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1.  Heart Failure with Presereved Ejection Fraction: A Heterogenous Disorder with Multi-Factorial Pathophysiology 
doi:10.1016/j.jacc.2013.10.007
PMCID: PMC4283457  PMID: 24184240
cardiac biomarkers; diastolic heart failure; echocardiography; mechanics; systolic strain
2.  Chronotropy: The Cinderella of Heart Failure Pathophysiology and Management 
JACC. Heart failure  2013;1(3):267-269.
doi:10.1016/j.jchf.2013.03.009
PMCID: PMC4282140  PMID: 24621879
heart failure; heart rate; chronotropic incompentence; exercise; biomarkers
3.  Update on heart failure with preserved ejection fraction 
Heart failure with preserved ejection fraction (HFPEF) is the most common form of heart failure (HF) in older adults, and is increasing in prevalence as the population ages. Morbidity and long-term mortality in HFPEF are substantial and can be similar to HF with reduced ejection fraction (HFREF), yet HFPEF therapy remains empirical and treatment guidelines are based primarily on expert consensus. Neurohormonal blockade has revolutionized the management of HFREF, but trials in HFPEF based on this strategy have been disappointing to date. However, many recent studies have increased knowledge about HFPEF. The concept of HFPEF has evolved from a ‘cardio-centric’ model to a syndrome that may involve multiple cardiovascular and non-cardiovascular mechanisms. Emerging data highlight the importance of non-pharmacological management strategies and assessment of non-cardiovascular comorbidities. Animal models, epidemiological cohorts, and small human studies suggest that oxidative stress and inflammation contribute to HFPEF, potentially leading to development of new therapeutic targets.
doi:10.1007/s12170-013-0350-9
PMCID: PMC4028705  PMID: 24860638
diastolic heart failure; treatment; mechanisms; hypertension
4.  Effect of Endurance Exercise Training on Endothelial function and Arterial Stiffness in Older Patients with Heart Failure and Preserved Ejection Fraction: A Randomized, Controlled, Single-Blind Trial 
Objectives
To evaluate the effects of endurance exercise training (ET) on endothelial dependent flow-mediated arterial dilation (FMD) and carotid artery stiffness and their potential contributions to the training-related increase in peak exercise oxygen consumption (VO2) in older patients with heart failure with preserved ejection fraction (HFPEF).
Background
Elderly HFFEF patients have severely reduced peak VO2 which improves with ET, however the mechanisms of this improvement are unclear. FMD and arterial distensibility are critical components of the exercise response and are reduced with aging. However, it's unknown whether these improve with ET in elderly HFPEF or contribute to the training-related improvement in peak VO2.
Methods
63 HFPEF patients (70±7 years) were randomized to 16 weeks of ET (walking, arm and leg ergometry, n=32) or attention control (CT; n=31). Peak VO2, brachial artery FMD in response to cuff ischemia, carotid artery distensibility by high-resolution ultrasound, LV function, and QOL were measured at baseline and follow-up.
Results
ET increased peak VO2 (ET: 15.8±3.3 vs. CT: 13.8±3.1 ml/kg/min, p=0.0001) and QOL. However, brachial artery FMD (ET: 3.8±3.0% vs. CT: 4.3±3.5%, p=0.88), and carotid arterial distensibility (ET: 0.97±0.56 vs. CT: 1.07±0.34 × 10-3mm × mmHg-1 p=0.65) were unchanged. Resting LV systolic and diastolic function were unchanged by ET.
Conclusions
In elderly HFPEF patients, 16 weeks of ET improved peak VO2 without altering endothelial function or arterial stiffness. This suggests that other mechanisms, such as enhanced skeletal muscle perfusion and / or oxygen utilization, may be responsible for the ET-mediated increase in peak VO2 in older HFPEF patients.
doi:10.1016/j.jacc.2013.04.033
PMCID: PMC3740089  PMID: 23665370
Heart Failure; Preserved ejection fraction; exercise; aging
5.  Impaired Aerobic Capacity and Physical Functional Performance in Older Heart Failure Patients With Preserved Ejection Fraction: Role of Lean Body Mass 
Background.
Exercise intolerance is the primary chronic symptom in patients with heart failure and preserved ejection fraction (HFPEF), the most common form of heart failure in older persons, and can result from abnormalities in cardiac, vascular, and skeletal muscle, which can be further worsened by physical deconditioning. However, it is unknown whether skeletal muscle abnormalities contribute to exercise intolerance in HFPEF patients.
