Low Fitness in Midlife: A Novel Therapeutic Target for Heart Failure with Preserved Ejection Fraction Prevention

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Low Fitness in Midlife: A Novel Therapeutic Target for Heart Failure with Preserved Ejection Fraction Prevention Ambarish Pandeya , Douglas Dardenb , Jarett D. Berrya, c,⁎ a

Division of Cardiology, Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, Texas Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, Texas c Department of Clinical Sciences, University of Texas Southwestern Medical Center, Dallas, Texas b

A R T I C LE I N F O

AB ST R A C T

Keywords:

Heart failure (HF) with preserved ejection fraction (HFpEF) is common and recalcitrant to

Cardiorespiratory fitness

any medical therapy, highlighting the need for novel strategies focused on its prevention.

Exercise training

Recent studies have shown that low cardiorespiratory fitness (CRF) in middle age identifies

Heart failure with preserved

a subgroup of individuals at particularly high risk for HF, particularly HFpEF. These findings

ejection fraction

suggest that low CRF in middle age represents an upstream marker for late-life HFpEF. Furthermore, evidence from recent epidemiological studies suggests that low CRF associated risk for HFpEF appears to be modifiable with improvement in CRF. The primary objective of this review is to provide an overview of the potential mechanisms through which exercise training and improvement in CRF may protect against the transition from a low fit stage to clinical HFpEF among at-risk sedentary, middle-age adults. © 2015 Elsevier Inc. All rights reserved.

Heart failure (HF) affects approximately 5.8 million people and accounts for an estimated annual healthcare cost of $34.8 billion.1 Moreover, while the incidence of atherosclerotic cardiovascular (CV) disease (CVD) has decreased steadily over the past 40 years, HF prevalence has remained largely unchanged.1–3 Additionally, HF with preserved ejection fraction/EF (HFpEF) is common and represents approximately 50% of HF admissions in the population.4 In contrast to HF with reduced EF (HFrEF), numerous therapies have failed in large randomized trials to mitigate the unfavorable natural history of HFpEF.5–7 Because HFpEF has proven to be recalcitrant to therapy once it occurs, the focus must be shifted to prevention. However, in order to prevent HFpEF, a more comprehensive

understanding of the natural history, pathophysiology, and targets for prevention are required.

What is HFpEF? HFPEF is a clinical syndrome of HF whereby systolic function, determined by the EF is grossly normal (i.e. > 45%). It is strongly associated with age (mean age > 74 years) and hypertension (HTN; 55%–65%) and is more common in women than in men (55%–65% women).2–4 Over the last several decades, it has become apparent that HFpEF is increasing in prevalence and now accounts for more

Statement of Conflict of Interest: see page 91. ⁎ Address reprint requests to Jarett D. Berry, MD, MS, Associate Professor of Medicine, Division of Cardiology, University of Texas Southwestern Medical Center, 5323 Harry Hines Blvd, Dallas, TX 75390-9047. E-mail address: [email protected] (J.D. Berry). http://dx.doi.org/10.1016/j.pcad.2015.05.007 0033-0620/© 2015 Elsevier Inc. All rights reserved.

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Abbreviations and Acronyms AMI = acute myocardial infarction CCLS = Cooper Center for Longitudinal Studies CRF = cardiorespiratory fitness CV = cardiovascular

than half of all HF cases. Furthermore, the mortality rate is similar in HFpEF and HFrEF.2,3

