mechanisms of exercise intolerance in heart failure with

Circulation Journal Vol.78, January 2014

20 BORLAUG BACirculation JournalOfficial Journal of the Japanese Circulation Societyhttp://www.j-circ.or.jp

eart failure (HF) represents an enormous worldwide health problem, afflicting 6 million Americans, 15 million Europeans, and quite possibly over 35 mil-

lion Asians.1 Half of patients with HF have preserved ejection fraction (HFpEF), and with current secular trends in the age-distribution and comorbidity profiles of the adult population, the prevalence of HFpEF is growing relative to HF with re-duced EF (HFrEF) by 1% per year.2 Exercise intolerance is the cornerstone clinical expression of HF, and exercise capacity is similarly impaired in HFpEF and HFrEF.3 However, in con-trast to HFrEF, there is no proven effective treatment for HFpEF.4 The reasons for this disparity are manifold, but among them, incomplete understanding of the pathophysiol-ogy looms large. Initial mechanistic paradigms focused on left ventricular (LV) diastolic dysfunction as the dominant mecha-nism driving HFpEF,5 but numerous recent studies have iden-tified abnormalities in LV systolic function, right ventricular (RV) function, chronotropic incompetence, abnormal system-ic and pulmonary vasodilation, endothelial dysfunction, and abnormalities in the periphery.6–24 To make progress in the treatment of HFpEF, these different mechanisms require fur-ther study. An important paradigm regarding HFpEF that has emerged in recent years is that the presence of normal cardio-vascular homeostasis at rest in no way guarantees preservation of reserve capacity under physiologic stressors, the most com-mon of which in daily life is physical exercise. Accordingly, detailed understanding the mechanisms of exercise reserve intolerance is critical to appreciating the complex pathophysi-ology of HFpEF. In this review, I shall review the roles of cardiac, vascular, and noncardiovascular systems in limiting exercise capacity in patients with HFpEF.

Review of Basic HemodynamicsCardiovascular hemodynamics, reviewed in detail elsewhere,25,26 are fundamentally dictated by cardiac-specific properties, au-tonomic tone, and external forces that modulate cardiovascular performance (afterload and preload). Afterload can be broadly defined as the forces that oppose cardiac ejection. Afterload is often incorrectly conceptualized as arterial blood pressure, but is more accurately reflected as systolic wall stress or aortic input impedance. The use of wall stress is problematic because it is potently affected by ventricular properties, as wall stress is directly related to chamber dimension and inversely to wall thickness. The ideal measure of afterload would be com-pletely independent of the ventricle. Aortic input impedance provides a measure of the total vascular opposition to ejection that is independent of the heart, but is cumbersome to use because it is expressed in the frequency domain and is there-fore difficult to use with time-domain measures of ventricular function. Effective arterial elastance (Ea) is an alternative time-domain measure that incorporates both mean resistive and oscillatory components of arterial load and is defined by the ratio of endsystolic arterial pressure to stroke volume (SV). Ea is directly related to mean systemic vascular resis-tance (SVR) and heart rate (HR) and inversely related to total arterial compliance.

Preload can be defined by the magnitude of distention or “stretching” of ventricular myocytes prior to contraction, which dictates the extent of myofiber shortening in the subsequent contraction. Preload is often erroneously conceptualized in practice as being equivalent to LV filling pressures (LVFP), when in fact, the most accurate measure of LV preload is chamber volume prior to the onset of isovolumic contraction

H

Received August 28, 2013; revised manuscript received October 30, 2013; accepted November 11, 2013; released online December 3, 2013The Division of Cardiovascular Diseases, Department of Medicine, Mayo Clinic, Rochester, MN, USAMailing address: Barry A. Borlaug, MD, Mayo Clinic College of Medicine, 200 First Street SW, Rochester, MN 55905, USA. E-mail:

[email protected] doi: 10.1253/circj.CJ-13-1103All rights are reserved to the Japanese Circulation Society. For permissions, please e-mail: [email protected]

Mechanisms of Exercise Intolerance in Heart Failure With Preserved Ejection Fraction

Barry A. Borlaug, MD

Approximately half of patients with heart failure (HF) have a preserved ejection fraction (HFpEF), and with the chang-ing age and comorbidity characteristics in the adult population, this number is growing rapidly. The defining symptom of HFpEF is exercise intolerance, but the specific mechanisms causing this common symptom remain debated and inadequately understood. Although diastolic dysfunction was previously considered to be the sole contributor to exercise limitation, recent studies have identified the importance of ventricular systolic, chronotropic, vascular, en-dothelial and peripheral factors that all contribute in a complex and highly integrated fashion to produce the signs and symptoms of HF. This review will explore the mechanisms underlying objective and subjective exercise intoler-ance in patients with HFpEF. (Circ J 2014; 78: 20 – 32)

