Traci M. Bartz

Burden of Comorbidities and Functional and Cognitive Impairments in Elderly Patients at the Initial Diagnosis of Heart Failure and Their Impact on Total Mortality : The Cardiovascular Health Study

OBJECTIVES The purpose of this study was to determine the prevalence of clinically relevant comorbidities and measures of physical and cognitive impairment in elderly persons with incident heart failure (HF). BACKGROUND Comorbidities and functional and cognitive impairments are common in the elderly and often associated with greater mortality risk. METHODS We examined the prevalence of 9 comorbidities and 4 measures of functional and cognitive impairments in 558 participants from the Cardiovascular Health Study who developed incident HF between 1990 and 2002. Participants were followed prospectively until mid-2008 to determine their mortality risk. RESULTS Mean age of participants was 79.2 ± 6.3 years with 52% being men. Sixty percent of participants had ≥3 comorbidities, and only 2.5% had none. Twenty-two percent and 44% of participants had ≥1 activity of daily living (ADL) and ≥1 instrumental activity of daily living (IADL) impaired respectively. Seventeen percent of participants had cognitive impairment (modified mini-mental state exam score <80, scores range between 0 and 100). During follow up, 504 participants died, with 1-, 5-, and 10-year mortality rates of 19%, 56%, and 83%, respectively. In a multivariable-adjusted model, the following were significantly associated with greater total mortality risk: diabetes mellitus (hazard ratio [HR]: 1.64; 95% confidence interval [CI]: 1.33 to 2.03), chronic kidney disease (HR: 1.32; 95% CI: 1.07 to 1.62 for moderate disease; HR: 3.00; 95% CI: 1.82 to 4.95 for severe), cerebrovascular disease (HR: 1.53; 95% CI: 1.22 to 1.92), depression (HR: 1.44; 95% CI: 1.09 to 1.90), functional impairment (HR: 1.30; 95% CI: 1.04 to 1.63 for 1 IADL impaired; HR: 1.49; 95% CI: 1.07 to 2.04 for ≥2 IADL impaired), and cognitive impairment (HR: 1.33; 95% CI: 1.02 to 1.73). Other comorbidities (hypertension, coronary heart disease, peripheral arterial disease, atrial fibrillation, and obstructive airway disease) and measures of functional impairments (ADLs and 15-ft walk time) were not associated with mortality. CONCLUSIONS Elderly patients with incident HF have a high burden of comorbidities and functional and cognitive impairments. Some of these conditions are associated with greater mortality risk.

Fetuin-A, Type 2 Diabetes, and Risk of Cardiovascular Disease in Older Adults: The Cardiovascular Health Study

OBJECTIVE Fetuin-A, a hepatic secretory protein that simultaneously inhibits arterial calcification and insulin action, is associated with type 2 diabetes, but its association with cardiovascular disease (CVD) is uncertain. Preliminary studies suggest that the association of fetuin-A with CVD might differ among individuals with or without type 2 diabetes. RESEARCH DESIGN AND METHODS This was a prospective study of 3,810 community-living individuals older than 65 years (511 with type 2 diabetes) and free of CVD in 1992 when fetuin-A levels were measured. Participants were followed-up for incident CVD through June 2008. RESULTS Mean age was 75 years, and 61% were women; 1,456 participants had an incident CVD event (248 among individuals with type 2 diabetes). The association of fetuin-A with CVD was modified by type 2 diabetes (P interaction = 0.02). Higher fetuin-A was associated with lower CVD risk among persons without type 2 diabetes [hazard ratio per SD 0.1 g/L higher fetuin-A, 0.93 (95% CI, 0.88–0.99)], whereas a trend in the opposite direction was observed among individuals with type 2 diabetes, although it was not statistically significant [1.07 (0.93–1.22)]. Among individuals without type 2 diabetes, similar effect modification was observed by obesity and insulin resistance. Consistently, higher fetuin-A was associated with lower CVD risk only in the subgroups without obesity or with HOMA-IR below the median [0.91 (0.85–0.97) and 0.87 (0.79–0.95), respectively]. CONCLUSIONS The association of fetuin-A with risk of CVD differs among elderly individuals with and without insulin resistance or type 2 diabetes.

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.