Methods.
This study evaluated lean body mass, peak exercise oxygen consumption (VO2), and the short physical performance battery in 60 older (69±7 years) HFPEF patients and 40 age-matched healthy controls.
Results.
In HFPEF versus healthy controls, peak percent total lean mass (60.1±0.8% vs. 66.6±1.0%, p < .0001) and leg lean mass (57.9±0.9% vs. 63.7±1.1%, p = .0001) were significantly reduced. Peak VO2 was severely reduced including when indexed to leg lean mass (79.3±18.5 vs. 104.3±20.4ml/kg/min, p < .0001). Peak VO2 was correlated with percent total (r = .51) and leg lean mass (.52, both p < .0001). The slope of the relationship of peak VO2 with percent leg lean mass was markedly reduced in HFPEF (11±5ml/min) versus healthy controls (36±5ml/min; p < .001). Short physical performance battery was reduced (9.9±1.4 vs. 11.3±0.8) and correlated with peak VO2 and total and leg lean mass (all p < .001).
Conclusion.
Older HFPEF patients have significantly reduced percent total and leg lean mass and physical functional performance compared with healthy controls. The markedly decreased peak VO2 indexed to lean body mass in HFPEF versus healthy controls suggests that abnormalities in skeletal muscle perfusion and/or metabolism contribute to the severe exercise intolerance in older HFPEF patients.
doi:10.1093/gerona/glt011
PMCID: PMC3712362  PMID: 23525477
Exercise; Cardiovascular; Functional performance; Physical function; Sarcopenia; Muscle
6.  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
7.  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
8.  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
9.  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
10.  Age Disparities in Heart Failure Research 
doi:10.1001/jama.2010.1592
PMCID: PMC3685493  PMID: 21045104
11.  Determinants of Exercise Intolerance in Elderly Heart Failure Patients with Preserved Ejection Fraction 
Objectives
To determine the mechanisms responsible for reduced aerobic capacity (peak VO2) in heart failure patients with preserved ejection fraction (HFPEF).
Background
HFPEF is the predominant form of HF in older persons. Exercise intolerance is the primary symptom among patients with HFPEF and a major determinant of reduced quality of life. In contrast to patients with HF and reduced EF, the mechanism of exercise intolerance in HFPEF is less well understood.
Methods
Left ventricular volumes (2D echocardiography), cardiac output (CO), VO2 and calculated arterial-venous oxygen content difference (A-VO2 Diff) were measured at rest and during incremental, exhaustive upright cycle exercise in 48 HFPEF patients (age 69±6 years) and 25 healthy age-matched controls (HC).
Results
In HFPEF compared to HC, VO2 was reduced at peak exercise (mean±SE: 14.3±0.5 vs. 20.4±0.6 mL·kg min−1; p<0.0001) and was associated with a reduced peak CO (6.3±0.2 vs. 7.6±0.2 L·min−1, p<0.0001) and A-VO2 Diff (17±0.4 vs. 19±0.4 ml·dl−1, p<0.0007). The strongest independent predictor of peak VO2 was the change in A-VO2 Diff from rest to peak exercise (A-VO2 Diff reserve) for both HFPEF (partial correlant 0.58, standardized β coefficient 0.66; p=0.0002) and HC (partial correlant 0.61, standardized β coefficient 0.41; p=0.005)
Conclusions
Both reduced CO and A-VO2 Diff contribute significantly to the severe exercise intolerance in elderly HFPEF patients. The finding that A-VO2 Diff reserve is an independent predictor of peak exercise VO2 suggests that peripheral, ‘non-cardiac’ factors are important contributors to exercise intolerance in these patients.
doi:10.1016/j.jacc.2011.02.055
PMCID: PMC3272542  PMID: 21737017
Exercise; Heart Failure; Aging
12.  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
13.  Exercise Training in Older Patients with Heart Failure and Preserved Ejection Fraction: A Randomized, Controlled, Single-Blind Trial 
Circulation. Heart failure  2010;3(6):659-667.
