Contribution of Ventricular Diastolic Dysfunction to Pulmonary Hypertension Complicating Chronic Systolic Heart Failure

ObjectivesThe aim of the study is to clarify the clinical role of Doppler-echocardiographic parameters of left ventricular diastolic dysfunction (LVDD) as determinants of pulmonary hypertension in patients experiencing left ventricular systolic dysfunction (LVSD) with and without the presence of functional mitral valve regurgitation (FMR).BackgroundPulmonary hypertension (pulmonary venous or mixed pulmonary venous-arterial hypertension) complicating LVSD is associated with poor outcomes beyond that of LVSD alone. The view of the contribution of LVDD as a determinant of pulmonary hypertension is controversial and not well defined as a tool in clinical practice.MethodsData from patients with LVEF ≤40% undergoing Doppler-echocardiography evaluations during the period from August 2001 to December 2004 were analyzed. Pulmonary systolic pressure (PSP), parameters of diastolic function (mitral valve [MV] transmitral flow velocity [E]/mitral annular diastolic velocity [e′] ratio, MV deceleration time [DT]), quantitated effective regurgitant orifice area (EROA) of FMR, and clinical characteristics were evaluated. Pulmonary hypertension was defined as an estimated PSP ≥45 mm Hg.ResultsCriteria were met in 1,541 patients; one-third (n = 533) demonstrating PSP ≥45 mm Hg (58 ± 10 mm Hg, range 45 to 102 mm Hg). Patients with pulmonary hypertension were older with higher E/e′ ratio, EROA, and lower DT and LVEF. In multivariate analysis, pulmonary hypertension was independently predicted not only by severity of FMR (EROA ≥20 mm2, odds ratio: 3.8, p < 0.001) but also by parameters of LVDD (E/e′ ratio ≥15, odds ratio: 3.31, p < 0.001; DT ≤150 ms, odds ratio: 3.8, p < 0.001). Receiver-operating characteristics curve analysis showed that EROA, E/e′ ratio, and DT provided significant incremental value in predicting pulmonary hypertension (c-statistic 0.830, p < 0.001).ConclusionsPatients with LVSD commonly have secondary pulmonary hypertension, which is largely determined by the severity of LVDD even with adjustment for FMR and low LVEF. Thus, measures of LVDD in routine clinical practice where PSP may not be estimated are important physiologic descriptors of hemodynamic status and are cumulatively linked in the prediction of pulmonary hypertension

B-type natriuretic peptide clinical activation in aortic stenosis : impact on long-term survival

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 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

Diastolic dysfunction and left atrial volume A population-based study

ObjectivesWe examined the association between diastolic function and left atrial volume indexed to body surface area (LAVi) in a population-based study.BackgroundAtrial enlargement has been suggested as a marker of the severity and duration of diastolic dysfunction (DD). However, the association between DD and atrial enlargement and their individual prognostic implications in the population is poorly defined.MethodsA cross-sectional sample of Olmsted County, Minnesota, residents ≥45 years of age (n = 2,042) underwent comprehensive Doppler echocardiography and medical record review.ResultsThe LAVi increased with worsening DD: 23 ± 6 ml/m2(normal), 25 ± 8 ml/m2(grade I DD), 31 ± 8 ml/m2(grade II DD), 48 ± 12 ml/m2(grades III to IV DD). In bivariate analyses, age, left ventricular mass index, and DD grade were positively associated, whereas female gender and ejection fraction (EF) were inversely associated with LAVi (p < 0.001 for all). When controlling for age, gender, cardiovascular (CV) disease, EF, and left ventricular mass, grade II DD was associated with a 24%, and grade III to IV DD was associated with a 62% larger LA volume (p < 0.0001 for both). The area under the receiver-operator characteristic curve for LAVi to detect grade I, grade II, or grade III to IV DD was 0.57, 0.81, and 0.98, respectively. Both DD and LAVi were predictive of all-cause mortality, but when controlling for DD, LAVi was not an independent predictor of mortality.ConclusionsThese data suggest that DD contributes to LA remodeling. Indeed, DD is a stronger predictor of mortality; presumably it better reflects the impact of CV disease within the general population

Quality assessment metrics for whole genome gene expression profiling of paraffin embedded samples