Key Words: Aging; Diastolic dysfunction; Exercise; Heart failure; Hemodynamics

REVIEW


21Exercise Intolerance in HFpEF

with exertion is, not surprisingly, metabolic demand for O2, and studies dating back over 50 years have shown that in gen-eral, for each 1 ml increase in VO2, there is an approximately 6 ml increase in QC in healthy humans.30,31

SV increases by approximately 40% during upright exer-cise, owing to both augmentation in LVEDV and reduction in LV endsystolic volume (ESV).29 Increases in RV EDV occur in response to enhanced venous return mediated by muscle and ventilatory pumps, and possibly dynamic reductions in blood volume in the large-capacity splanchnic veins.27 This increase in venous return to the thorax during early exercise is opti-mally coupled to 2 compliant ventricles that can accommodate increases in EDV without excessive rises in ventricular filling pressure (end-diastolic pressures, EDP). Net ventricular cham-ber compliance (change in volume per change in pressure) is related to chamber volumes as well to factors within the car-diac myocyte (eg, cytosolic calcium levels, titin phosphoryla-tion and isotype expression), the extracellular matrix (collagen content and cross-linking), the right heart and the pericardi-um.32 Increases in EDV lead to increased stretch of cardiac myocytes that serves to enhance the force of contraction via the Frank-Starling mechanism. To allow the ventricle to fill to a larger EDV in a shorter interval of time, without pathologic increases in EDP, there is exercise-induced enhancement in early diastolic relaxation, suction and untwist that is mediated predominantly by adrenergic stimulation.33 Recent research indicates that LV chamber stiffness can be dynamically re-duced by cyclic adenosine monophosphate- (cAMP) and cy-clic guanosine monophosphate- (cGMP) dependent phosphor-ylation of macromolecules in the cardiac myocyte, such as titin,34–36 though it is unknown if this protein phosphorylation affects elastance (stiffness) acutely during exercise. Protein kinase C also phosphorylates titin, but in contrast to the cAMP- and cGMP-dependent pathways, PKC phosphoryla-tion increases stiffness.37 Titin affects chamber stiffness via additional phosphorylation-independent mechanisms such as variable expression ratios between the more complaint (N2BA) and Stiff (N2B) titin isoforms as well oxidation of N2B spring elements.38

To achieve adequate filling of the LV, there must be suffi-cient augmentation of RV ejection during exercise. This is achieved via RV contractile reserve as well as by pulmonary artery (PA) vasodilation.22 Owing to the high compliance and low resistance in the pulmonary vasculature, normal individu-als accommodate large increases in pulmonary cardiac output (QP) without significant increase in PA pressure. However, recent studies have suggested that at least mild to moderate increases in PA pressure during exercise may be part of nor-mal aging, particularly above the age of 50.39

Although EDV may increase by 20–40%, this reserve be-comes exhausted quite early on during the course of exercise, and further increases in SV must be mediated by more vigorous emptying of the heart (reduction in ESV).27,29 This is achieved by increases in contractility and enhanced arterial vasodilation. Depending on the parameter used to assess it, LV contractility increases 1–3-fold during exercise.15 There is also vasorelax-ation, mediated by muscular arteriolar dilation, endothelium-dependent dilation and reduction in mean SVR.27 However, total arterial afterload, expressed by effective Ea, increases at maximal exercise.40 This is because increases in HR and de-creases in compliance exceed the reduction in SVR at peak exertion.25 The coupling of the heart to the vasculature can be expressed by the ratio of Ea to Ees, a load-independent mea-sure of contractility.25,40 This coupling ratio (Ea/Ees) varies inversely with EF and drops significantly during exercise to

(LV end-diastolic volume, LVEDV). Filling pressures are re-lated to preload by the compliance properties of the heart and the kinetics of relaxation, especially at higher HRs. Preload is affected by venous return, diastolic function, the right heart, and the pericardium.

