This study sought to analyze patients with tricuspid regurgitation (TR) diagnosed in the community setting (Olmsted County) by Doppler echocardiography to define the prevalence, characteristics, and ...implications of clinically significant (greater or equal to moderate) TR.
The prevalence, cause distribution, and significance of TR are mostly unknown.
All adult residents of Olmsted County, Minnesota, who underwent clinically indicated Doppler echocardiography between 1990 and 2000 were evaluated for presence of greater or equal to moderate TR. The characteristics and outcome of TR carriers was then analyzed.
During the study period, 417 community residents were diagnosed with greater or equal to moderate TR corresponding to an U.S. age- and sex-adjusted prevalence of 0.55% with 95% confidence interval (0.50 to 0.60). TR adjusted prevalence was higher in women (p < 0.01) and strongly linked to age (p < 0.0001). Isolated TR (without significant comorbidities, structural left valve disease, pulmonary hypertension, or overt cardiac cause) represented 8.1% of patients with greater or equal to moderate TR. Isolated TR adjusted for age, sex, ejection fraction, atrial fibrillation, and Charlson comorbidity index independently predicted higher mortality (adjusted risk ratio: 1.68; 95% confidence interval: 1.04 to 2.60; p = 0.03) for qualitative definition. Mortality in patients with greater or equal to moderate isolated TR was higher than in the matched cases with trivial TR (p = 0.0014; matching for age, sex, atrial fibrillation, ejection fraction, comorbidity index). Only 2.6% of patients ever had tricuspid valve surgery during follow-up.
Clinically significant (greater or equal to moderate) TR is common in community residents diagnosed by Doppler echocardiography and increases with age. Isolated TR is associated with excess mortality, thus TR represents an important public health problem.
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Abstract Objectives The aim of this study was to assess the outcome of isolated tricuspid regurgitation (TR) and the added value of quantitative evaluation of its severity. Background TR is of ...uncertain clinical outcome due to confounding comorbidities. Isolated TR (without significant comorbidities, structural valve disease, significant pulmonary artery systolic pressure elevation by Doppler, or overt cardiac cause) is of unknown clinical outcome. Methods In patients with isolated TR assessed both qualitatively and quantitatively by a proximal isovelocity surface area method, a long-term outcome analysis was conducted. Patients with severe comorbid diseases were excluded. Results The study involved 353 patients with isolated TR (age 70 years; 33% male; ejection fraction, 63%; all with right ventricular systolic pressure <50 mm Hg). Severe isolated TR was diagnosed in 76 patients (21.5%) qualitatively and 68 patients (19.3%) by quantitative criteria (effective regurgitant orifice ERO ≥40 mm2 ). The 10-year survival and cardiac event rates were 63 ± 5% and 29 ± 5%. Severe isolated TR independently predicted higher mortality (adjusted hazard ratio: 1.78 95% confidence interval (CI): 1.10 to 2.82, p = 0.02 for qualitative definition and 2.67 95% CI: 1.66 to 4.23 for an ERO ≥40 mm2 , p < 0.0001). The addition of grading by quantitative criteria in nested models eliminated the significance of the qualitative grading and improved the model prediction (p < 0.001 for survival and p = 0.02 for cardiac events). The 10-year survival rate was lower with an ERO ≥40 mm2 versus <40 mm2 (38 ± 7% vs. 70 ± 6%; p < 0.0001), independent of all characteristics, right ventricular size or function, comorbidity, or pulmonary pressure (p < 0.0001 for all), and lower than expected in the general population (p < 0.001). Freedom from cardiac events was lower with an ERO ≥40 mm2 versus <40 mm2 independently of all characteristics, right ventricular size or function, comorbidity, or pulmonary pressure (p < 0.0001 for all). Cardiac surgery for severe isolated TR was rarely performed (16 ± 5% 5 years after diagnosis). Conclusions Isolated TR can be severe and is associated with excess mortality and morbidity, warranting heightened attention to diagnosis and quantitation. Quantitative assessment of TR, particularly ERO measurement, is a powerful independent predictor of outcome, superior to standard qualitative assessment.
