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1.  Carotid Arterial Stiffness and Its Relationship to Exercise Intolerance in Older Patients with Heart Failure and Preserved Ejection Fraction 
Hypertension  2012;61(1):112-119.
Heart failure with a preserved ejection fraction (HFpEF) is the dominant form of heart failure in the older population. The primary chronic symptom in HFpEF is severe exercise intolerance, however, its pathophysiology and therapy are not well understood. We tested the hypothesis that older patients with HFpEF have increased arterial stiffness beyond that which occurs with normal aging and that this contributes to their severe exercise intolerance.
Sixty-nine patients ≥ 60 years with HFpEF and 62 healthy volunteers (24 young healthy subjects ≤ 30 years (YHC) and 38 older healthy subjects ≥ 60 years old (OHC) were examined. Carotid arterial stiffness was assessed using high-resolution ultrasound and peak exercise oxygen consumption (VO2) was measured using expired gas analysis.
Peak VO2 was severely reduced in the HFpEF patients compared to OHC (14.1±2.9 vs. 19.7±3.7 ml/kg/min; p<0.001) and in both was reduced compared to YHC subjects, (32.0±7.2 ml/kg/min; both p<0.001). In HFpEF compared to OHC, carotid arterial distensibility was reduced (0.97±0.45 vs. 1.33±0.55 × 10−3 mmHg−1, p=0.008) and Young’s elastic modulus (YEM) was increased (1320±884 vs. 925±530 kPa, p<0.02). Carotid arterial distensibility was directly (0.28; p=0.02) and YEM was inversely (−0.32; p=0.01) related with peak VO2.
Carotid arterial distensibility is decreased in HFpEF beyond the changes due to normal aging and is related to peak VO2. This supports the hypothesis that increased arterial stiffness contributes to exercise intolerance in HFpEF and is a potential therapeutic target.
doi:10.1161/HYPERTENSIONAHA.111.00163
PMCID: PMC3712338  PMID: 23150511
Aging; heart failure with preserved ejection fraction; arterial stiffness; exercise capacity
2.  Age Disparities in Heart Failure Research 
doi:10.1001/jama.2010.1592
PMCID: PMC3685493  PMID: 21045104
3.  Chronotropic Incompetence: Causes, Consequences, and Management 
Circulation  2011;123(9):1010-1020.
doi:10.1161/CIRCULATIONAHA.110.940577
PMCID: PMC3065291  PMID: 21382903
Heart rate; exercise; chronotropic incompetence; aging; heart failure
4.  Effect of Aldosterone Antagonism on Exercise Tolerance, Doppler Diastolic Function, and Quality of Life in Older Women With Diastolic Heart Failure 
Optimal therapy for diastolic heart failure (DHF), the most common form of heart failure in older persons, is unclear. To determine the effect of aldosterone antagonism in DHF, we conducted an open-label preliminary trial of spironolactone 25mg/day in 11 women with DHF. Cardiopulmonary exercise testing, Doppler-echocardiography, and a quality of life (QOL) survey were administered at baseline and after 4-months. Peak exercise VO2 increased by 8.3% (p=0.001), the ratio of Doppler diastolic early filling velocity to mitral annulus velocity decreased by 25% (p=0.02), QOL score improved by 21% (p=0.16 for trend), and median NYHA class improved from class III to class II (p=0.004). Findings from this preliminary study confirm the role of aldosterone in the pathophysiology of DHF and suggest that aldosterone antagonism may benefit such patients. These hypotheses are currently being tested in two separated NIH-funded, randomized trials, the Spironolactone For Failure in the Elderly (SPIFFIE) and the Treatment Of Preserved Cardiac Function Heart Failure with an Aldosterone antagonist (TOPCAT) trials.
doi:10.1111/j.1751-7133.2009.00056.x
PMCID: PMC2922000  PMID: 19379452
5.  EXERCISE INTOLERANCE 
Heart failure clinics  2008;4(1):99-115.
doi:10.1016/j.hfc.2007.12.002
PMCID: PMC2700357  PMID: 18313628
6.  Angiotensin-Converting Enzyme Inhibitors and Outcomes in Heart Failure and Preserved Ejection Fraction 
The American journal of medicine  2013;126(5):401-410.
BACKGROUND
The role of angiotensin-converting enzyme (ACE) inhibitors in patients with heart failure and preserved ejection fraction remains unclear.
METHODS
Of the 10,570 patients ≥65 years with heart failure and preserved ejection fraction (≥40%) in OPTIMIZE-HF (2003–2004) linked to Medicare (through December, 2008), 7304 were not receiving angiotensin receptor blockers and had no contraindications to ACE inhibitors. After excluding 3115 patients with pre-admission ACE inhibitor use, the remaining 4189 were eligible for new discharge prescriptions for ACE inhibitors, and 1706 received them. Propensity scores for the receipt of ACE inhibitors, calculated for each of the 4189 patients, were used to assemble a cohort of 1337 pairs of patients, balanced on 114 baseline characteristics.