BACKGROUND: Formalin fixed, paraffin embedded tissues are most commonly used for routine pathology analysis and for long term tissue preservation in the clinical setting. Many institutions have large archives of Formalin fixed, paraffin embedded tissues that provide a unique opportunity for understanding genomic signatures of disease. However, genome-wide expression profiling of Formalin fixed, paraffin embedded samples have been challenging due to RNA degradation. Because of the significant heterogeneity in tissue quality, normalization and analysis of these data presents particular challenges. The distribution of intensity values from archival tissues are inherently noisy and skewed due to differential sample degradation raising two primary concerns; whether a highly skewed array will unduly influence initial normalization of the data and whether outlier arrays can be reliably identified. FINDINGS: Two simple extensions of common regression diagnostic measures are introduced that measure the stress an array undergoes during normalization and how much a given array deviates from the remaining arrays post-normalization. These metrics are applied to a study involving 1618 formalin-fixed, paraffin-embedded HER2-positive breast cancer samples from the N9831 adjuvant trial processed with Illumina’s cDNA-mediated Annealing Selection extension and Ligation assay. CONCLUSION: Proper assessment of array quality within a research study is crucial for controlling unwanted variability in the data. The metrics proposed in this paper have direct biological interpretations and can be used to identify arrays that should either be removed from analysis all together or down-weighted to reduce their influence in downstream analyses

Sex differences and survival in adults with bicuspid aortic valves : verification in 3 contemporary echocardiographic cohorts

Background-—Sex-related differences in morbidity and survival in bicuspid aortic valve (BAV) adults are fundamentally unknown. Contemporary studies portend excellent survival for BAV patients identified at early echocardiographic-clinical stages. Whether BAV adults incur a survival disadvantage throughout subsequent echocardiographic-clinical stages remains undetermined. Methods and Results-—Analysis was done of 3 different cohorts of consecutive patients with echocardiographic diagnosis of BAV identified retrospectively: (1) a community cohort of 416 patients with first BAV diagnosis (age 35 21 years, follow-up 16 7 years), (2) a tertiary clinical referral cohort of 2824 BAV adults (age 51 16 years, follow-up 9 6 years), and (3) a surgical referral cohort of 2242 BAV adults referred for aortic valve replacement (AVR) (age 62 14 years, follow-up 6 5 years). For the community cohort, 20-year risks of aortic regurgitation (AR), AVR, and infective endocarditis were higher in men (all P=0.04); for a total BAV-related morbidity risk of 52 4% vs 35 6% in women (P=0.01). The cohort’s 25-year survival was identical to that in the general population (P=0.98). AR independently predicted mortality in women (P=0.001). Baseline AR was more common in men (P=0.02) in the tertiary cohort, with 20-year survival lower than that in the general population (P<0.0001); age-adjusted relative death risk was 1.16 (95% confidence interval [CI] 1.05-1.29) for men versus 1.67 (95% CI 1.38-2.03) for women (P=0.001). AR independently predicted mortality in women (P=0.01). Baseline AR and infective endocarditis were higher in men (both =0.001) for the surgical referral cohort, with 15-year survival lower than that in the general population (P<0.0001); age-adjusted relative death risk was 1.34 (95% CI 1.22-1.47) for men versus 1.63 (95% CI 1.40-1.89) for women (P=0.026). AR and NYHA class independently predicted mortality in women (both P=0.04). Conclusions-—Within evolving echocardiographic-clinical stages, the long-term survival of adults with BAV is not benign, as both men and women incur excess mortality. Although BAV-related morbidity is higher in men in the community, and AR and infective endocarditis are more prevalent in men, women exhibit a significantly higher relative risk of death in tertiary and surgical referral cohorts, which is independently associated with A

Sex differences in the genetic architecture of cognitive resilience to Alzheimer\u27s disease.