CONTEXT Heart failure incidence increases with advancing age, and approximately half of patients with heart failure have preserved left ventricular ejection fraction. Although diastolic dysfunction ...plays a role in heart failure with preserved ejection fraction, little is known about age-dependent longitudinal changes in diastolic function in community populations. OBJECTIVE To measure changes in diastolic function over time and to determine the relationship between diastolic dysfunction and the risk of subsequent heart failure. DESIGN, SETTING, AND PARTICIPANTS Population-based cohort of participants enrolled in the Olmsted County Heart Function Study. Randomly selected participants 45 years or older (N = 2042) underwent clinical evaluation, medical record abstraction, and echocardiography (examination 1 1997-2000). Diastolic left ventricular function was graded as normal, mild, moderate, or severe by validated Doppler techniques. After 4 years, participants were invited to return for examination 2 (2001-2004). The cohort of participants returning for examination 2 (n = 1402 of 1960 surviving 72%) then underwent follow-up for ascertainment of new-onset heart failure (2004-2010). MAIN OUTCOME MEASURES Change in diastolic function grade and incident heart failure. RESULTS During the 4 (SD, 0.3) years between examinations 1 and 2, diastolic dysfunction prevalence increased from 23.8% (95% confidence interval CI, 21.2%-26.4%) to 39.2% (95% CI, 36.3%-42.2%) (P < .001). Diastolic function grade worsened in 23.4% (95% CI, 20.9%-26.0%) of participants, was unchanged in 67.8% (95% CI, 64.8%-70.6%), and improved in 8.8% (95% CI, 7.1%-10.5%). Worsened diastolic dysfunction was associated with age 65 years or older (odds ratio, 2.85 95% CI, 1.77-4.72). During 6.3 (SD, 2.3) years of additional follow-up, heart failure occurred in 2.6% (95% CI, 1.4%-3.8%), 7.8% (95% CI, 5.8%-13.0%), and 12.2% (95% CI, 8.5%-18.4%) of persons whose diastolic function normalized or remained normal, remained or progressed to mild dysfunction, or remained or progressed to moderate or severe dysfunction, respectively (P < .001). Diastolic dysfunction was associated with incident heart failure after adjustment for age, hypertension, diabetes, and coronary artery disease (hazard ratio, 1.81 95% CI, 1.01-3.48). CONCLUSIONS In a population-based cohort undergoing 4 years of follow-up, prevalence of diastolic dysfunction increased. Diastolic dysfunction was associated with development of heart failure during 6 years of subsequent follow-up.
Neutrophils are the most abundant type of white blood cell, and are an essential component of the innate immune system. They characteristically arrive rapidly at sites of infection and injury, and ...release a variety of cytokines and toxic molecules to eliminate pathogens and elicit an acute inflammatory response. Research into the function of neutrophils in cancer suggest they have divergent roles. Indeed, while most studies have found neutrophils to be associated with cancer progression, others have also documented anticancer effects. In this review, we describe the investigations into neutrophil populations that have been implicated in promoting tumor growth and metastasis as well those demonstrating antitumor functions. The collective research suggests a complex role for neutrophils in cancer biology, which raises the prospect of their targeting for the treatment of cancer.