RESULTS
Matched patients had a mean age of 81 years, mean ejection fraction of 55%, 64% were women and 9% African American. Initiation of ACE inhibitor therapy was associated with lower risk of the primary composite endpoint of all-cause mortality or heart failure hospitalization during 2.4 years of median follow-up (hazard ratio {HR}, 0.91; 95% confidence interval {CI}, 0.84–0.99; p=0.028), but not with individual endpoints of all-cause mortality (HR, 0.96; 95% CI, 0.88–1.05; p=0.373) or heart failure hospitalization (HR, 0.93; 95% CI, 0.83–1.05; p=0.257).
CONCLUSION
In hospitalized older patients with heart failure and preserved ejection fraction not receiving angiotensin receptor blockers, discharge initiation of ACE inhibitor therapy was associated with a modest improvement in the composite endpoint of total mortality or heart failure hospitalization, but had no association with individual endpoint components.
doi:10.1016/j.amjmed.2013.01.004
PMCID: PMC3656660  PMID: 23510948
ACE inhibitors; Heart Failure; Preserved Ejection Fraction
7.  Heart Failure with Preserved Ejection Fraction in African-Americans – The Atherosclerosis Risk in Communities (ARIC) Study 
JACC. Heart failure  2013;1(2):156-163.
Objectives
In an entirely African-American cohort, we compared clinical characteristics, cardiac structure and function, and all cause mortality in heart failure (HF) with preserved ejection fraction (HFpEF) in relation to HF with reduced ejection fraction (HFrEF) and those without HF.
Background
African-Americans are at increased risk for HF. Nevertheless, there are limited phenotypic and prognostic data in African-Americans with HFpEF compared to those with HFrEF and those without HF.
Methods
Middle-aged African-Americans from the Jackson cohort of the Atherosclerosis Risk in Communities study (n=2,445) underwent echocardiography between 1993 and 1995. HF prevalence was available in 1,962 for whom left ventricular ejection fraction (LVEF) could be quantified. Participants with HF were categorized as having HFpEF (LVEF ≥ 50%) or HFrEF (LVEF < 50%), or no HF, with comparisons made between groups.
Results
HF was identified in 116 (5.9%) participants (n=85 [73%] HFpEF; n=31 [27%] HFrEF). Compared to those without HF, those with HFpEF were older, more likely to be female, had more frequent comorbidities, and concentric hypertrophy. In relation to HFrEF, those with HFpEF were more likely female, but less likely to have coronary heart disease, diabetes mellitus, chronic kidney disease, left atrial enlargement, and eccentric hypertrophy. Over a median 13.7 years of follow up, risk of death differed between groups, with age and sex adjusted hazard ratios of 1.51 (95%CI 1.01–2.25) for HFpEF vs. those without HF, and 2.50 (95%CI 1.37–4.58) for HFrEF vs. HFpEF.
Conclusions
In this cohort of middle-aged African-Americans, HFpEF was the most common form of HF, and was associated with a substantially better prognosis than HFrEF, but worse than those without HF.
doi:10.1016/j.jchf.2013.01.003
PMCID: PMC3650857  PMID: 23671819
African-Americans; heart failure with preserved ejection fraction; heart failure with reduced ejection fraction; echocardiography; mortality
8.  Relationship of Flow-Mediated Arterial Dilation and Exercise Capacity in Older Patients With Heart Failure and Preserved Ejection Fraction 
Background.
Older heart failure patients with preserved ejection fraction (HFpEF) have severely reduced exercise capacity and quality of life. Both brachial artery flow-mediated dilation (FMD) and peak exercise oxygen uptake (peak VO2) decline with normal aging. However, uncertainty remains regarding whether FMD is reduced beyond the degree associated with normal aging and if this contributes to reduced peak VO2 in elderly HFpEF patients.
Methods.
Sixty-six older (70 ± 7 years) HFpEF patients and 47 healthy participants (16 young, 25 ± 3 years, and 31 older, 70 ± 6 years) were studied. Brachial artery diameter was measured before and after cuff occlusion using high-resolution ultrasound. Peak VO2 was measured using expired gas analysis during upright cycle exercise.
Results.
Peak VO2 was severely reduced in older HFpEF patients compared with age-matched healthy participants (15.2 ± 0.5 vs 19.6 ± 0.6 mL/kg/min, p < .0001), and in both groups, peak VO2 was reduced compared with young healthy controls (28.5 ± 0.8 mL/kg/min; both p < .0001). Compared with healthy young participants, brachial artery FMD (healthy young, 6.13% ± 0.53%) was significantly reduced in healthy older participants (4.0 ± 0.38; p < .0002) and in HFpEF patients (3.64% ± 0.28%; p < .0001). However, FMD was not different in HFpEF patients compared with healthy older participants (p = .86). Although brachial artery FMD was modestly related to peak VO2 in univariate analyses (r = .19; p = .048), it was not related in multivariate analyses that accounted for age, gender, and body size.
Conclusion.