The failure of HFpEF treatment

CVD = cardiovascular disease To date, multiple largescale clinical trials have failed to reach their DM = diabetes mellitus primary outcome in EF = ejection fraction the treatment of patients with established ET = exercise training HFpEF (I-PRESERVE, HF = heart failure CHARM-Preserved, and TOPCAT).5,6,8 While there HFpEF = heart failure with are differences across preserved ejection fraction these trials regarding HFrEF = heart failure with patient characteristics, reduced ejection fraction inclusion criteria, and HTN = hypertension pharmacologic strategy, the consistent findLV = left ventricle or ventricular ing from these trials LVH = left ventricular hypertrophy has been that antagonism of the renin–anMETs = metabolic equivalents giotensin–aldosterone MetS = metabolic syndrome pathway has not modified the natural histoMI = myocardial infarction ry of HFpEF in the way PA = physical activity that has been observed with HFrEF. The failure of these trials, particularly the failure of aldosterone antagonism in TOPCAT, suggests fundamental challenges to the current HFpEF paradigm. In this review, we suggest that HFpEF reflects the natural history of low cardiorespiratory fitness (CRF) across the lifespan. We also discuss the potential role of exercise training (ET) in modifying the progression from a low fit state to clinical HFpEF in sedentary individuals. DD = diastolic dysfunction

Low CRF in middle age: a risk for long-term HF The CV benefits of physical activity (PA) have been known for decades, with numerous studies demonstrating strong associations between higher PA and a reduced risk for the development of established CVD risk factors, such as diabetes mellitus (DM), HTN, and obesity/weight gain.9 Large-scale, observational cohort-studies have also shown consistently that higher self-reported PA is associated with a lower rate of adverse CV outcomes.10–12 More recently, these findings have been extended to HF, with observational cohort studies demonstrating that higher levels of self-reported PA are associated with lower risk for HF events.13,14 Furthermore, in a dose–response meta-analysis of such epidemiological studies we observed a consistent dose dependent inverse association between self-reported PA levels and risk for HF.15

Exercise capacity or CRF, an objective measure of peak aerobic capacity determined by maximal exercise test, is a stronger predictor of risk for CVD events as compared with PA.10,16 A single measurement of CRF in midlife is strongly associated with lifetime risk for CVD mortality decades later.10,17 In a recent study from Cooper Center for Longitudinal study (CCLS), we observed that higher levels of CRF in mid-life are also protective against future risk for non-fatal CVD events, such as myocardial infraction (MI) and HF hospitalization.18 A 1-unit greater CRF level in metabolic equivalents (METs) achieved in midlife was associated with ≈20% lower risk for HF hospitalization after the age of 65 years but only 10% lower risk for acute MI (AMI) in men and no association in women (Fig 1). These findings suggest that higher CRF levels are more protective against risk for HF than for AMI.18 Similarly, Khan et al.19 have also reported a dose-dependent inverse association between CRF and HF risk in a Finnish cohort of middle-aged men. Taken together, these studies highlight the potential role of low CRF in healthy, middle-aged adults as a significant risk factor for HF.

Low CRF is an early stage marker for HFpEF A recent follow up study from the Framingham Heart Study demonstrated that the inverse association between higher levels of PA and HF is consistent for HFpEF but not HFrEF, suggesting that low PA and CRF levels may preferentially predispose to an increased risk for HFpEF over HFrEF at a later age.20 This notion is further supported by recent work from our group and others that have shown notable similarities in phenotypic characteristics associated with low CRF and HFpEF. Diastolic dysfunction (DD) and abnormal left ventricular (LV) remodeling represent important intermediate phenotypes in the natural history of symptomatic HFpEF.21 In a cross sectional analysis of healthy participants from CCLS, we observed a significant inverse association between CRF levels and prevalence of DD and abnormal concentric remodeling (see Fig 2).22 Along these lines, mechanistic studies by Arbab-Zadeh et al.23 have demonstrated an increased end-diastolic LV ventricular stiffness among participants with sedentary lifestyle and low CRF, similar to that observed among patients with HFpEF. The phenotypic similarities among low fit and HFpEF patients have also been reported at the vascular level, with increased arterial stiffness and abnormal vascular ventricular coupling among low fit participants similar to what is observed among HFpEF patients.24,25 Taken together, these findings suggest that low CRF identifies participants with early stage impairment in CV structure and function who are at increased risk for development of clinical HFpEF with progressive impairment in functional CV reserve.