Objectives This study was conducted to define the association between serum B-type natriuretic peptide (BNP) activation and survival after the diagnosis of aortic stenosis (AS). Background In AS, the ...link between BNP levels and clinical outcome is in dispute. Failure to account for the normal shifting of BNP ranges with aging in men and women, not using hard endpoints (survival), and not enrolling large series of patients have contributed to the uncertainty. Methods A program of prospective measurement of BNP levels with Doppler echocardiographic AS assessment during the same episode of care was conducted. BNP ratio (measured BNP/maximal normal BNP value specific to age and sex) >1 defined BNP clinical activation. Results In 1,953 consecutive patients with at least moderate AS (aortic valve area 1.03 ± 0.26 cm2 ; mean gradient 36 ± 19 mm Hg), median BNP level was 252 pg/ml (interquartile range: 98 to 592 pg/ml); BNP ratio 2.46 (interquartile range 1.03 to 5.66); ejection fraction (EF) 57% ± 15%, and symptoms present in 60% of patients. After adjustment for all survival determinants, BNP clinical activation (BNP ratio >1) independently predicted mortality after diagnosis (p < 0.0001; hazard ratio HR: 1.91; 95% CI: 1.55 to 2.35) and provided incremental power to the survival predictive model (p < 0.0001). Eight-year survival was 62 ± 3% with normal BNP levels, 44 ± 3% with BNP ratio of 1 to 2 (adjusted HR: 1.49; 95% CI: 1.17 to 1.90), 25 ± 4% with BNP ratio of 2 to 3 (adjusted HR: 2.12; 95% CI: 1.63 to 2.75), and 15 ± 2% with BNP ratio of ≥3 (adjusted HR: 2.43; 95% CI: 1.94 to 3.05). This strong link to survival was confirmed in asymptomatic patients with normal EF (adjusted HR: 2.35 95% CI: 1.57 to 3.56 for BNP clinical activation and 2.10 95% CI: 1.32 to 3.36 for BNP ratio of 1 to 2, 2.25 95% CI: 1.31 to 3.87 for BNP ratio of 2 to 3, 3.93 95% CI: 2.40 to 6.43 for BNP ratio of ≥3). Aortic valve replacement was associated with survival improved by a similarly high margin (p = 0.54) with BNP ratio of <2 (HR: 0.68; 95% CI: 0.52 to 0.89; p = 0.003) or BNP ratio of >2 (HR: 0.56; 95% CI: 0.47 to 0.66; p < 0.0001). Conclusions In this large series of patients with AS, BNP clinical activation was associated with excess long-term mortality incrementally and independently of all baseline characteristics. Higher mortality with higher BNP clinical activation, even in asymptomatic patients, emphasizes the importance of appropriate clinical interpretation of BNP levels in managing patients with AS.
Early detection improves hepatocellular carcinoma (HCC) outcomes, but better noninvasive surveillance tools are needed. We aimed to identify and validate methylated DNA markers (MDMs) for HCC ...detection. Reduced representation bisulfite sequencing was performed on DNA extracted from 18 HCC and 35 control tissues. Candidate MDMs were confirmed by quantitative methylation‐specific PCR in DNA from independent tissues (74 HCC, 29 controls). A phase I plasma pilot incorporated quantitative allele‐specific real‐time target and signal amplification assays on independent plasma‐extracted DNA from 21 HCC cases and 30 controls with cirrhosis. A phase II plasma study was then performed in 95 HCC cases, 51 controls with cirrhosis, and 98 healthy controls using target enrichment long‐probe quantitative amplified signal (TELQAS) assays. Recursive partitioning identified best MDM combinations. The entire MDM panel was statistically cross‐validated by randomly splitting the data 2:1 for training and testing. Random forest (rForest) regression models performed on the training set predicted disease status in the testing set; median areas under the receiver operating characteristics curve (AUCs; and 95% confidence interval CI) were reported after 500 iterations. In phase II, a six‐marker MDM panel (homeobox A1 HOXA1, empty spiracles homeobox 1 EMX1, AK055957, endothelin‐converting enzyme 1 ECE1, phosphofructokinase PFKP, and C‐type lectin domain containing 11A CLEC11A) normalized by beta‐1,3‐galactosyltransferase 6 (B3GALT6) level yielded a best‐fit AUC of 0.96 (95% CI, 0.93‐0.99) with HCC sensitivity of 95% (88%‐98%) at specificity of 92% (86%‐96%). The panel detected 3 of 4 (75%) stage 0, 39 of 42 (93%) stage A, 13 of 14 (93%) stage B, 28 of 28 (100%) stage C, and 7 of 7 (100%) stage D HCCs. The AUC value for alpha‐fetoprotein (AFP) was 0.80 (0.74‐0.87) compared to 0.94 (0.9‐0.97) for the cross‐validated MDM panel (P < 0.0001). Conclusion: MDMs identified in this study proved to accurately detect HCC by plasma testing. Further optimization and clinical testing of this promising approach are indicated.