The ventricle can be characterized by its capacity to eject blood (systolic function) and to fill with blood (diastolic func-tion). Systolic function reflects the heart’s pumping ability and is most often measured clinically by the EF. However, EF varies directly with preload and inversely with afterload (as is true of all measures of systolic shortening or thickening). Al-ternative measures that account for both preload and afterload, such as LV endsystolic elastance (Ees), stress-corrected frac-tional shortening, or preload-recruitable stroke work are more specific measures of LV chamber contractility that are inde-pendent of load.

Diastolic function is often dichotomized into “active” and “passive” functions, though these distinctions are arbitrary and there is considerable overlap between them. “Active” function generally refers to early diastolic processes involved in cross-bridge detachment, calcium reuptake and rapid pressure decay during isovolumic relaxation and early filling. Active diastolic function is usually measured by the time constant of early dia-stolic pressure decay (τ) or the velocity/extent of tissue motion during early filling. Passive diastolic function generally refers to the mechanical properties of heart muscle that dictate the degree of pressure elevation to achieve a given preload vol-ume (end-diastolic chamber elastance or Eed, an approxima-tion for the slope of the end-diastolic pressure-volume rela-tionship). Eed is determined by stiffness within the cardiac myocytes as well as the extracellular matrix, chamber, and pericardium.

If systolic and diastolic ventricular properties are held con-stant, an isolated increase in afterload will increase blood pres-sure and decrease SV, whereas an isolated increase in preload will increase blood pressure and increase SV. The converse effects will occur with reductions in afterload and preload. Autonomic tone potently influences cardiovascular status: in-creases in sympathetic stimulation peripherally enhance ve-nous return, contractility, chronotropy and lusitropy, whereas increases in parasympathetic tone reduce HR and vascular re-sistance. Ventricular reserve function reflects the heart’s capac-ity to deal with the increases in preload and afterload that ac-company physiologic stresses such as exercise. As shall be discussed, reserve capacity is often dissonant with resting, steady state cardiovascular function, particularly in patients with HFpEF.

Normal Exercise PhysiologyTo cope with the increased metabolic demands of physical ex-ercise, the human body relies upon complex interactions among the heart, lungs, vasculature, endothelium, skeletal muscle and autonomic nervous system.27,28 Exercise capacity is most often quantified as the peak oxygen consumption (peak VO2) achieved during maximal effort exercise. According to the Fick principle, VO2 is defined by the product of cardiac output (QC) and arterial-venous oxygen content difference (AVO2diff). In normal men, VO2 increases 7.7-fold during maximal exercise, achieved by a 3.1-fold increase in QC and 2.5-fold increase in AVO2diff.29 Cardiac output is equal to the product of SV and HR, whereas AVO2diff is determined by the abilities to oxy-genate blood in the lungs, transport O2 to tissues bound to hemoglobin, and then distribute, extract and utilize O2 in ex-ercising muscle. The variable that “drives” increases in QC


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blood volume), meaning that without regional vasoconstriction during exercise, systemic hypotension would routinely devel-op. The capacity of the vasculature to rapidly dilate or constrict allows for redistribution of blood volume and flow to meet metabolic requirements while optimizing blood pressure to maintain perfusion. Many of these changes in local perfusion are regulated by central neural command,27 but distribution of flow is also importantly regulated at the tissue level by factors generated by contracting skeletal muscle. Local decreases in pH as well as increases in potassium, adenosine diphosphate, carbon dioxide, and temperature serve to dilate arterioles and precapillary sphincters to optimally couple delivery of blood flow to meeting local demands. Among the local factors gener-ated, elaboration of nitric oxide (NO) plays a critically impor-tant role in enhancing regional blood flow during stress.42 Chemoreceptors and metaboreceptors located within muscle and vasculature provide further neural feedback that modulates central efferent autonomic output and may contribute to symp-toms of dyspnea and fatigue.43,44

allow for greater ejection capacity.SV recruitment typically plateaus during exertion at ap-

proximately 50% peak VO2, and further increases in QC are achieved purely by HR.29 The rapid increase in HR from rest to approximately 100 beats/min is mediated by acute with-drawal of parasympathetic tone; further increases are mediated by increased sympathetic outflow.27 The dominant contributor to the age-related drop in maximal QC during exercise is loss of chronotropic reserve.41

Enhanced peripheral O2 distribution, utilization and extrac-tion (ie, AVO2diff reserve) during exercise plays an equally important role as QC reserve.18,27 Although the heart increases its output, this enhanced flow needs to be matched to tissues where perfusion is most needed, which is achieved by regional vasodilation in skeletal and cardiac muscle and vasoconstric-tion in non-exercising regions such as the skin, splanchnic beds, and kidneys.27 The importance of the latter is appreciated by considering that when fully dilated, the body’s blood ves-sels can hold over 20 L of blood (4-fold greater than the usual