Trajectories of Dehydroepiandrosterone Sulfate Predict Mortality in Older Adults: The Cardiovascular Health Study

BACKGROUND Dehydroepiandrosterone sulfate (DHEAS) has been proposed as an antiaging hormone, but its importance is unclear. Assessment of an individuals ability to maintain a DHEAS set point, through examination of multiple DHEAS levels over time, may provide insight into biologic aging. METHODS Using Cox proportional hazard models, we examined the relationship between DHEAS trajectory patterns and all-cause death in 950 individuals aged >or=65 years who were enrolled in the Cardiovascular Health Study and had DHEAS levels measured at three to six time points. RESULTS Overall, there was a slight decline in DHEAS levels over time (-0.013 microg/mL/y). Three trajectory components were examined: slope, variability, and baseline DHEAS. When examined individually, a steep decline or extreme variability in DHEAS levels was associated with higher mortality (p < .001 for each), whereas baseline DHEAS level was not. In adjusted models including all three components, steep decline (hazard ratio [HR] 1.75, confidence interval [CI] 1.32-2.33) and extreme variability (HR 1.89, CI 1.47-2.43) remained significant predictors of mortality, whereas baseline DHEAS level remained unpredictive of mortality (HR 0.97 per standard deviation, CI 0.88-1.07). The effect of trajectory pattern was more pronounced in men than in women. Individuals with both a steep decline and extreme variability in DHEAS levels had a significantly higher death rate than those with neither pattern (141 vs 48 deaths per 1,000 person-years, p < .001). CONCLUSIONS Our data show significant heterogeneity in the individual trajectories of DHEAS levels and suggest that these trajectories provide important biologic information about the rate of aging, whereas the DHEAS level itself does not.

Molecular mechanisms underlying variations in lung function: a systems genetics analysis

BACKGROUND Lung function measures reflect the physiological state of the lung, and are essential to the diagnosis of chronic obstructive pulmonary disease (COPD). The SpiroMeta-CHARGE consortium undertook the largest genome-wide association study (GWAS) so far (n=48,201) for forced expiratory volume in 1 s (FEV1) and the ratio of FEV1 to forced vital capacity (FEV1/FVC) in the general population. The lung expression quantitative trait loci (eQTLs) study mapped the genetic architecture of gene expression in lung tissue from 1111 individuals. We used a systems genetics approach to identify single nucleotide polymorphisms (SNPs) associated with lung function that act as eQTLs and change the level of expression of their target genes in lung tissue; termed eSNPs. METHODS The SpiroMeta-CHARGE GWAS results were integrated with lung eQTLs to map eSNPs and the genes and pathways underlying the associations in lung tissue. For comparison, a similar analysis was done in peripheral blood. The lung mRNA expression levels of the eSNP-regulated genes were tested for associations with lung function measures in 727 individuals. Additional analyses identified the pleiotropic effects of eSNPs from the published GWAS catalogue, and mapped enrichment in regulatory regions from the ENCODE project. Finally, the Connectivity Map database was used to identify potential therapeutics in silico that could reverse the COPD lung tissue gene signature. FINDINGS SNPs associated with lung function measures were more likely to be eQTLs and vice versa. The integration mapped the specific genes underlying the GWAS signals in lung tissue. The eSNP-regulated genes were enriched for developmental and inflammatory pathways; by comparison, SNPs associated with lung function that were eQTLs in blood, but not in lung, were only involved in inflammatory pathways. Lung function eSNPs were enriched for regulatory elements and were over-represented among genes showing differential expression during fetal lung development. An mRNA gene expression signature for COPD was identified in lung tissue and compared with the Connectivity Map. This in-silico drug repurposing approach suggested several compounds that reverse the COPD gene expression signature, including a nicotine receptor antagonist. These findings represent novel therapeutic pathways for COPD. INTERPRETATION The system genetics approach identified lung tissue genes driving the variation in lung function and susceptibility to COPD. The identification of these genes and the pathways in which they are enriched is essential to understand the pathophysiology of airway obstruction and to identify novel therapeutic targets and biomarkers for COPD, including drugs that reverse the COPD gene signature in silico. FUNDING The research reported in this article was not specifically funded by any agency. See Acknowledgments for a full list of funders of the lung eQTL study and the Spiro-Meta CHARGE GWAS.

Association of annular calcification and aortic valve sclerosis with brain findings on magnetic resonance imaging in community dwelling older adults: the cardiovascular health study.

OBJECTIVES The objective of this study was to investigate the associations of mitral annular calcification, aortic annular calcification, and aortic valve sclerosis with covert magnetic resonance imaging (MRI)-defined brain infarcts. BACKGROUND Clinically silent brain infarcts defined by MRI are associated with increased risk for cognitive decline, dementia, and future overt stroke. Left-sided cardiac valvular and annular calcifications are suspected as risk factors for clinical ischemic stroke. METHODS A total of 2,680 CHS (Cardiovascular Health Study) participants without clinical histories of stroke or transient ischemic attack underwent brain MRI in 1992 and 1993, 1 to 2 years before echocardiographic exams (1994 to 1995). RESULTS The mean age of the participants was 74.5 ± 4.8 years, and 39.3% were men. The presence of any annular or valvular calcification (mitral annular calcification, aortic annular calcification, or aortic valve sclerosis), mitral annular calcification alone, or aortic annular calcification alone was significantly associated with a higher prevalence of covert brain infarcts in unadjusted analyses (p < 0.01 for all). In models adjusted for age, sex, race, body mass index, physical activity, creatinine, systolic blood pressure, total cholesterol, high-density lipoprotein cholesterol, smoking, diabetes, coronary heart disease, and congestive heart failure, the presence of any annular or valve calcification remained associated with covert brain infarcts (risk ratio: 1.24; 95% confidence interval: 1.05 to 1.47). The degree of annular or valvular calcification severity showed a direct relation with the presence of covert MRI findings. CONCLUSIONS Left-sided cardiac annular and valvular calcifications are associated with covert MRI-defined brain infarcts. Further study is warranted to identify mechanisms and determine whether intervening in the progression of annular and valvular calcification could reduce the incidence of covert brain infarcts as well as the associated risk for cognitive impairment and future stroke.