Objectives The purpose of this paper was to assess the link between left atrial (LA) volume at diagnosis and outcome of patients with mitral regurgitation (MR). Background Left atrial enlargement is ...a consequence of organic MR, but its association with clinical outcome independently of MR severity is uncertain. Methods We prospectively enrolled 492 patients (age 63 ± 15 years, 60% men) in sinus rhythm with organic MR (regurgitant volume 68 ± 42 ml/beat) and performed at baseline triple echocardiographic quantitation (MR severity, LA volume, and left ventricular characteristics). Outcome with medical and surgical management was analyzed. Results Left atrial volume indexed to body surface area (LA index) was 55 ± 26 ml/m2 (<40 ml/m2 in 158 patients, 40 to 59 ml/m2 in 160 patients, and ≥60 ml/m2 in 174 patients). Under medical management, 5-year survival was 80 ± 2.9% and cardiac events 28 ± 3%. Adjusting for established predictors of outcome, LA index was independently associated with survival after diagnosis (hazard ratio HR: 1.3 95% confidence interval (CI): 1.1 to 1.5 per 10 ml/m2 increment, p = 0.001). Patients with LA index ≥60 ml/m2 had lower 5-year survival than those with no or mild LA enlargement (p < 0.0001) and than the rates of survival expected in the U.S. population (53 ± 8.6% vs. 76%, p = 0.017). Compared with patients with LA index <40 ml/m2 , those with LA index ≥60 ml/m2 had increased mortality (HR: 2.8 95% CI: 1.2 to 6.5, p = 0.016) and cardiac events (HR: 5.2 95% CI: 2.6 to 10.9, p < 0.0001) with medical management. Mitral surgery was associated with decreased mortality (HR: 0.46 95% CI: 0.26 to 0.84, p = 0.01) and cardiac events (HR: 0.38 95% CI: 0.23 to 0.62, p = 0.0001) and after surgery patients with LA index ≥60 ml/m2 versus <60 ml/m2 did not incur excess mortality or cardiac events (both p > 0.30). Conclusions In organic MR, LA index at diagnosis predicts long-term outcome, incrementally to known predictors of outcome. This marker of risk is particularly important because mitral surgery in these patients markedly improves outcome and restores life expectancy. LA index should be measured in routine clinical practice for risk-stratification and for clinical decision making in patients with organic MR.
This study was conducted to define the association between serum B-type natriuretic peptide (BNP) activation and survival after the diagnosis of aortic stenosis (AS).
In AS, the link between BNP ...levels and clinical outcome is in dispute. Failure to account for the normal shifting of BNP ranges with aging in men and women, not using hard endpoints (survival), and not enrolling large series of patients have contributed to the uncertainty.
A program of prospective measurement of BNP levels with Doppler echocardiographic AS assessment during the same episode of care was conducted. BNP ratio (measured BNP/maximal normal BNP value specific to age and sex) >1 defined BNP clinical activation.