Figure 1. Diastolic reserve limitations during exercise in patients with heart failure with preserved ejection fraction (HFpEF). (A) In a typical HFpEF patient, there is dramatic elevation in mean left ventricular diastolic pressure (mLVDP) during exercise associ-ated with limited hastening of isovolumic relaxation (reduction in the time constant of relaxation, τ). Inadequate relaxation reserve during exercise is coupled with an acute shift upward and to the left in the diastolic pressure-volume relationship, with an increase in operant diastolic elastance (Ed) as shown in an example patient (B) and in group data (C,D). The solid lines/bar graphs show raw unadjusted pressure-volume data and the dashed lines/hashed bar graphs show elastance data corrected for the effects of incomplete relaxation. (Adapted with permission from Borlaug et al.47)



function, it does not appear that exercise limitation in HFpEF is related to an inability to adequately fill the LV to a large enough EDV.

However, despite apparent preservation of EDV reserve, there is compelling evidence for failure of the Frank-Starling mechanism (the ability to translate an increase in filling pres-sure to an increase in cardiac ejection) in HFpEF. Shibata et al observed that the increase in SV relative to beat-to-beat chang-es in LV end-diastolic pressure (LVEDP: estimated by PA diastolic pressure) was impaired in HFpEF patients compared to age-matched controls.45 In a separate study, Abudiab et al noted that for any increase in LVEDP, the increase in cardiac output was markedly attenuated in patients with HFpEF com-pared to controls.23

Clinically, this failure of the Frank-Starling reserve is most clearly manifest as an elevation in LVFP, and recent studies have provided insight into the pathogenesis of this process. Westermann et al performed conductance catheter analysis in 70 HFpEF patients and 20 controls, and observed both pro-longed relaxation and increased diastolic elastance.46 Although elastance did not change during isometric handgrip, filling pressures increased as would be predicted by the upward shift in the resting LV diastolic pressure-volume relationship. In another invasive exercise study, Borlaug et al measured LV pressures using high-fidelity micromanometer catheters with simultaneous echocardiography to determine LV volumes at rest and during dynamic supine exercise in patients with HFpEF.47 LV diastolic pressures increased by approximately 50% with exercise (P<0.0001), despite a trend towards a re-

Pathophysiology of Exercise Intolerance in HFpEFDiastolic LimitationsDiastolic dysfunction remains fundamental to HFpEF and is the most richly studied component of the pathophysiology. In the first study to examine the hemodynamic changes during exercise in HFpEF, Kitzman et al6 used nuclear scintigraphy to assess LV volumes during right heart catheterization of 7 HFpEF patients and 10 age-matched controls performing max-imal effort upright exercise.6 They observed markedly de-pressed peak VO2 in the HFpEF patients, which was related predominantly to an inability to enhance SV and EDV. Despite the flat EDV response, patients developed marked increases in EDP (estimated as the pulmonary capillary wedge pressure, PCWP), leading the authors to conclude that exercise intoler-ance in HFpEF is related predominantly to failure of the Frank-Starling mechanism. However, more recent studies have ques-tioned whether the increase in EDV with exercise is truly impaired in HFpEF. Borlaug et al performed maximal effort exercise testing with simultaneous nuclear scintigraphy in HFpEF patients compared with closely matched aged hyper-tensive controls, and observed no difference in the ability to recruit EDV during exercise.10 There was no correlation be-tween the change in EDV with exercise and peak VO2 in that study, further questioning the contributory role of reduced aerobic capacity. A more recent study using echocardiogra-phy to assess LV volumes noted a slightly greater increase in EDV with exercise in HFpEF patients as compared to con-trols.18 Thus, despite the common presence of diastolic dys-

Figure 2. Filling pressures and pulmonary artery (PA) pressures during exercise in early heart failure with preserved ejection fraction (HFpEF). (A) Despite normal resting pulmonary capillary wedge pressures (PCWP), patients with early-stage HFpEF de-velop a dramatic elevation in PCWP with even 1 min of low level (20 Watts) exercise, that rapidly returns to baseline values with cessation of exercise. (B) This increase in PCWP is secondary to exercise-induced elevation in LV end-diastolic pressure (LVEDP) in HFpEF and is coupled with secondary, passive elevation in PA pressures (C), causing exercise-induced PA hypertension. (Adapted with permission from Borlaug et al.49)