Background
HF with preserved left ventricular ejection fraction (HFPEF) is the most common form of HF in the older population. Exercise intolerance is the primary chronic symptom in HFPEF patients and is a strong determinant of their reduced quality of life (QOL). Exercise training (ET) improves exercise intolerance and QOL in HF patients with reduced ejection fraction. However, the effect of ET in HFPEF has not been examined in a randomized, controlled trial.
Methods and Results
This was a randomized, attention-controlled, single blind study of 16 weeks of medically supervised ET (3 days per week) on exercise intolerance and QOL in 53 elderly (mean age 70±6 yrs; range 60–82; 46 women, 7 men) patients with isolated HFPEF (EF ≥ 50%, and no significant coronary, valvular, or pulmonary disease). Attention controls received biweekly follow-up telephone calls. Forty-six patients completed the study (24 ET, 22 controls). Attendance at exercise sessions in the ET group was excellent (88%; range 64–100%). There were no trial-related adverse events. Peak exercise oxygen uptake, the primary outcome, increased significantly in the ET group compared to the control group (13.8±2.5 to 16.1±2.6 ml/kg/min, change 2.3±2.2 ml/kg/min vs. 12.8±2.6 to 12.5±3.4, change −0.3±2.1 ml/kg/min) (p=0.0002). There were significant improvements in peak power output, exercise time, 6 minute walk distance, and ventilatory anaerobic threshold (all p<0.002). There was improvement in the physical QOL score (p=0.03) but not the total score (p=0.11).
Conclusions
ET improves peak and submaximal exercise capacity in older patients with HFPEF.
doi:10.1161/CIRCHEARTFAILURE.110.958785
PMCID: PMC3065299  PMID: 20852060
heart failure; aging; exercise intolerance; exercise training
14.  A Randomized Double-Blind Trial of Enalapril in Older Patients With Heart Failure and Preserved Ejection Fraction 
Circulation. Heart failure  2010;3(4):477-485.
Background
Exercise intolerance is the primary symptom in older patients with heart failure and preserved ejection fraction (HFPEF); however, little is known regarding its mechanisms and therapy.
Methods and Results
Seventy-one stable elderly (70±1 years) patients (80% women) with compensated HFPEF and controlled blood pressure were randomized into a 12-month follow-up double-blind trial of enalapril 20 mg/d versus placebo. Assessments were peak exercise oxygen consumption; 6-minute walk test; Minnesota Living with HF Questionnaire; MRI; Doppler echocardiography; and vascular ultrasound. Compliance by pill count was excellent (94%). Twenty-five patients in the enalapril group versus 34 in the placebo group completed the 12-month follow-up. During follow-up, there was no difference in the primary outcome of peak exercise oxygen consumption (enalapril, 14.5±3.2 mL/kg/min; placebo, 14.3±3.4 mL/kg/min; P=0.99), or in 6-minute walk distance, aortic distensibility (the primary mechanistic outcome), left ventricle mass, or neurohormonal profile. The effect size of enalapril on peak exercise oxygen consumption was small (0.7%; 95% CI, 4.2% to 5.6%). There was a trend toward improved Minnesota Living with HF Questionnaire total score (P=0.07), a modest reduction in systolic blood pressure at peak exercise (P=0.02), and a marginal improvement in carotid arterial distensibility (P=0.04).
Conclusions
In stable, older patients with compensated HFPEF and controlled blood pressure, 12 months of enalapril did not improve exercise capacity or aortic distensibility. These data, combined with those from large clinical event trials, suggest that angiotensin inhibition does not substantially improve key long-term clinical outcomes in this group of patients. This finding contrasts sharply with observations in HF with reduced EF and highlights our incomplete understanding of this important and common disorder.
doi:10.1161/CIRCHEARTFAILURE.109.898916
PMCID: PMC2944779  PMID: 20516425
aging; exercise; heart failure; diastole; vasculature
15.  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
16.  EXERCISE INTOLERANCE 
Heart failure clinics  2008;4(1):99-115.
doi:10.1016/j.hfc.2007.12.002
PMCID: PMC2700357  PMID: 18313628
17.  Cardiac Rehabilitation Exercise and Self Care for Chronic Heart Failure 
JACC. Heart failure  2013;1(6):540-547.