Low CRF and risk for HFpEF: is it modifiable? Recent studies have reported a significant association between changes in PA and CRF levels and risk for HF. In a Framingham heart study analysis, the investigators observed a significant increase in risk for HF among participants who

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Fig 2 – Prevalence of diastolic dysfunction among CCLS male participants stratified by their mid-life fitness levels (adapted from Brinker et al.22 JACC: Heart Failure 2014).

across multiple intermediate phenotypes. It starts with development of risk factors, such as HTN and obesity in the setting of normal cardiac structure and function (stage A) and is followed by progressive subclinical cardiac dysfunction characterized by hypertrophy, remodeling, and DD/stiffening (stage B) and finally transitions to symptomatic, clinical HFpEF (stage C).27 Transition through these stages involves progressive impairment in functional CV reserve such that stage C patients have greater CV reserve limitation than stage B patients, who in turn display more reserve limitation than stage A patients. Evidence from epidemiological as well as ET studies suggests

Fig 1 – (A) Heart Failure hospitalization free survival after age of 65 among male participants of the Cooper Center For Longitudinal Study stratified by their mid-life fitness levels. (B) Myocardial infarction free hospitalization free survival after age of 65 among male participants of the Cooper Center for Longitudinal Study stratified by their mid-life fitness levels (adapted from Berry et al.18 Circulation: Heart Failure 2013).

had a decline in their PA levels between two consecutive examinations.20 Similarly, in a recent study from the CCLS, we have demonstrated that 1 MET improvement in CRF over a period of 4.4 year follow-up was associated with up to 17% reduction in HF risk at a later age26 (Fig 3). Taken together, these observational study findings suggest that low CRF associated risk of HF may be modifiable and ET in sedentary middle age individuals could be an effective strategy to reduce the burden of HF in later life.

ET for HFPEF prevention: how does it work? The natural history of HFPEF among sedentary adults is not fully understood but can best be characterized as a transition

Fig 3 – Heart failure hospitalization rates among CCLS male participants stratified by their midlife fitness change categories. Fitness change categories are determined based on transition of participants from one fitness group to another between their initial and follow up examinations. Low fit represents participants in the lowest age and sex adjusted fitness quintile (Q1) at baseline and/or follow-up. Not low fit group represents participants in the age and sex adjusted fitness quintiles Q2–Q5 (adapted from Pandey et al.26 AHJ 2015).

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that improvement in CRF and ET can increase the CV reserve significantly at each stage of transition and thus, play an important role in delaying the progression of HFpEF.

pathway through which higher CRF levels in middle age may confer a lower risk for HF hospitalization decades later in older age is at least in part independent of the development of future established HF risk factors.26

ET in stage A HF patients: impact on risk factor profile ET in stage B HF patients: impact on LV structure and function One potential mechanism through which low CRF and physical inactivity might be associated with long-term risk for HFpEF is through its effects on CV and non-CV risk factors. Low CRF is associated with increased downstream prevalence of CVD risk factors such as, HTN, diabetes, as well as non-cardiac co-morbidities, which in turn predisposes to a greater risk for HFpEF in later life.26,28 Several longitudinal observational studies have assessed the impact of change in CRF over time on development of CVD risk factors. In a study from the CCLS, Lee et al.29 demonstrated that maintaining or improving CRF over time was associated with lower risk of developing HTN, metabolic syndrome (MetS), and hypercholesterolemia among healthy adults. Similarly, findings from the CARDIA study showed that improving CRF was associated with a lower risk for developing type 2 DM and MetS.30 These observations are also supported by several ET trials that have demonstrated a significant improvement in risk factors such as HTN and obesity among sedentary participants who undergo supervised aerobic ET.31 Taken together, these findings suggest that ET and improvement in CRF levels have a favorable impact on the CVD risk profile among sedentary participants. This may delay the transition from stage A to stage B HF and thus, reduce the risk for HFpEF among at risk patients. However, in a recent CCLS-Medicare follow-up study, we observed that lower midlife CRF was associated with a higher risk for HF hospitalization independent of and across all levels of chronic disease burden (see Fig 4), suggesting that the