These results suggest that endothelial dysfunction may not be a significant independent contributor to the severely reduced exercise capacity in elderly HFpEF patients.
doi:10.1093/gerona/gls099
PMCID: PMC3598353  PMID: 22522508
Exercise capacity; Aging; Flow-mediated dilation; Heart failure with preserved ejection fraction; Endothelial function
9.  Aldosterone Antagonists and Outcomes in Real-World Older Patients with Heart Failure and Preserved Ejection Fraction 
JACC. Heart failure  2013;1(1):40-47.
Objectives
The purpose of this study was to examine the clinical effectiveness of aldosterone antagonists in older patients with heart failure and preserved ejection fraction (HF-PEF).
Background
Aldosterone antagonists improve outcomes in HF and reduced EF. However, their role in HF-PEF remains unclear.
Methods
Of the 10,570 hospitalized older (age ≥65 years) HF-PEF (EF ≥40%) patients in Medicare-linked OPTIMIZE-HF (Organized Program to Initiate Lifesaving Treatment in Hospitalized Patients with Heart Failure) trial, 8013 had no prior aldosterone antagonist use and no current contraindications, of whom 492 (6% of 8013) received new prescriptions for aldosterone antagonists. We assembled a matched cohort of 487 pairs of patients receiving and not receiving aldosterone antagonists, who had similar propensity to receive these drugs, and were balanced on 116 baseline characteristics.
Results
Patients had a mean age of 80 years, a mean EF of 54%, 59% were women, and 8% were African American. During 2.4 year of mean follow-up (through December, 2008), the primary composite endpoint of all-cause mortality or HF hospitalization occurred in 392 (81%) and 393 (81%) patients receiving and not receiving aldosterone antagonists, respectively (hazard ratio {HR}, 0.97; 95% confidence interval {CI}, 0.84–1.11; p=0.628). Aldosterone antagonists had no association with all-cause mortality (HR, 1.03; 95% CI, 0.89–1.20; p=0.693) or HF hospitalization (HR, 0.88; 95% CI, 0.73–1.07; p=0.188). Among 8013 pre-match patients, multivariable-adjusted HR for primary composite endpoint associated with aldosterone antagonist use was 0.93 (95% CI, 0.83–1.03; p=0.144).
Conclusions
In older HF-PEF patients, aldosterone antagonists had no association with clinical outcomes. Findings from the ongoing randomized controlled TOPCAT (Treatment of Preserved Cardiac Function Heart Failure With an Aldosterone Antagonist) trial will provide further insights into their effect in HF-PEF.
doi:10.1016/j.jchf.2012.08.001
PMCID: PMC3694622  PMID: 23814702
Aldosterone antagonists; Heart failure; Preserved ejection fraction
10.  Clinical Characteristics, Response to Exercise Training and Outcomes in Heart Failure Patients with Chronic Obstructive Pulmonary Disease: Findings from HF-ACTION 
American heart journal  2012;165(2):193-199.
Background
To investigate the clinical characteristics, exercise training response, beta-blocker selectivity and outcomes in heart failure (HF) patients with chronic obstructive pulmonary disease (COPD).
Methods
We performed an analysis of HF-ACTION, which randomized 2,331 HF patients with ejection fraction ≤35% to usual care with or without aerobic exercise training. We examined clinical characteristics and outcomes [mortality/hospitalization, mortality, cardiovascular (CV) mortality/CV hospitalization, and CV mortality/HF hospitalization] by physician-reported COPD status using adjusted Cox models and explored an interaction with exercise training. The interaction between beta-blocker cardioselectivity and outcomes was investigated.
Results
Of patients with COPD status documented (N=2311), 11% (N=249) had COPD. COPD patients were older, had more comorbidities, and lower use of beta-blockers compared to those without COPD. At baseline, COPD patients had lower peak VO2 and higher VE/VCO2 slope. During a median follow-up of 2.5 years, COPD was associated with increased mortality/hospitalization, mortality, and CV mortality/HF hospitalization. After multivariable adjustment, the risk of CV mortality/HF hospitalization remained increased (Hazard Ratio [HR] 1.46, 95% Confidence Interval [CI]: 1.14–1.87), while mortality/hospitalization (HR 1.15, 95% CI: 0.96–1.37) and mortality (HR 1.33, 95% CI: 0.99–1.76) were not significantly increased. There was no interaction between COPD and exercise training on outcomes or between COPD and beta-blocker selectivity on mortality/hospitalization (all P>0.1).
Conclusions
COPD in HF patients was associated with older age, more comorbidities, reduced exercise capacity, and increased CV mortality/HF hospitalization, but not a differential response to exercise training. Beta-blocker selectivity was not associated with differences in outcome for patients with versus without COPD.
doi:10.1016/j.ahj.2012.10.029
PMCID: PMC3762597  PMID: 23351822
heart failure; COPD; exercise training
11.  Reliability of Peak Exercise Testing in Patients with Heart Failure with Preserved Ejection Fraction 
The American journal of cardiology  2012;110(12):1809-1813.