Chronic heart failure (CHF) is highly prevalent in older individuals and a major cause of morbidity, mortality, hospitalizations and disability. Cardiac rehabilitation (CR) exercise training and CHF self-care counseling have each been shown to improve clinical status and clinical outcomes in CHF. Systematic reviews and meta-analyses of CR exercise training alone (without counseling) have demonstrated consistent improvements in CHF symptoms in addition to reductions of cardiac mortality and hospitalizations, although individual trials have been less conclusive of the latter two findings. The largest single trial, HF-ACTION, showed a reduction in the adjusted risk for the combined end point of all-cause mortality or hospitalization (HR: 0.89, 95% CI: 0.81-0.99; P=0.03). Quality of life and mental depression also improved. CHF-related counseling whether provided in isolation or in combination with CR exercise training improves clinical outcomes and reduces CHF-related hospitalizations We review current evidence on the benefits and risks of CR and self-care counseling in patients with CHF, provide recommendations for patient selection for third party payers, and discuss the role of CR in promoting self-care and behavioral changes.
doi:10.1016/j.jchf.2013.09.002
PMCID: PMC4271268  PMID: 24622007
Chronic Heart Failure; Cardiac Rehabilitation; Exercise Training; Self-Care; Counseling
18.  Secondary Prevention of Atherosclerotic Cardiovascular Disease in Older Adults: A Scientific Statement From the American Heart Association 
Circulation  2013;128(22):2422-2446.
doi:10.1161/01.cir.0000436752.99896.22
PMCID: PMC4171129  PMID: 24166575
secondary prevention; older age; atherosclerotic cardiovascular disease; coronary heart disease
19.  Biomarkers of Myocardial Stress and Fibrosis as Predictors of Mode of Death in Patients with Chronic Heart Failure 
JACC. Heart failure  2014;2(3):260-268.
Objective
To determine whether biomarkers of myocardial stress and fibrosis improve prediction of mode of death in patients with chronic heart failure.
Background
The two most common modes of death in patients with chronic heart failure are pump failure and sudden cardiac death. Prediction of mode of death may facilitate treatment decisions. The relationship between NT-proBNP, galectin-3, and ST2, biomarkers that reflect different pathogenic pathways in heart failure (myocardial stress and fibrosis), and mode of death is unknown.
Methods
HF-ACTION was a randomized controlled trial of exercise training vs. usual care in patients with chronic heart failure due to left ventricular systolic dysfunction (LVEF<35%). An independent clinical events committee prospectively adjudicated mode of death. NT-proBNP, galectin-3, and ST2 levels were assessed at baseline in 813 subjects. Associations between biomarkers and mode of death were assessed using cause-specific Cox-proportional hazards modeling, and interaction testing was used to measure differential association between biomarkers and pump failure versus sudden cardiac death. Discrimination and risk reclassification metrics were used to assess the added value of galectin-3 and ST2 in predicting mode of death risk beyond a clinical model that included NT-proBNP.
Results
After a median follow up of 2.5 years, there were 155 deaths: 49 from pump failure 42 from sudden cardiac death, and 64 from other causes. Elevations in all biomarkers were associated with increased risk of both pump failure and sudden cardiac death in both adjusted and unadjusted analyses. In each case, increases in the biomarker had a stronger association with pump failure than sudden cardiac death but this relationship was attenuated after adjustment for clinical risk factors. Clinical variables along with NT-proBNP levels were stronger predictors of pump failure (C statistic: 0.87) than sudden cardiac death (C statistic: 0.73). Addition of ST2 and galectin-3 led to improved net risk classification of 11% for sudden cardiac death, but not pump failure.
Conclusions
Clinical predictors along with NT-proBNP levels were strong predictors of pump failure risk, with insignificant incremental contributions of ST2 and galectin-3. Predictability of sudden cardiac death risk was less robust and enhanced by information provided by novel biomarkers.
doi:10.1016/j.jchf.2013.12.004
PMCID: PMC4224312  PMID: 24952693
heart failure; biomarker; prognosis; mode of death
20.  Soluble ST2 in Ambulatory Patients with Heart Failure: Association with Functional Capacity and Long-Term Outcomes 
Circulation. Heart failure  2013;6(6):1172-1179.
Background
ST2 is involved in cardioprotective signaling in the myocardium and has been identified as a potentially promising biomarker in HF. We evaluated ST2 levels and their association with functional capacity and long-term clinical outcomes in a cohort of ambulatory heart failure (HF) patients enrolled in the HF-ACTION study—a multicenter, randomized study of exercise training in HF.
