for each coronary artery. However, coronary plaque area was on the order of five times greater than calcium area. Furthermore, minimal diffuse segmental coronary plaque could be present despite the absence of coronary calcium detectable by EBCT. Conclusions This histopathologic study confirms an intimate relation between whole heart, coronary artery, and segmental coronary atherosclerotic plaque area and EBCT coronary calcium area but suggests that there is a threshold value for plaque area below which coronary calcium is either absent or not detectable by this methodology.

Background Observational and randomized studies designed to compare surgical and medical therapies in patients with left main coronary artery disease (LMCD) have shown that coronary artery bypass graft (CABG) surgery prolongs life in most patients with LMCD. The present report of 1484 patients with LMCD in the Coronary Artery Surgery Study (CASS) Registry extends the originally published 5-year surgical and medical group survival analysis to more than 16 years of follow-up and permits analysis of LMCD patient subgroups. Methods and Results The CASS Registry contains 1484 patients with ≥50% left main coronary artery stenosis initially treated with either surgical or nonsurgical therapy. The 15-year cumulative survival estimates were 37% for the 1153 patients in the surgical group compared with 27% for the 331 patients in the medical group. Median survival in the surgical group was 13.3 years (12.8 to 13.8 years, 95% confidence limits) compared with only 6.6 years (5.4 to 7.9 years) in the medical group (difference, 6.7 years; P <.0001). Median survival was also significantly longer in the surgical group stratified by age, sex, anginal class, left ventricular (LV) function, coronary anatomy, and the extent of LMCD. However, CABG surgery did not significantly prolong median survival in patient subgroups with (1) left main coronary stenosis of 50% to 59%; (2) normal LV systolic function; (3) normal or mildly abnormal LV systolic function and a right coronary artery stenosis ≥70%; and (4) a nonstenotic (≤70%) right coronary artery. The 15-year cumulative survival for patients with normal LV systolic function in the surgical and medical groups was 42% and 51%, respectively. Median survival was 14.7 years in the surgical group and >15 years in the medical group ( P =NS). In patients with normal LV systolic function and a right coronary artery stenosis ≥70%, the 15-year cumulative survival rates were also similar in the surgical and medical groups (40% and 48%, respectively). Median survival was 14.3 years in the surgical group and 14.2 years in the medical group ( P =NS). The 15-year cumulative survival estimates for all subgroups were affected by convergence of the surgical and medical survival group curves owing to a disproportionate increase in the late surgical group mortality. Overall, 25% of patients in the medical group ultimately underwent CABG surgery. If all medical group patients had survived long enough, about 47% would be estimated to have had surgery by 15 years. Conclusions This report, which extends follow-up of more than 16 years in CASS Registry patients with LMCD, shows that CABG surgery prolongs life in most clinical and angiographic subgroups. However, median survival was not prolonged by CABG surgery in patients with normal LV systolic function, even if a significant right coronary artery stenosis (≥70%) also was present. These results extend our understanding of the natural history of LMCD and permit a more accurate estimate of long-term surgical and medical group survival.

BACKGROUND Although recent investigations report the elevation of plasma endothelin (ET) in congestive heart failure (CHF), it remains unclear if this elevation is that of the biologically active peptide ET-1 or of its precursor big-ET. Furthermore, it is unclear if such elevation is associated with increased myocardial ET and if the molecular form from cardiac tissue is altered ET. Last, it remains to be established whether circulating ET is increased at the earliest stage of CHF in patients with asymptomatic left ventricular dysfunction and correlates with the magnitude of ventricular dysfunction. METHODS AND RESULTS The present study was designed to investigate concentrations and molecular forms of ET in plasma and cardiac tissue in healthy subjects and CHF patients with New York Heart Association (NYHA) class I through IV using cardiac radionuclide angiogram, cardiac myocardial biopsy, radioimmunoassay, gel permeation chromatography (GPC), and immunohistochemical staining (IHCS). Plasma ET was increased only in patients with moderate (NYHA class III) or severe (NYHA class IV) CHF compared with healthy subjects and individuals with asymptomatic (NYHA class I) or mild (NYHA class II) CHF. The elevation of circulating ET in CHF showed a negative correlation with left ventricular ejection fraction and cardiac index and a positive correlation with functional class and left ventricular end-diastolic volume index. GPC demonstrated that immunoreactive plasma ET was ET-1 in healthy subjects and both mature ET-1 and its precursor big-ET in severe CHF patients, with big-ET the predominant molecular form. Cardiac tissue concentrations and IHCS revealed ET presence in healthy atrial and ventricular tissue, which were not different in severe CHF. GPC revealed that the molecular form of cardiac ET was ET-1 in both healthy and CHF hearts. CONCLUSIONS The present study establishes for the first time that the elevation of plasma ET in severe human CHF represents principally elevation of big-ET. Second, ET is present in healthy and failing myocardia, and its activity by both immunohistochemistry and radioimmunoassay is not changed in CHF. Furthermore, the elevated plasma ET is characteristic of severe CHF and not asymptomatic or mild CHF. In addition, the degree of plasma elevation of ET correlates with the magnitude of alterations in cardiac hemodynamics and functional class. The present study confirms and extends previous investigations of ET in human CHF and establishes the evolution of circulating and local cardiac ET in the spectrum of human CHF.

Abstract —Effects of sleep deprivation on neural cardiovascular control may have important clinical implications. We tested the hypothesis that sleep deprivation increases heart rate, blood pressure, and sympathetic activity and potentiates their responses to stressful stimuli. We studied 8 healthy subjects (aged 40±5 years, 6 men and 2 women). Blood pressure, heart rate, forearm vascular resistance, and muscle sympathetic nerve activity were measured at rest and during 4 stressors (sustained handgrip, maximal forearm ischemia, mental stress, and cold pressor test). Measurements were obtained twice, once after normal sleep and once after a night of sleep deprivation. All measurements were obtained in a blinded, randomized manner. In comparison with normal sleep, sleep deprivation resulted in an increase in blood pressure (normal sleep versus sleep deprivation=82±8 versus 86±7 mm Hg, mean±SEM, P =0.012) and a decrease in muscle sympathetic nerve activity (normal sleep versus sleep deprivation=28±6 versus 22±6 bursts/min, P =0.017). Heart rate, forearm vascular resistance, and plasma catecholamines were not significantly changed by sleep deprivation, nor did sleep deprivation affect autonomic and hemodynamic responses to stressful stimuli. Sleep deprivation results in increased resting blood pressure, decreased muscle sympathetic nerve activity, and no change in heart rate. Thus, the pressor response to sleep deprivation is not mediated by muscle sympathetic vasoconstriction or tachycardia.