Exercise intolerance is the primary symptom among heart failure patients with preserved ejection fraction (HFpEF), is a major determinant of their reduced quality of life, and an important outcome in clinical trials. Although cardiopulmonary exercise testing (CPET) provides peak and submaximal diagnostic indices, the reliability of peak treadmill CPET in patients ≥ 55 years of age with HFpEF has not been examined. Two CPETs were performed in 52 HFpEF patients (age 70 ± 7 years). The two tests were separated by an average of 23 ± 13 days (median: 22 days) and performed under identical conditions, with no intervention or change in status between visits except for initiation of a placebo run-in. A multi-step protocol for patient screening, education, and quality control was utilized. Mean peak VO2 was similar on test 1 and test 2 (14.4 ± 2.4 vs. 14.3 ± 2.3 ml/kg/min). The correlation coefficients and intraclass correlations (ICC) from the testing days were as follows: VO2 r = 0.85, p < 0.001, ICC = 0.855; ventilatory anaerobic threshold r= 0.79, p < 0.001, ICC= 0.790; VE/VCO2 slope r = 0.87, p < 0.001, ICC = 0.864; HR r = 0.94, p < 0.001, ICC = 0.938. These results challenge conventional wisdom that serial baseline testing is required in clinical trials with exercise capacity outcomes. In conclusion, in women and men with HFpEF and severe physical dysfunction, key submaximal and peak exercise testing variables exhibited good reliability and were not significantly altered by a learning effect or placebo administration.
doi:10.1016/j.amjcard.2012.08.015
PMCID: PMC3511643  PMID: 22981266
heart failure preserved ejection fraction; cardiopulmonary exercise testing; test reproducibility
12.  Relation between Volume of Exercise and Clinical Outcomes in Patients with Heart Failure 
Background
The HF-ACTION (Heart Failure: A Controlled Trial Investigating Outcomes of Exercise Training) trial showed that among patients with heart failure (HF), regular exercise confers a modest reduction in the adjusted risk for all-cause mortality or hospitalization.
Objective
This study determined whether greater volumes of exercise were associated with greater reductions in clinical events.
Methods
Patients randomized to the exercise training arm of HF-ACTION who were event-free at 3 mo after randomization were included (n= 959). Median follow-up was 28.2 months. Clinical end points were all-cause mortality or hospitalization and cardiovascular mortality or HF hospitalization.
Results
A reverse J-shaped association was observed between exercise volume and adjusted clinical risk. Based on Cox regression, exercise volume was not a significant linear predictor but was a logarithmic predictor (p=0.03) for all-cause mortality or hospitalization. For cardiovascular mortality or HF hospitalization, exercise volume was a significant (p=0.001) linear and logarithmic predictor. Moderate exercise volumes of 3 to <5 and 5 to <7 MET-hr per week were associated with reductions in subsequent risk that exceeded 30%. Exercise volume was positively associated with the change in peak oxygen uptake at 3 months (r=0.10; p=0.005).
Conclusions
In patients with chronic systolic HF, volume of exercise is associated with the risk for clinical events, with only moderate levels (3–7 MET-hr per week) of exercise needed to observe a clinical benefit. Although further study is warranted to confirm the relationship between volume of exercise completed and clinical events, our findings support the use of regular exercise in the management of these patients.
Clinical Trial Registry: http://clinicaltrials.gov/ct2/show/NCT00047437
doi:10.1016/j.jacc.2012.08.958
PMCID: PMC3804919  PMID: 23062530
exercise training; dose response; cardiac rehabilitation
13.  Lipopolysaccharide-Binding Protein, a Surrogate Marker of Microbial Translocation, Is Associated With Physical Function in Healthy Older Adults 
Background.
Physical function declines, and markers of inflammation increase with advancing age, even in healthy persons. Microbial translocation (MT) is the systemic exposure to mucosal surface microbes/microbial products without overt bacteremia and has been described in a number of pathologic conditions. We hypothesized that markers of MT, soluble CD14 (sCD14) and lipopolysaccharide (LPS) binding protein (LBP), may be a source of chronic inflammation in older persons and be associated with poorer physical function.
Methods.
We assessed cross-sectional relationships among two plasma biomarkers of MT (sCD14 and LBP), physical function (hand grip strength, short physical performance battery [SPPB], gait speed, walking distance, and disability questionnaire), and biomarkers of inflammation (C-reactive protein (CRP), interleukin-6 (IL-6), tumor necrosis factor-alpha (TNF-α), TNF-α soluble receptor 1 [TNFsR1]) in 59 older (60–89 years), healthy (no evidence of acute or chronic illness) men and women.
Results.
LBP was inversely correlated with SPPB score and grip strength (p = .02 and p < .01, respectively) and positively correlated with CRP (p = 0.04) after adjusting for age, gender, and body mass index. sCD14 correlated with IL-6 (p = .01), TNF-α (p = .05), and TNFsR1 (p < .0001). Furthermore, the correlations between LBP and SPPB and grip strength remained significant after adjusting for each inflammatory biomarker.