Plasma free fatty acids and risk of atrial fibrillation (from the Cardiovascular Health Study).

Atrial fibrillation (AF) is a highly prevalent cardiac arrhythmia in clinical practice, affecting approximately 2.3 million residents of the United States and 4.5 million residents of the European Union. It is unclear whether plasma free fatty acids (FFAs) influence the risk of AF in older adults. The aim of this study was to prospectively examine the association between plasma FFAs and incident AF in a prospective cohort of 4,175 men and women ≥65 years old from the Cardiovascular Health Study. Plasma concentrations of FFAs were measured 2 times during the 1992 to 1993 examination. Incident AF was ascertained based on study electrocardiographic and hospitalization records during follow-up. We used Cox regression to estimate relative risks of AF. Average age at baseline was 74.6 ± 5.1 years. During a mean follow-up of 10.0 years, 1,041 new cases of AF occurred. Crude incidence rates of AF were 23.7, 23.3, 23.9, and 29.7 cases/1,000 person-years across consecutive quartiles of plasma FFAs. There was a positive association between plasma FFAs and risk of AF. Multivariable adjusted hazard ratios (95% confidence intervals) for incident AF were 1.00 (referent), 1.02 (0.85 to 1.21), 1.05 (0.88 to 1.26), and 1.29 (1.08 to 1.55) from the lowest to highest quartiles of FFAs, respectively. In a secondary analysis restricted to the first 5 years of follow-up, this association persisted. In conclusion, our data show an increased risk of AF with higher plasma FFAs in community-dwelling older adults.

Association Between Left Atrial Abnormality on ECG and Vascular Brain Injury on MRI in the Cardiovascular Health Study

Background and Purpose— Emerging evidence suggests that atrial disease is associated with vascular brain injury in the absence of atrial fibrillation. Methods— The Cardiovascular Health Study prospectively enrolled community-dwelling adults aged ≥65 years. Among participants who underwent MRI, we examined associations of ECG left atrial abnormality with brain infarcts and leukoaraiosis. P-wave terminal force in lead V1 was the primary measure of left atrial abnormality; P-wave area and duration were secondary predictors. We excluded participants with atrial fibrillation before or on their index ECG. Primary outcomes were incident infarcts and worsening leukoaraiosis from initial to follow-up scan ≈5 years later. Secondary outcomes were prevalent infarcts and degree of leukoaraiosis on initial MRI. Relative risk (RR) and linear regression models were adjusted for vascular risk factors. Results— Among 3129 participants with ≥1 scan, each SD increase in P-wave terminal force in lead V1 was associated with a 0.05-point (95% confidence interval [CI], 0.0003–0.10) higher baseline white matter grade on a 10-point scale. P-wave terminal force in lead V1 was associated with prevalent infarcts of any type (RR per SD, 1.09; 95% CI, 1.04–1.16) and more so with prevalent nonlacunar infarcts (RR per SD, 1.22; 95% CI, 1.08–1.38). Among 1839 participants with 2 scans, P-wave terminal force in lead V1 was associated with worsening leukoaraiosis (RR per SD, 1.09; 95% CI, 1.01–1.18), but not with incident infarcts (RR per SD, 1.06; 95% CI, 0.93–1.20). Sensitivity analyses adjusting for incident atrial fibrillation found similar results. P-wave area and duration were not associated with outcomes. Conclusions— ECG left atrial abnormality is associated with vascular brain injury in the absence of documented atrial fibrillation.