Another potential mechanism through which CRF in middle age might lower HFpEF risk in later life is through more direct effects of PA and ET on cardiac structure and function. In fact, ET trials among high-risk individuals with concentric LV hypertrophy (LVH) and poorly controlled HTN have demonstrated a significant reduction in LV mass and wall thickness with supervised aerobic ET.32 Similarly, 1 year of vigorous ET has been shown to significantly increase CRF, induce physiological LV remodeling, and improve diastolic function among sedentary but otherwise seniors as well as younger adults.33,34 Moreover, LV end diastolic stiffness improved significantly with one year of intensive endurance ET among younger participants but not in seniors.33,34 Taken together, findings from these studies suggest that ET, preferably at an early age, has direct and favorable effects on LV compliance and diastolic function that may delay the development of clinical HFpEF in at risk patients.

ET in stage B HF patients: impact on myocardial strain pattern Recently, there has been increasing interest in characterizing the contributions of subtle abnormalities in systolic function toward pathogenesis and progression of HFpEF with studies identifying significant impairment in peak systolic strain patterns among HFpEF patients.35 ET trials among patients with DM and MetS, who are at increased risk for HFPEF, have demonstrated a significant improvement in CRF as well as peak systolic strain pattern, particularly with high intensity ET.36 These findings suggest that ET may modify HFpEF risk by improving the systolic strain patterns among sedentary at risk participants.

ET in stage B HF patients: impact on vascular stiffness Arterial stiffness, a measure of LV afterload, increases with sedentary aging and is associated with abnormalities in dynamic arterial ventricular coupling.37 Training studies have demonstrated a significant reduction in effective arterial stiffness as well as arterial ventricular coupling with ET.38,39 These improvements in arterial stiffness and arterial ventricular coupling may play a role in augmenting the stroke volume during ET and, thereby, delay the development of clinical HFpEF among these participants.

ET for HFpEF prevention: how much is enough? Fig 4 – Prevalence of HF among participant groups according to fitness levels and increasing number of comorbidities at age older than 65 years. Multivariable adjusted hazard ratio for heart failure hospitalization associated with total comorbidity burden at older than 65 years (defined as a continuous variable) is 1.25 (1.16–1.35) per co-morbidity (adapted from Pandey et al.26 AHJ 2015).

While several epidemiological studies have reported that leisure time PA and recreational ET is associated with significant reduction in HF risk, the dose of ET required to significantly reduce HF risk remains unknown. In a recent dose response meta-analysis we observed that participants engaging in guideline recommended minimum levels of PA (500 MET-min/week,

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2008 US Federal Guidelines) had only modest (<10%) reductions in HF risk and doses of PA in excess of current guideline recommended levels are required to significantly reduce HF risk (19% at 1000 MET-min/week and 34% at 2000 MET-min/week).15 These findings are further supported by the recently published mechanistic data by Bhella et al.40 who demonstrated that lifelong moderate to high dose ET can significantly prevent most of the decrease in LV compliance and distensibility observed with sedentary aging. Recent ET studies have also explored the relationship between supervised ET dose and associated CV response. Okazaki et al. 41 demonstrated that the relationship between the ET dose and improvements in blood pressure or reflex control of heart rate does not follow a linear relationship and may have U-shaped relation with a maximal response at moderate amounts of ET. In contrast, findings from the DREW study suggest that higher dose of ET is associated with greater improvements in CRF, blood pressure control and visceral adiposity. 31 Apart from dose, the intensity of ET associated with optimum CV benefit remains uncertain. There is a substantial body of evidence suggesting that higher intensity ET—compared to moderate intensity ET—is associated with lower risk for CV morbidity and mortality.42–44 In addition, ET trials have reported nearly a two-fold greater improvement in peak oxygen consumption with high intensity aerobic interval ET compared to moderate intensity continuous ET.45–48 Furthermore, a recent study observed that compared with moderate intensity continuous ET, high intensity aerobic interval ET was associated with a significant improvement in diastolic function, systolic strain pattern and CRF in sedentary patients with type-2 DM who are at an increased risk for future HFpEF.36 Taken together, these data suggest that high intensity aerobic interval ET may represent a more effective ET strategy for HFpEF prevention.