Conclusions.
In healthy older individuals, LBP, a surrogate marker of MT, is associated with worse physical function and inflammation. Additional study is needed to determine whether MT is a marker for or a cause of inflammation and the associated functional impairments.
doi:10.1093/gerona/gls178
PMCID: PMC3636679  PMID: 22960476
Microbial translocation; Inflammation; Physical function; Microbiome
14.  Frailty and Multiple Comorbidities in the Elderly Patient with Heart Failure: Implications for Management 
Heart failure reviews  2012;17(0):581-588.
Heart failure (HF) in the elderly is a major public health problem, and its prevalence is rising. Outcomes of HF in the elderly have not changed in the past 2 decades despite the introduction of novel HF therapies. This may be due to the combined impact of multiple comorbidities and frailty. The majority of elderly patients with HF are frail with multiple comorbidities. These comorbidities, along with frailty, contribute to the poor outcome of HF in the elderly and pose independent management challenges. More research is needed to: better understand the interaction between frailty and multiple comorbidities and the mechanisms by which they impact HF and its management; develop prognostic tools that incorporate frailty and multiple comorbidities and provide more accurate prediction of outcomes; test available treatments in typical elderly patients; and develop and test novel interventions that directly address the adverse impact of multiple co-morbidities and frailty.
doi:10.1007/s10741-011-9258-y
PMCID: PMC3804644  PMID: 21626426
Aging; chronic diseases; rehospitalization; outcomes
15.  Angiotensin receptor blockers and outcomes in real-world older patients with heart failure and preserved ejection fraction: a propensity-matched inception cohort clinical effectiveness study 
European Journal of Heart Failure  2012;14(10):1179-1188.
Aims
To examine the clinical effectiveness of angiotensin receptor blockers (ARBs) in older patients with heart failure and preserved ejection fraction (HF-PEF).
Methods and results
Of the 10 570 hospitalized HF-PEF patients, aged ≥65 years, EF ≥40%, in OPTIMIZE-HF (2003–2004), linked to Medicare data (up to 31 December 2008), 3806 were not receiving angiotensin-converting enzyme inhibitors or prior ARB therapy. Of these, 303 (8%) patients received new discharge prescriptions for ARBs. Propensity scores for the receipt of ARBs, estimated for each of the 3806 patients, were used to assemble a cohort of 296 pairs of patients receiving and not receiving ARBs, who were balanced on 114 baseline characteristics. Patients had a mean age of 80 years, mean EF of 55%, 69% were women, and 12% were African American. During 6 years of follow-up, the primary composite endpoint of all-cause mortality or HF hospitalization occurred in 79% (235/296) and 81% (241/296) of patients receiving and not receiving ARBs, respectively [hazard ratio (HR) associated with ARB use 0.88, 95% confidence interval (CI) 0.74–1.06; P = 0.179]. ARB use had no association with individual endpoints of all-cause mortality (HR 0.93, 95% CI 0.76–1.14; P = 0.509), HF hospitalization (HR 0.90, 95% CI, 0.72–1.14; P = 0.389), or all-cause hospitalization (HR 0.91, 95% CI 0.77–1.08; P = 0.265). These associations remained unchanged when we compared any (prevalent and new prescriptions) ARB use vs. non-use in a separately assembled propensity-matched cohort of 1137 pairs of HF-PEF patients.
Conclusions
In real-world older HF-PEF patients, ARB use was not associated with improved clinical outcomes.
doi:10.1093/eurjhf/hfs101
PMCID: PMC3448391  PMID: 22759445
Angiotensin receptor blockers; Heart failure; Preserved ejection fraction
16.  Aging and physical mobility in group-housed Old World monkeys 
Age  2011;34(5):1123-1131.
While indices of physical mobility such as gait speed are significant predictors of future morbidity/mortality in the elderly, mechanisms of these relationships are not understood. Relevant animal models of aging and physical mobility are needed to study these relationships. The goal of this study was to develop measures of physical mobility including activity levels and gait speed in Old World monkeys which vary with age in adults. Locomotor behaviors of 21 old (\documentclass[12pt]{minimal} \usepackage{amsmath} \usepackage{wasysym} \usepackage{amsfonts} \usepackage{amssymb} \usepackage{amsbsy} \usepackage{mathrsfs} \usepackage{upgreek} \setlength{\oddsidemargin}{-69pt} \begin{document}$$ \overline x $$\end{document} = 20 yoa) and 24 young (\documentclass[12pt]{minimal} \usepackage{amsmath} \usepackage{wasysym} \usepackage{amsfonts} \usepackage{amssymb} \usepackage{amsbsy} \usepackage{mathrsfs} \usepackage{upgreek} \setlength{\oddsidemargin}{-69pt} \begin{document}$$ \overline x $$\end{document} = 9 yoa) socially housed adult females of three species were recorded using focal sample and ad libitum behavior observation methods. Self-motivated walking speed was 17% slower in older than younger adults. Likewise, young adults climbed more frequently than older adults. Leaping and jumping were more common, on average, in young adults, but this difference did not reach significance. Overall activity levels did not vary significantly by age, and there were no significant age by species interactions in any of these behaviors. Of all the behaviors evaluated, walking speed measured in a simple and inexpensive manner appeared most sensitive to age and has the added feature of being least affected by differences in housing characteristics. Thus, walking speed may be a useful indicator of decline in physical mobility in nonhuman primate models of aging.