Genetically Elevated Fetuin-A Levels, Fasting Glucose Levels, and Risk of Type 2 Diabetes: The Cardiovascular Health Study

OBJECTIVE Fetuin-A levels are associated with higher risk of type 2 diabetes, but it is unknown if the association is causal. We investigated common (>5%) genetic variants in the fetuin-A gene (AHSG) fetuin-A levels, fasting glucose, and risk of type 2 diabetes. RESEARCH DESIGN AND METHODS Genetic variation, fetuin-A levels, and fasting glucose were assessed in 2,893 Caucasian and 542 African American community-living individuals 65 years of age or older in 1992–1993. RESULTS Common AHSG variants (rs4917 and rs2248690) were strongly associated with fetuin-A concentrations (P < 0.0001). In analyses of 259 incident cases of type 2 diabetes, the single nucleotide polymorphisms (SNPs) were not associated with diabetes risk during follow-up and similar null associations were observed when 579 prevalent cases were included. As expected, higher fetuin-A levels were associated with higher fasting glucose concentrations (1.9 mg/dL [95% CI, 1.2–2.7] higher per SD in Caucasians), but Mendelian randomization analyses using both SNPs as unbiased proxies for measured fetuin-A did not support an association between genetically predicted fetuin-A levels and fasting glucose (−0.3 mg/dL [95% CI, −1.9 to 1.3] lower per SD in Caucasians). The difference between the associations of fasting glucose with actual and genetically predicted fetuin-A level was statistically significant (P = 0.001). Results among the smaller sample of African Americans trended in similar directions but were statistically insignificant. CONCLUSIONS Common variants in the AHSG gene are strongly associated with plasma fetuin-A concentrations, but not with risk of type 2 diabetes or glucose concentrations, raising the possibility that the association between fetuin-A and type 2 diabetes may not be causal.

Predicting Heart Failure With Preserved and Reduced Ejection Fraction: The International Collaboration on Heart Failure Subtypes

Background—Heart failure (HF) is a prevalent and deadly disease, and preventive strategies focused on at-risk individuals are needed. Current HF prediction models have not examined HF subtypes. We sought to develop and validate risk prediction models for HF with preserved and reduced ejection fraction (HFpEF, HFrEF). Methods and Results—Of 28,820 participants from 4 community-based cohorts, 982 developed incident HFpEF and 909 HFrEF during a median follow-up of 12 years. Three cohorts were combined, and a 2:1 random split was used for derivation and internal validation, with the fourth cohort as external validation. Models accounted for multiple competing risks (death, other HF subtype, and unclassified HF). The HFpEF-specific model included age, sex, systolic blood pressure, body mass index, antihypertensive treatment, and previous myocardial infarction; it had good discrimination in derivation (c-statistic 0.80; 95% confidence interval [CI], 0.78–0.82) and validation samples (internal: 0.79; 95% CI, 0.77–0.82 and external: 0.76; 95% CI: 0.71–0.80). The HFrEF-specific model additionally included smoking, left ventricular hypertrophy, left bundle branch block, and diabetes mellitus; it had good discrimination in derivation (c-statistic 0.82; 95% CI, 0.80–0.84) and validation samples (internal: 0.80; 95% CI, 0.78–0.83 and external: 0.76; 95% CI, 0.71–0.80). Age was more strongly associated with HFpEF, and male sex, left ventricular hypertrophy, bundle branch block, previous myocardial infarction, and smoking with HFrEF (P value for each comparison ⩽0.02). Conclusions—We describe and validate risk prediction models for HF subtypes and show good discrimination in a large sample. Some risk factors differed between HFpEF and HFrEF, supporting the notion of pathogenetic differences among HF subtypes.Background— Heart failure (HF) is a prevalent and deadly disease, and preventive strategies focused on at-risk individuals are needed. Current HF prediction models have not examined HF subtypes. We sought to develop and validate risk prediction models for HF with preserved and reduced ejection fraction (HFpEF, HFrEF). Methods and Results— Of 28,820 participants from 4 community-based cohorts, 982 developed incident HFpEF and 909 HFrEF during a median follow-up of 12 years. Three cohorts were combined, and a 2:1 random split was used for derivation and internal validation, with the fourth cohort as external validation. Models accounted for multiple competing risks (death, other HF subtype, and unclassified HF). The HFpEF-specific model included age, sex, systolic blood pressure, body mass index, antihypertensive treatment, and previous myocardial infarction; it had good discrimination in derivation (c-statistic 0.80; 95% confidence interval [CI], 0.78–0.82) and validation samples (internal: 0.79; 95% CI, 0.77–0.82 and external: 0.76; 95% CI: 0.71–0.80). The HFrEF-specific model additionally included smoking, left ventricular hypertrophy, left bundle branch block, and diabetes mellitus; it had good discrimination in derivation (c-statistic 0.82; 95% CI, 0.80–0.84) and validation samples (internal: 0.80; 95% CI, 0.78–0.83 and external: 0.76; 95% CI, 0.71–0.80). Age was more strongly associated with HFpEF, and male sex, left ventricular hypertrophy, bundle branch block, previous myocardial infarction, and smoking with HFrEF ( P value for each comparison ≤0.02). Conclusions— We describe and validate risk prediction models for HF subtypes and show good discrimination in a large sample. Some risk factors differed between HFpEF and HFrEF, supporting the notion of pathogenetic differences among HF subtypes.