ET prescription for HFpEF prevention: does one size fit all? Prior studies have observed a substantial amount of variability in the change in CRF in response to supervised ET. 49–51 In a recent sub-analysis from the DREW study, we reported that approximately 30% of obese, HTN, sedentary postmenopausal women, who are at increased risk for HFpEF, experienced no improvement in CRF after 6 months of moderate intensity ET.52 We also observed that presence of LVH and adverse LV remodeling were independent predictors of non-response to moderate intensity ET.52 These findings have important implications for ET programs implemented among sedentary middle-aged adults to prevent HFpEF. First, it highlights the importance of early initiation of ET interventions in at risk participants before development of significant abnormalities in LV structure and function. Second, it highlights the need for more targeted, personalized interventions with higher intensity and/or dose of ET, or using specific modalities, such as a combination of resistance and endurance ET, to improve CRRF among at risk participants with underlying LVH and adverse remodeling, which puts them at highest risk for

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HFpEF as well as non-response to conventional moderate intensity ET.

ET in patients with clinical HFpEF: is it too late for ET? Apart from its potential role as a novel and effective tool for HFpEF prevention, ET can also be used as a therapeutic strategy for management of patients with established HFpEF. In a recent meta-analysis, we demonstrated that ET is associated with significant improvements in CRF and quality of life among HFpEF patients.53 Furthermore, we did not observe any significant improvement in LV diastolic function with ET among these patients. Moreover, ET in HFpEF patients has not been associated with an improvement in cardiac output or measures of LV afterload (arterial stiffness).54–56 Taken together, the available literature suggests that ET may improve exercise tolerance through peripheral mechanisms leading to an improved oxygen extraction in the active skeletal muscles.54,56 This is in contrast to the favorable effects of ET on LV structure, function and afterload that are reported among sedentary but otherwise healthy participants.32–34,36,39

Conclusion Low CRF is an independent and modifiable risk factor for HF. Furthermore, findings from recent studies done by our group and others suggest that low CRF is more strongly associated with a greater increase in risk for HFpEF as compared with HFrEF, and ET is an effective tool for improving CRF among sedentary low fit adults and is associated with favorable changes in cardiac structure and function that may delay progression from a low fit state to clinical HFpEF. Future randomized, controlled trials are needed to better evaluate the role of ET in prevention and treatment of HFpEF.

Disclosures None.

Statement of conflict of interest None.

Funding Sources Dr. Berry receives funding from (1) the Dedman Family Scholar in Clinical Care endowment at University of Texas Southwestern Medical Center and (2) grant 14SFRN20740000 from the American Heart Association Prevention Network. The corresponding author had full access to all data in the study and had final responsibility for the decision to submit for publication. All authors have read and agree to the manuscript as written.