doi:10.1007/s11357-011-9350-1
PMCID: PMC3448999  PMID: 22203457
Gait speed; Nonhuman primate; Aging; Physical mobility; Activity
17.  Usefulness of Doppler Echocardiographic Left Ventricular Diastolic Function and Peak Exercise Oxygen Consumption to Predict Cardiovascular Outcomes in Patients with Systolic Heart Failure (From HF-ACTION) 
The American journal of cardiology  2012;110(6):862-869.
HF-ACTION was a multicenter, randomized, controlled trial designed to examine the safety and efficacy of aerobic exercise training versus usual care in 2,331 patients with systolic heart failure (HF). In HF-ACTION patients with resting transthoracic echocardiographic (echo) measurements, we examined predictive value of 8 echo-Doppler measurements—left ventricular (LV) diastolic dimension, mass, systolic (ejection fraction) and diastolic function (mitral valve [MV] peak early diastolic-to-peak late diastolic [E/A], peak MV early diastolic velocity-to-tissue Doppler peak early diastolic myocardial velocity [E/E’] ratios, and deceleration time), left atrial (LA) dimension, and mitral regurgitation severity (MR)—for primary endpoint of all-cause death or hospitalization and secondary endpoint of cardiovascular disease (CVD) death or HF hospitalization. We also compared prognostic value of echo variables versus peak oxygen consumption (VO2). MV E/A and E/E’ ratios were more powerful independent predictors of clinical endpoints than was LV ejection fraction (LVEF), but less powerful than peak VO2. In multivariate analyses for predicting primary endpoint, adding E/A ratio to a basic demographic/clinical model increased C-index from 0.61 to 0.62, compared with 0.64 after adding peak VO2. For secondary endpoint, 6 echo variables, but not LVEF or LA dimension, provided independent predictive power over basic model. Addition of E/E’ or E/A to the basic model increased C-index from 0.70 to 0.72 and 0.73, respectively (all p <0.0001). Simultaneously adding E/A and peak VO2 to basic model increased C-index to 0.75 (p <0.0005). No echo variable was significantly related to 0-to-3 month change in exercise peak VO2. In conclusion, addition of echo LV diastolic function variables improves prognostic value of a basic demographic/clinical model for CVD outcomes.
doi:10.1016/j.amjcard.2012.05.015
PMCID: PMC3432165  PMID: 22683041
Systolic heart failure; echocardiography; exercise training; clinical outcomes
18.  Aging reduces left atrial performance during adrenergic stress in middle aged and older patients 
Cardiology journal  2012;19(1):45-52.
Background
During adrenergic stress, the influence of age on left atrial (LA) function is unknown. We hypothesized that aging decreases LA total emptying fraction (LAEF) during maximal adrenergic stress. The aim of the study was to determine the influence of aging on LA function during adrenergic stress in middle aged and older patients.
Methods
We enrolled 167 middle aged and elderly participants, and measured LA and left ventricular (LV) volumes using a multi-slice three-dimensional cine white blood cardiovascular magnetic resonance (CMR) technique before and during intravenous dobutamine infused to achieve 80% of the maximum heart rate response for age. Paired sample t-test was used to detect differences in LA and LV volumes between baseline and peak dose stage of dobutamine stress CMR, and multivariable linear regression was used to identify predictors of LA function.
Results
Participants averaged 68 ± 8 years in age, 53% were men, 25% exhibited coronary artery disease, 35% had diabetes, 9% had a remote history of atrial fibrillation, 90% had hypertension, and 11% had inducible LV wall motion abnormalities indicative of ischemia during dobutamine CMR. Increasing age correlated with LA volumes (maximal and minimal) and inversely correlated with LAEF at rest and after peak adrenergic stress. Age was an independent predictor of LAEF during adrenergic stress, even after accounting for gender, LV volumes, and other co-morbidities including inducible ischemia.
Conclusions
Age is associated with a decrease in LA function during adrenergic stress even after adjusting for co-morbidities associated with cardiovascular disease and LV function.
PMCID: PMC3767009  PMID: 22298167
aging; left atrial function; adrenergic stress; cardiac MRI
19.  Relationship of Tc-99m Tetrofosmin Gated Rest SPECT Myocardial Perfusion Imaging to Death and Hospitalization in Heart Failure Patients: Results from the Nuclear Ancillary Study of the HF-ACTION Trial 
American heart journal  2011;161(6):1038-1045.