In 1,953 consecutive patients with at least moderate AS (aortic valve area 1.03 ± 0.26 cm(2); mean gradient 36 ± 19 mm Hg), median BNP level was 252 pg/ml (interquartile range: 98 to 592 pg/ml); BNP ratio 2.46 (interquartile range 1.03 to 5.66); ejection fraction (EF) 57% ± 15%, and symptoms present in 60% of patients. After adjustment for all survival determinants, BNP clinical activation (BNP ratio >1) independently predicted mortality after diagnosis (p < 0.0001; hazard ratio HR: 1.91; 95% CI: 1.55 to 2.35) and provided incremental power to the survival predictive model (p < 0.0001). Eight-year survival was 62 ± 3% with normal BNP levels, 44 ± 3% with BNP ratio of 1 to 2 (adjusted HR: 1.49; 95% CI: 1.17 to 1.90), 25 ± 4% with BNP ratio of 2 to 3 (adjusted HR: 2.12; 95% CI: 1.63 to 2.75), and 15 ± 2% with BNP ratio of ≥3 (adjusted HR: 2.43; 95% CI: 1.94 to 3.05). This strong link to survival was confirmed in asymptomatic patients with normal EF (adjusted HR: 2.35 95% CI: 1.57 to 3.56 for BNP clinical activation and 2.10 95% CI: 1.32 to 3.36 for BNP ratio of 1 to 2, 2.25 95% CI: 1.31 to 3.87 for BNP ratio of 2 to 3, 3.93 95% CI: 2.40 to 6.43 for BNP ratio of ≥3). Aortic valve replacement was associated with survival improved by a similarly high margin (p = 0.54) with BNP ratio of <2 (HR: 0.68; 95% CI: 0.52 to 0.89; p = 0.003) or BNP ratio of >2 (HR: 0.56; 95% CI: 0.47 to 0.66; p < 0.0001).
In this large series of patients with AS, BNP clinical activation was associated with excess long-term mortality incrementally and independently of all baseline characteristics. Higher mortality with higher BNP clinical activation, even in asymptomatic patients, emphasizes the importance of appropriate clinical interpretation of BNP levels in managing patients with AS.
Discriminant markers for pancreatic cancer detection are needed. We sought to identify and validate methylated DNA markers for pancreatic cancer using next-generation sequencing unbiased by known ...targets.
At a referral center, we conducted four sequential case-control studies: discovery, technical validation, biologic validation, and clinical piloting. Candidate markers were identified using variance-inflated logistic regression on reduced-representation bisulfite DNA sequencing results from matched pancreatic cancers, benign pancreas, and normal colon tissues. Markers were validated technically on replicate discovery study DNA and biologically on independent, matched, blinded tissues by methylation-specific PCR. Clinical testing of six methylation candidates and mutant KRAS was performed on secretin-stimulated pancreatic juice samples from 61 patients with pancreatic cancer, 22 with chronic pancreatitis, and 19 with normal pancreas on endoscopic ultrasound. Areas under receiver-operating characteristics curves (AUC) for markers were calculated.
Sequencing identified >500 differentially hyper-methylated regions. On independent tissues, AUC on 19 selected markers ranged between 0.73 and 0.97. Pancreatic juice AUC values for CD1D, KCNK12, CLEC11A, NDRG4, IKZF1, PKRCB, and KRAS were 0.92*, 0.88, 0.85, 0.85, 0.84, 0.83, and 0.75, respectively, for pancreatic cancer compared with normal pancreas and 0.92*, 0.73, 0.76, 0.85*, 0.73, 0.77, and 0.62 for pancreatic cancer compared with chronic pancreatitis (*, P = 0.001 vs. KRAS).
We identified and validated novel DNA methylation markers strongly associated with pancreatic cancer. On pilot testing in pancreatic juice, best markers (especially CD1D) highly discriminated pancreatic cases from controls.
Mass Spectrometry utilizing labeling allows multiple specimens to be subjected to mass spectrometry simultaneously. As a result, between-experiment variability is reduced. Here we describe use of ...fundamental concepts of statistical experimental design in the labeling framework in order to minimize variability and avoid biases. We demonstrate how to export data in the format that is most efficient for statistical analysis. We demonstrate how to assess the need for normalization, perform normalization, and check whether it worked. We describe how to build a model explaining the observed values and test for differential protein abundance along with descriptive statistics and measures of reliability of the findings. Concepts are illustrated through the use of three case studies utilizing the iTRAQ 4-plex labeling protocol.
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