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REFERENCES

1. Roger VL, Go AS, Lloyd-Jones DM, et al. Heart disease and stroke statistics–2012 update: a report from the American Heart Association. Circulation. 2012;125:e2-e220. 2. Owan TE, Hodge DO, Herges RM, Jacobsen SJ, Roger VL, Redfield MM. Trends in prevalence and outcome of heart failure with preserved ejection fraction. N Engl J Med. 2006;355: 251-259. 3. Bhatia RS, Tu JV, Lee DS, et al. Outcome of heart failure with preserved ejection fraction in a population-based study. N Engl J Med. 2006;355:260-269. 4. Dhingra A, Garg A, Kaur S, et al. Epidemiology of heart failure with preserved ejection fraction. Curr Heart Fail Rep. 2014;11: 354-365. 5. Bergstrom A, Andersson B, Edner M, Nylander E, Persson H, Dahlstrom U. Effect of carvedilol on diastolic function in patients with diastolic heart failure and preserved systolic function. Results of the Swedish Doppler-echocardiographic study (SWEDIC). Eur J Heart Fail. 2004;6:453-461. 6. Massie BM, Carson PE, McMurray JJ, et al. Irbesartan in patients with heart failure and preserved ejection fraction. N Engl J Med. 2008;359:2456-2467. 7. Pitt B, Pfeffer MA, Assmann SF, et al. Spironolactone for heart failure with preserved ejection fraction. N Engl J Med. 2014;370: 1383-1392. 8. Yusuf S, Pfeffer MA, Swedberg K, et al. Effects of candesartan in patients with chronic heart failure and preserved left-ventricular ejection fraction: the CHARM-Preserved Trial. Lancet. 2003;362:777-781. 9. Haskell WL, Lee IM, Pate RR, et al. Physical activity and public health: updated recommendation for adults from the American College of Sports Medicine and the American Heart Association. Circulation. 2007;116:1081-1093. 10. Berry JD, Willis B, Gupta S, et al. Lifetime risks for cardiovascular disease mortality by cardiorespiratory fitness levels measured at ages 45, 55, and 65 years in men. The Cooper Center Longitudinal Study. J Am Coll Cardiol. 2011;57:1604-1610. 11. Manson JE, Greenland P, LaCroix AZ, et al. Walking compared with vigorous exercise for the prevention of cardiovascular events in women. N Engl J Med. 2002;347:716-725. 12. Paffenbarger Jr RS, Hyde RT, Wing AL, Hsieh CC. Physical activity, all-cause mortality, and longevity of college alumni. N Engl J Med. 1986;314:605-613. 13. Djousse L, Driver JA, Gaziano JM. Relation between modifiable lifestyle factors and lifetime risk of heart failure. JAMA. 2009;302:394-400. 14. Kenchaiah S, Sesso HD, Gaziano JM. Body mass index and vigorous physical activity and the risk of heart failure among men. Circulation. 2009;119:44-52. 15. Pandey A, Garg S, Khunger M, et al. Dose response relationship between physical activity and risk of heart failure: a meta-analysis. Circulation. 2015. [EPI Lifestyle Conference supplement:MP02]. 16. Wang CY, Haskell WL, Farrell SW, et al. Cardiorespiratory fitness levels among US adults 20-49 years of age: findings from the 1999–2004 National Health and Nutrition Examination Survey. Am J Epidemiol. 2010;171:426-435. 17. Gupta S, Rohatgi A, Ayers CR, et al. Cardiorespiratory fitness and classification of risk of cardiovascular disease mortality. Circulation. 2011;123:1377-1383. 18. Berry JD, Pandey A, Gao A, et al. Physical fitness and risk for heart failure and coronary artery disease. Circ Heart Fail. 2013;6:627-634. 19. Khan H, Kunutsor S, Rauramaa R, et al. Cardiorespiratory fitness and risk of heart failure: a population-based follow-up study. Eur J Heart Fail. 2014;16:180-188.