Background
We hypothesized that the severity of resting perfusion abnormalities assessed by the summed rest score (SRS) would be associated with a higher rate of adverse outcomesin patients with heart failure (HF) and reduced left ventricular (LV) ejection fraction (EF).
Methods
A subset of 240 subjects from HF-ACTION underwent resting Tc99m tetrofosmin gated single photon emission computed tomography (SPECT) myocardial perfusion imaging(MPI). Images were evaluated using a 17-segment model to derive the SRS and additional nuclear variables.
Results
After adjusting for pre-specified covariates, SRS was significantly associated with the primary endpoint (hazard ratio [HR] 0.98; 95% confidence interval [CI] 0.97–1.00, P=0.04), with a higher SRS corresponding to lower risk of an event. This association was not present in the unadjusted analysis. The relationship between SRS and the primary outcome was likely due to a higher event ratein patients with ischemic HF and a low SRS. The LV phase standard deviation (SD) was not predictive of the primary outcome (HR 1.00; 95% CI 0.99–1.01, P=0.49). In a post hoc analysis, nuclear variables provided incremental prognostic information when added to clinical information (P=0.006).
Conclusions
Gated SPECT MPI provides important information in patients with HF and reduced LVEF. In the adjusted analysis, SRS has an unexpected relationship with the primary endpoint. Phase SD was not associated with the primary endpoint. Rest gated SPECT MPI provides incrementally greater prognostic information than clinical information alone.
doi:10.1016/j.ahj.2011.02.007
PMCID: PMC3739977  PMID: 21641348
heart failure; SPECT; outcomes; coronary artery disease; cardiomyopathy
20.  Method for Establishing Authorship in a Multicenter Clinical Trial 
Annals of internal medicine  2009;151(6):414-420.
With the emergence of large multicenter trials over the past 20 years, the numbers of investigators involved and publications resulting from each study have grown exponentially. An efficient, fair, and effective way to establish authorship on study-related manuscripts could diminish conflict among the investigators and help ensure robust and timely dissemination of study results. This article describes a process developed by the investigators in the HF-ACTION (Heart Failure: A Controlled Trial Investigating Outcomes of Exercise Training) trial (ClinicalTrials.gov registration number: NCT00047437) to establish authorship of the manuscripts describing the baseline characteristics, study design, and trial outcomes in an equitable and transparent manner based on objective, quantifiable contributions to the study as a whole. The HF-ACTION investigators developed a scoring system that assigned points to investigators by using the criteria established for enrollment, adherence to the exercise program, data completion, committee service, and other trial efforts. The scoring system has been successfully implemented for baseline manuscripts and has allowed many investigators to participate in the HF-ACTION publication process.
PMCID: PMC3730830  PMID: 19755366
21.  Effect of Endurance Training on the Determinants of Peak Exercise Oxygen Consumption in Elderly Patients with Stable Compensated Heart Failure and Preserved Ejection Fraction 
Objective
Evaluate the mechanism(s) for improved exercise capacity after endurance exercise training (ET) in elderly patients with heart failure and preserved ejection fraction (HFPEF). Background: Exercise intolerance, measured objectively by reduced peak oxygen consumption (VO2), is the primary chronic symptom in HFPEF and is improved by ET. However, the mechanism(s) are unknown.
Methods
Forty stable, compensated HFPEF outpatients (mean age 69 ± 6 yrs) were examined at baseline and after 4 months of ET (n=22) or attention control (n=18). VO2 and its determinants were assessed during rest and peak upright cycle exercise.
Results
Following ET, peak VO2 was higher than controls (16.3 ± 2.6 vs. 13.1 ± 3.4 ml/kg/min; p=0.002). This was associated with higher peak heart rate (139 ± 16 vs. 131 ± 20 beats/min; p=0.03), but no difference in peak end-diastolic volume (77 ± 18 vs. 77 ± 17 ml; p=0.51), stroke volume (48 ± 9 vs. 46 ± 9 ml; p=0.83), or cardiac output (6.6 ± 1.3 vs. 5.9 ± 1.5 L/min; p=0.32). However, estimated peak arterial-venous oxygen difference (A-VO2 Diff) was significantly higher in ET (19.8 ± 4.0 vs. 17.3 ± 3.7 ml/dl; p=0.03). The effect of ET on cardiac output was responsible for < 15% of the improvement in peak VO2.
Conclusions
In elderly stable compensated HFPEF patients, peak A-VO2 Diff was higher following ET and was the primary contributor to improved peak VO2. This suggests that peripheral mechanisms (improved microvascular and/or skeletal muscle function) contribute to the improved exercise capacity after ET in HFPEF.
doi:10.1016/j.jacc.2012.02.055
PMCID: PMC3429944  PMID: 22766338
Heart failure; preserved ejection fraction; exercise; elderly; peripheral
22.  Exercise Training Improves Heart Rate Variability in Older Patients with Heart Failure: A Randomized, Controlled, Single-Blinded Trial 
Background
Reduced heart rate variability (HRV) in older patients with heart failure (HF) is common and indicates poor prognosis. Exercise training (ET) has been shown to improve HRV in younger patients with HF. However the effect of ET on HRV in older patients with HF is not known.