Approximately 30% of elderly adults are cognitively unimpaired at time of death despite the presence of Alzheimer\u27s disease neuropathology at autopsy. Studying individuals who are resilient to the cognitive consequences of Alzheimer\u27s disease neuropathology may uncover novel therapeutic targets to treat Alzheimer\u27s disease. It is well established that there are sex differences in response to Alzheimer\u27s disease pathology, and growing evidence suggests that genetic factors may contribute to these differences. Taken together, we sought to elucidate sex-specific genetic drivers of resilience. We extended our recent large scale genomic analysis of resilience in which we harmonized cognitive data across four cohorts of cognitive ageing, in vivo amyloid PET across two cohorts, and autopsy measures of amyloid neuritic plaque burden across two cohorts. These data were leveraged to build robust, continuous resilience phenotypes. With these phenotypes, we performed sex-stratified [n (males) = 2093, n (females) = 2931] and sex-interaction [n (both sexes) = 5024] genome-wide association studies (GWAS), gene and pathway-based tests, and genetic correlation analyses to clarify the variants, genes and molecular pathways that relate to resilience in a sex-specific manner. Estimated among cognitively normal individuals of both sexes, resilience was 20-25% heritable, and when estimated in either sex among cognitively normal individuals, resilience was 15-44% heritable. In our GWAS, we identified a female-specific locus on chromosome 10 [rs827389, β (females) = 0.08, P (females) = 5.76 × 10-09, β (males) = -0.01, P(males) = 0.70, β (interaction) = 0.09, P (interaction) = 1.01 × 10-04] in which the minor allele was associated with higher resilience scores among females. This locus is located within chromatin loops that interact with promoters of genes involved in RNA processing, including GATA3. Finally, our genetic correlation analyses revealed shared genetic architecture between resilience phenotypes and other complex traits, including a female-specific association with frontotemporal dementia and male-specific associations with heart rate variability traits. We also observed opposing associations between sexes for multiple sclerosis, such that more resilient females had a lower genetic susceptibility to multiple sclerosis, and more resilient males had a higher genetic susceptibility to multiple sclerosis. Overall, we identified sex differences in the genetic architecture of resilience, identified a female-specific resilience locus and highlighted numerous sex-specific molecular pathways that may underly resilience to Alzheimer\u27s disease pathology. This study illustrates the need to conduct sex-aware genomic analyses to identify novel targets that are unidentified in sex-agnostic models. Our findings support the theory that the most successful treatment for an individual with Alzheimer\u27s disease may be personalized based on their biological sex and genetic context

Genetic variants and functional pathways associated with resilience to Alzheimer\u27s disease.

Approximately 30% of older adults exhibit the neuropathological features of Alzheimer\u27s disease without signs of cognitive impairment. Yet, little is known about the genetic factors that allow these potentially resilient individuals to remain cognitively unimpaired in the face of substantial neuropathology. We performed a large, genome-wide association study (GWAS) of two previously validated metrics of cognitive resilience quantified using a latent variable modelling approach and representing better-than-predicted cognitive performance for a given level of neuropathology. Data were harmonized across 5108 participants from a clinical trial of Alzheimer\u27s disease and three longitudinal cohort studies of cognitive ageing. All analyses were run across all participants and repeated restricting the sample to individuals with unimpaired cognition to identify variants at the earliest stages of disease. As expected, all resilience metrics were genetically correlated with cognitive performance and education attainment traits (P-values \u3c 2.5 × 10-20), and we observed novel correlations with neuropsychiatric conditions (P-values \u3c 7.9 × 10-4). Notably, neither resilience metric was genetically correlated with clinical Alzheimer\u27s disease (P-values \u3e 0.42) nor associated with APOE (P-values \u3e 0.13). In single variant analyses, we observed a genome-wide significant locus among participants with unimpaired cognition on chromosome 18 upstream of ATP8B1 (index single nucleotide polymorphism rs2571244, minor allele frequency = 0.08, P = 2.3 × 10-8). The top variant at this locus (rs2571244) was significantly associated with methylation in prefrontal cortex tissue at multiple CpG sites, including one just upstream of ATPB81 (cg19596477; P = 2 × 10-13). Overall, this comprehensive genetic analysis of resilience implicates a putative role of vascular risk, metabolism, and mental health in protection from the cognitive consequences of neuropathology, while also providing evidence for a novel resilience gene along the bile acid metabolism pathway. Furthermore, the genetic architecture of resilience appears to be distinct from that of clinical Alzheimer\u27s disease, suggesting that a shift in focus to molecular contributors to resilience may identify novel pathways for therapeutic targets

International Nonregimes: A Research Agenda1

Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/146934/1/j.1468-2486.2007.00672.x.pd