Methods and Results
HF-ACTION randomized 2331 patients with left ventricular ejection fraction <0.35 and New York Heart Association class II–IV HF to either exercise training or usual care. ST2 was analyzed in a subset of 910 patients with evaluable plasma samples. Correlations and Cox models were used to assess the relationship among ST2, functional capacity, and long-term outcomes.
The median baseline ST2 level was 23.7 ng/mL (interquartile range, 18.6–31.8). ST2 was modestly associated with measures of functional capacity. In univariable analysis, ST2 was significantly associated with death or hospitalization (hazard ratio [HR], 1.48; p<0.0001), cardiovascular death or HF hospitalization (HR, 2.14; p<0.0001), and all-cause mortality (HR, 2.33; p<0.0001)(all HRs for log-base2 ng/mL). In multivariable models, ST2 remained independently associated with outcomes after adjustment for clinical variables and amino-terminal pro–B-type natriuretic peptide. However, ST2 did not add significantly to reclassification of risk as assessed by changes in the C statistic, net reclassification improvement, and integrated discrimination improvement.
Conclusions
ST2 was modestly associated with functional capacity and was significantly associated with outcomes in a well-treated cohort of ambulatory HF patients, although it did not significantly affect reclassification of risk.
doi:10.1161/CIRCHEARTFAILURE.113.000207
PMCID: PMC4188425  PMID: 24103327
heart failure; biomarker; prognosis
21.  Prevention of heart failure in older adults may require higher levels of physical activity than needed for other cardiovascular events 
International journal of cardiology  2013;168(3):1905-1909.
Background
Little is known if the levels of physical activity required for the prevention of incident heart failure (HF) and other cardiovascular events vary in community-dwelling older adults.
Methods
We studied 5503 Cardiovascular Health Study (CHS) participants, age ≥65 years, free of baseline HF. Weekly metabolic equivalent task-minutes (MET-minutes), estimated using baseline total leisure-time energy expenditure, were used to categorize participants into four physical activity groups: inactive (0 MET-minutes; n=489; reference), low (1–499; n=1458), medium (500–999; n=1086) and high (≥1000; n=2470).
Results
Participants had a mean (±SD) age of 73 (±6) years, 58% were women, and 15% African American. During 13 years of follow-up, centrally-adjudicated incident HF occurred in 26%, 23%, 20%, and 19% of participants with no, low, medium and high physical activity, respectively (trend p <0.001). Compared with inactive older adults, age-sex-race-adjusted hazard ratios (95% confidence intervals) for incident HF associated with low, medium and high physical activity were 0.87 (0.71–1.06; p=0.170), 0.68 (0.54–0.85; p=0.001) and 0.60 (0.49–0.74; p<0.001), respectively (trend p <0.001). Only high physical activity had significant independent association with lower risk of incident HF (HR, 0.79; 95% CI, 0.64–0.97; p=0.026). All levels of physical activity had significant independent association with lower risk of incident acute myocardial infarction (AMI), stroke and cardiovascular mortality.
Conclusion
In community-dwelling older adults, high level of physical activity was associated with lower risk of incident HF, but all levels of physical activity were associated with lower risk of incident AMI, stroke, and cardiovascular mortality.
doi:10.1016/j.ijcard.2012.12.053
PMCID: PMC4142221  PMID: 23380700
Physical activity; MET-minutes; Incident heart failure; Older adults
22.  Anemia and Associated Clinical Outcomes in Patients with Heart Failure Due to Reduced Left Ventricular Systolic Function 
Clinical cardiology  2013;36(10):611-620.
Background
Anemia is associated with decreased functional capacity, reduced quality of life, and worsened outcomes among patients with heart failure (HF) due to reduced left ventricular ejection fraction (HFREF). We sought to evaluate the independent effect of anemia on clinical outcomes among those with HFREF.
Methods
The HF-ACTION trial was a prospective, randomized trial of exercise therapy versus usual care in 2331 patients with HFREF. Patients with New York Heart Association class 2–4 HF and left ventricular ejection fractions of ≤ 35% were recruited. Hemoglobin (Hb) was measured up to one year prior to entry and was stratified by quintile. Anemia was defined as baseline Hb < 13 g/dl and <12 g/dl in men and women, respectively. Hb was assessed in two models; a global prediction model that had been previously developed and a modified model including variables associated with anemia and the studied outcomes.