20. Kraigher-Krainer E, Lyass A, Massaro JM, et al. Association of physical activity and heart failure with preserved vs. reduced ejection fraction in the elderly: the Framingham Heart Study. Eur J Heart Fail. 2013;15:742-746. 21. Lam CS, Roger VL, Rodeheffer RJ, et al. Cardiac structure and ventricular-vascular function in persons with heart failure and preserved ejection fraction from Olmsted County, Minnesota. Circulation. 2007;115:1982-1990. 22. Brinker SK, Pandey A, Ayers CR, et al. Association of cardiorespiratory fitness with left ventricular remodeling and diastolic function: the Cooper Center Longitudinal Study. JACC Heart Fail. 2014;2:238-246. 23. Arbab-Zadeh A, Dijk E, Prasad A, et al. Effect of aging and physical activity on left ventricular compliance. Circulation. 2004;110:1799-1805. 24. Tanaka H, Dinenno FA, Monahan KD, Clevenger CM, DeSouza CA, Seals DR. Aging, habitual exercise, and dynamic arterial compliance. Circulation. 2000;102:1270-1275. 25. Vaitkevicius PV, Fleg JL, Engel JH, et al. Effects of age and aerobic capacity on arterial stiffness in healthy adults. Circulation. 1993;88:1456-1462. 26. Pandey A, Patel M, Gao A, et al. Changes in mid-life fitness predicts heart failure risk at a later age independent of interval development of cardiac and noncardiac risk factors: the Cooper Center Longitudinal Study. Am Heart J. 2015;169: 290-297. 27. Borlaug BA. Fatness, fitness, stiffness, and age: how does it lead to heart failure? JACC Heart Fail. 2014;2:247-249. 28. Lam CS, Lyass A, Kraigher-Krainer E, et al. Cardiac dysfunction and noncardiac dysfunction as precursors of heart failure with reduced and preserved ejection fraction in the community. Circulation. 2011;124:24-30. 29. Lee DC, Sui X, Church TS, Lavie CJ, Jackson AS, Blair SN. Changes in fitness and fatness on the development of cardiovascular disease risk factors hypertension, metabolic syndrome, and hypercholesterolemia. J Am Coll Cardiol. 2012;59:665-672. 30. Carnethon MR, Sternfeld B, Schreiner PJ, et al. Association of 20-year changes in cardiorespiratory fitness with incident type 2 diabetes: the coronary artery risk development in young adults (CARDIA) fitness study. Diabetes Care. 2009;32: 1284-1288. 31. Church TS, Earnest CP, Skinner JS, Blair SN. Effects of different doses of physical activity on cardiorespiratory fitness among sedentary, overweight or obese postmenopausal women with elevated blood pressure: a randomized controlled trial. JAMA. 2007;297:2081-2091. 32. Kokkinos PF, Narayan P, Colleran JA, et al. Effects of regular exercise on blood pressure and left ventricular hypertrophy in African-American men with severe hypertension. N Engl J Med. 1995;333:1462-1467. 33. Arbab-Zadeh A, Perhonen M, Howden E, et al. Cardiac remodeling in response to 1 year of intensive endurance training. Circulation. 2014;130:2152-2161. 34. Fujimoto N, Prasad A, Hastings JL, et al. Cardiovascular effects of 1 year of progressive and vigorous exercise training in previously sedentary individuals older than 65 years of age. Circulation. 2010;122:1797-1805. 35. Kraigher-Krainer E, Shah AM, Gupta DK, et al. Impaired systolic function by strain imaging in heart failure with preserved ejection fraction. J Am Coll Cardiol. 2014;63: 447-456. 36. Hollekim-Strand SM, Bjorgaas MR, Albrektsen G, Tjonna AE, Wisloff U, Ingul CB. High-intensity interval exercise effectively improves cardiac function in patients with type 2 diabetes mellitus and diastolic dysfunction: a randomized controlled trial. J Am Coll Cardiol. 2014;64:1758-1760.