Methods and Results
Sixty-six participants (36% males), age 69±5 years, with HF and both preserved ejection fraction (HFPEF) and reduced ejection fraction (HFREF), were randomly assigned to 16 weeks of supervised ET (ET group) versus attention-control (AC group). Two HRV parameters (the standard deviation of all normal RR intervals (SDNN) and the root mean square of successive differences in normal RR intervals (RMSSD)) were measured at baseline and after completion of the study. When compared with the AC group, the ET group had a significantly greater increase in both SDNN (15.46 ± 5.02 ms in ET versus 2.37 ± 2.13 ms in AC, P = 0.016), and RMSSD (17.53 ± 7.83 ms in ET versus 1.69 ± 2.63 ms in AC, P = 0.003). This increase was seen in both genders and HF categories.
Conclusion
ET improves HRV in older patients with both HFREF and HFPEF.
doi:10.1111/j.1751-7133.2011.00282.x
PMCID: PMC3400715  PMID: 22536936
23.  Exercise Intolerance 
Cardiology clinics  2011;29(3):461-477.
doi:10.1016/j.ccl.2011.06.002
PMCID: PMC3694583  PMID: 21803233
Diastolic heart failure; Heart rate; Hypertrophic cardiomyopathy; Systolic heart failure
24.  Factors Related to Morbidity and Mortality in Patients with Chronic Heart Failure with Systolic Dysfunction: The HF-ACTION Predictive Risk Score Model 
Circulation. Heart failure  2011;5(1):63-71.
Background
We aimed to develop a multivariable statistical model for risk stratification in patients with chronic heart failure (HF) with systolic dysfunction, using patient data that are routinely collected and easily obtained at the time of initial presentation.
Methods and Results
In a cohort of 2331 patients enrolled in the HF-ACTION study (New York Heart Association [NYHA] class II-IV, left ventricular ejection fraction [LVEF] ≤0.35, randomized to exercise training and usual care vs. usual care alone, median follow-up 2.5 years), we performed risk modeling using Cox proportional hazards models and analyzed the relationship between baseline clinical factors and the primary composite endpoint of death or all-cause hospitalization and the secondary endpoint of all-cause death alone. Prognostic relationships for continuous variables were examined using restricted cubic spline functions, and key predictors were identified using a backward variable selection process and bootstrapping methods. For ease of use in clinical practice, point-based risk scores were developed from the risk models. Exercise duration on the baseline cardiopulmonary exercise (CPX) test was the most important predictor of both the primary endpoint and all-cause death. Additional important predictors for the primary endpoint risk model (in descending strength) were Kansas City Cardiomyopathy Questionnaire (KCCQ) symptom stability score, higher blood urea nitrogen (BUN), and male sex (all P <0.0001). Important additional predictors for the mortality risk model were higher BUN, male sex, and lower body mass index (BMI) (all P <0.0001).
Conclusions
Risk models using simple, readily obtainable clinical characteristics can provide important prognostic information in ambulatory patients with chronic HF with systolic dysfunction.
Clinical Trial Registration
URL: http:///www.clinicaltrials.gov. Unique identifier: NCT00047437.
doi:10.1161/CIRCHEARTFAILURE.111.963462
PMCID: PMC3692371  PMID: 22114101
heart failure; systolic dysfunction; risk score; risk model; exercise capacity
25.  Heart Rate Response to a Timed Walk & Cardiovascular Outcomes in Older Adults: The Cardiovascular Health Study 
Cardiology  2012;122(2):69-75.
OBJECTIVES
To determine the relationship between heart rate response during low-grade physical exertion (six-minute walk) with mortality and adverse cardiovascular outcomes in the elderly.
METHODS
Participants in the Cardiovascular Health Study, who completed a six-minute walk test, were included. We used delta heart rate (difference between post-walk heart rate and resting heart rate) as a measure of chronotropic response and examined its association with 1) all-cause mortality and 2) incident coronary heart disease (CHD) event, using multivariable Cox regression models.
RESULTS
We included 2224 participants (mean age 77±4 years; 60% women, 85% white). The average delta heart rate was 26 beats/min. Participants in the lowest tertile of delta heart rate (<20 beats/min) had higher risk-adjusted mortality (hazard ratio [HR] 1.18; 95% confidence interval [CI][1.00, 1.40]) and incident CHD (HR 1.37; 95% CI[1.05, 1.78]) compared to subjects in the highest tertile (≥30 beats/min), with a significant linear trend across tertiles (P for trend <0.05 for both outcomes). This relationship was not significant after adjustment for distance walked.
CONCLUSION
Impaired chronotropic response during six-minute walk test was associated with an increased risk of mortality and incident CHD among the elderly. This association was attenuated after adjusting for distance walked.
doi:10.1159/000338736
PMCID: PMC3516408  PMID: 22722364
coronary heart disease; exercise; heart rate; elderly

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