Results
Hemoglobin was available at baseline in 1763 subjects (76% of total study population); their median age was 59.0 years, 73% were male, and 62% were Caucasian. The prevalence of anemia was 515/1763 (29%). Older age, female gender, African American race, diabetes, hypertension, and lower estimated glomerular filtration rates were all more frequent in lower Hb quintiles. Over a median follow-up of 30 months, the primary outcome of all-cause mortality or all-cause hospitalization occurred in 78% of those with anemia and 64% in those without, p<0.001. The secondary outcomes of all-cause mortality alone, cardiovascular mortality or cardiovascular hospitalization, and cardiovascular mortality or HF hospitalization occurred in 23 % vs 15%, 67% vs 54%, and 44 vs 29%, respectively, p<0.001. Heart failure hospitalizations occurred in 36% vs 22%, and urgent outpatient visits for HF exacerbations occurred in 67% and 55%, respectively, p<0.001. For the global model, there was an association observed for anemia and all-cause mortality or hospitalization, adjusted hazard ratio (HR)=1.15, 95% CI 1.01–1.32, p=0.04, but other outcomes were not significant at p<0.05. In the modified model, the adjusted HR for anemia and the primary outcome of all-cause mortality or all-cause hospitalization was 1.25, 95% CI 1.10–1.42, p<0.001. There were independent associations between anemia and all-cause death, HR=1.11, 95% CI 0.87–1.42, p=0.38; cardiovascular death or cardiovascular hospitalization, HR=1.16, 95% CI 1.01–1.33, p=0.035; and cardiovascular death and heart failure hospitalization, HR=1.27, 95% CI 1.06–1.51, p=0.008.
Conclusions
Anemia modestly is associated with increased rates of death, hospitalization, and HF exacerbation in patients with chronic HFREF. After adjusting for other important covariates, anemia is independently associated with an excess hazard for all-cause mortality and all-cause hospitalization. Anemia is also associated with combinations of cardiovascular death and cardiovascular/heart failure hospitalizations as composite endpoints.
doi:10.1002/clc.22181
PMCID: PMC4008125  PMID: 23929781
heart failure; chronic kidney disease; anemia; glomerular filtration rate; renal insufficiency; hospitalization; mortality
23.  Association between resting heart rate, chronotropic index, and long-term outcomes in patients with heart failure receiving β-blocker therapy: data from the HF-ACTION trial 
European Heart Journal  2013;34(29):2271-2280.
Aims
The aim of this study was to assess the association between resting heart rate (HR), chronotropic index (CI), and clinical outcomes in optimally treated chronic heart failure (HF) patients on β-blocker therapy.
Methods and results
We performed a sub-study in 1118 patients with HF and reduced ejection fraction (EF < 35%) included in the HF-ACTION trial. Patients in sinus rhythm who received a β-blocker and who performed with maximal effort on the exercise test were included. Chronotropic index was calculated as an index of HR reserve achieved, by using the equation (220-age) for estimating maximum HR. A sensitivity analysis using an equation developed for HF patients on β-blockers was also performed. Cox proportional hazards models were fit to assess the association between CI and clinical outcomes. Median (25th, 75th percentiles) follow-up was 32 (21, 44) months. In a multivariable model including resting HR and CI as continuous variables, neither was associated with the primary outcome of all-cause mortality or hospitalization. However, each 0.1 unit decrease in CI <0.6 was associated with 17% increased risk of all-cause mortality (hazard ratio 1.17, 95% confidence interval 1.01–1.36; P = 0.036), and 13% increased risk of cardiovascular mortality or HF hospitalization (hazard ratio 1.13, 1.02–1.26; P = 0.025). Overall, 666 of 1118 (60%) patients had a CI <0.6. Chronotropic index did not retain statistical significance when dichotomized at a value of ≤0.62.
Conclusion
In HF patients receiving optimal medical therapy, a decrease in CI <0.6 was associated with adverse clinical outcomes. Obtaining an optimal HR response to exercise, even in patients receiving optimal β-blocker therapy, may be a therapeutic target in the HF population.
doi:10.1093/eurheartj/ehs433
PMCID: PMC3858021  PMID: 23315907
Heart rate; Heart rate reserve; Chronotropic incompetence; Chronotropic index; Chronic heart failure
24.  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
25.  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

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