P R O G RE S S I N CA RDI O V A S CU L A R D I SE A S E S 5 8 ( 2 0 15 ) 8 7–9 3

37. Redfield MM, Jacobsen SJ, Borlaug BA, Rodeheffer RJ, Kass DA. Age- and gender-related ventricular-vascular stiffening: a community-based study. Circulation. 2005;112:2254-2262. 38. Fournier SB, Donley DA, Bonner DE, Devallance E, Olfert IM, Chantler PD. Improved arterial-ventricular coupling in metabolic syndrome after exercise training: a pilot study. Med Sci Sports Exerc. 2015;47:2-11. 39. Montero D, Roche E, Martinez-Rodriguez A. The impact of aerobic exercise training on arterial stiffness in pre- and hypertensive subjects: a systematic review and meta-analysis. Int J Cardiol. 2014;173:361-368. 40. Bhella PS, Hastings JL, Fujimoto N, et al. Impact of lifelong exercise “dose” on left ventricular compliance and distensibility. J Am Coll Cardiol. 2014;64:1257-1266. 41. Okazaki K, Iwasaki K, Prasad A, et al. Dose-response relationship of endurance training for autonomic circulatory control in healthy seniors. J Appl Physiol. 2005;99:1041-1049. 42. Lee IM, Sesso HD, Oguma Y, Paffenbarger Jr RS. Relative intensity of physical activity and risk of coronary heart disease. Circulation. 2003;107:1110-1116. 43. Schnohr P, Marott JL, Jensen JS, Jensen GB. Intensity versus duration of cycling, impact on all-cause and coronary heart disease mortality: the Copenhagen City Heart Study. Eur J Prev Cardiol. 2012;19:73-80. 44. Tanasescu M, Leitzmann MF, Rimm EB, Willett WC, Stampfer MJ, Hu FB. Exercise type and intensity in relation to coronary heart disease in men. JAMA. 2002;288:1994-2000. 45. Ismail H, McFarlane JR, Nojoumian AH, Dieberg G, Smart NA. Clinical outcomes and cardiovascular responses to different exercise training intensities in patients with heart failure: a systematic review and meta-analysis. JACC Heart Fail. 2013;1: 514-522. 46. Nybo L, Sundstrup E, Jakobsen MD, et al. High-intensity training versus traditional exercise interventions for promoting health. Med Sci Sports Exerc. 2010;42:1951-1958. 47. Rognmo O, Hetland E, Helgerud J, Hoff J, Slordahl SA. High intensity aerobic interval exercise is superior to moderate intensity exercise for increasing aerobic capacity in patients

48.

49.

50.

51.

52.

53.

54.

55.

56.

93

with coronary artery disease. Eur J Cardiovasc Prev Rehabil. 2004;11:216-222. Wisloff U, Stoylen A, Loennechen JP, et al. Superior cardiovascular effect of aerobic interval training versus moderate continuous training in heart failure patients: a randomized study. Circulation. 2007;115:3086-3094. Bouchard C, Rankinen T. Individual differences in response to regular physical activity. Med Sci Sports Exerc. 2001;33: S446-S451. [discussion S452-3]. Hautala AJ, Makikallio TH, Kiviniemi A, et al. Cardiovascular autonomic function correlates with the response to aerobic training in healthy sedentary subjects. Am J Physiol Heart Circ Physiol. 2003;285:H1747-H1752. Skinner JS, Jaskolski A, Jaskolska A, et al. Age, sex, race, initial fitness, and response to training: the HERITAGE Family Study. J Appl Physiol. 2001;90:1770-1776. Pandey A, Ayers C, Blair SN, et al. Cardiac determinants of heterogeneity in fitness change in response to moderate intensity aerobic exercise training: the DREW study. J Am Coll Cardiol. 2015;65:1057-1058. Pandey A, Parashar A, Kumbhani DJ, et al. Exercise training in patients with heart failure and preserved ejection fraction: meta-analysis of randomized control trials. Circ Heart Fail. 2015;8:33-40. Kitzman DW, Brubaker PH, Herrington DM, et al. 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. J Am Coll Cardiol. 2013;62:584-592. Fujimoto N, Prasad A, Hastings JL, et al. Cardiovascular effects of 1 year of progressive endurance exercise training in patients with heart failure with preserved ejection fraction. Am Heart J. 2012;164:869-877. Haykowsky MJ, Brubaker PH, Stewart KP, Morgan TM, Eggebeen J, Kitzman DW. Effect of endurance training on the determinants of peak exercise oxygen consumption in elderly patients with stable compensated heart failure and preserved ejection fraction. J Am Coll Cardiol. 2012;60:120-128.