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who are clinically euvolemic, with normal resting hemody-namics and normal B-type natriuretic peptide (BNP) levels.49 The increase in LVEDP during exercise in HFpEF is extraor-dinarily rapid, occurring in the first minute at low workload, and mercurial, with pressures rapidly returning to normal al-most immediately upon cessation of activity (Figure 2).49,50 This intermittent nature of the filling pressure elevation con-founds treatment and also likely explains why BNP levels are frequently normal in HFpEF.4 Abnormal patterns of gas ex-change correlate with the kinetics of elevated filling pressures in patients with HFpEF undergoing exercise during cardiac catheterization, providing further insight into the nature of expired gas abnormalities observed during metabolic stress testing.51

In a noninvasive echocardiographic exercise study, Tan et al found that patients with HFpEF displayed lower tissue Doppler early diastolic (E’) velocities at rest coupled with inadequate enhancement in E’ during exercise.14 Similar im-pairments in E’ reserve have been reported in response to dobutamine infusion in HFpEF.17 In addition to relaxation, E’ velocity is determined by left atrial pressure at the mitral valve

duction in LVEDV, coupled with a 50% increase in end-dia-stolic LV elastance (Figure 1). The single-beat diastolic vol-ume relationship not only steepens (increased stiffness) but shifts upward in parallel, suggesting some element of pericar-dial restraint that likely contributes to the increase in filling pressures. As such, LV minimal diastolic pressure, which normally decreases during exercise to enhance filling by “suc-tion”, was observed to increase by 55% in patients with HFpEF (Figure 1). LV relaxation, assessed by τ was pro-longed at rest, and importantly, the normal hastening of relax-ation (decrease in τ) was impaired in HFpEF, such that the proportion of diastole that elapsed prior to complete relax-ation actually increased as opposed to the normal reduction.47 Exercise-induced increases in LVEDP correlated with chang-es in diastolic relaxation rates, chamber stiffness and Ea, but were not related to alterations in EDV, HR or QC. In another study, Wachter et al observed that rapid atrial pacing was as-sociated with less enhancement in LV relaxation and greater reduction in EDV in patients with HFpEF as compared to controls.48

Elevated LVFP in HFpEF is observed even among patients

Figure 3. Contractile reserve limitations during exercise in heart failure with preserved ejection fraction (HFpEF). Bar graphs show the changes from baseline to 20 Watts of workload in preload-recruitable stroke work (PRSW, A), endsystolic elastance (Ees, B), and peak power index (PWR/EDV) in healthy controls (blue), asymptomatic hypertensive patients (HTN, green) and HFpEF patients (red). Even at low level submaximal workload, there is substantial systolic reserve limitation in the HFpEF patients when using these load-independent measures. (D) The ability to enhance contractility tightly correlates with exercise capacity (peak VO2), support-ing a mechanistic contribution. (Adapted with permission from Borlaug et al.15)



studies have shown that despite overall preservation of EF, patients with HFpEF display subtle but significant abnormali-ties in chamber and myocardial contractility,12 as well as im-pairments in regional deformation as detected by tissue Doppler and strain-based imaging techniques.7,8,14,53,54 In addition, al-though the resting EF is normal, the exercise-induced enhance-ment in EF is impaired in patients with HFpEF when compared to matched controls.10,15,55 Impaired EF reserve could be caused by afterload mismatch or impaired contractile reserve, and al-though there is clearly evidence of vascular stiffening and abnormal vasorelaxation in HFpEF,10,15,55,56 Borlaug et al used load-independent measures to show that contractile reserve is markedly impaired in HFpEF patients compared to age-matched healthy and hypertensive controls, even at low sub-maximal matched workloads (Figure 3).15 In their study, the magnitude of contractile response directly correlated with peak VO2 (Figure 3D), further supporting a role for systolic reserve dysfunction in the exercise intolerance in HFpEF.

opening and the extent/velocity of LV untwisting during early diastole.52 Tan et al found that at rest, the extent and velocity of LV untwisting was impaired in HFpEF patients compared with controls, and further tended to be impaired during dy-namic exercise, indicating that in addition to inadequate relax-ation reserve, limitations in LV untwisting contribute.14 Using nuclear scintigraphy, Phan et al observed that while peak dia-stolic filling rates were similar in HFpEF patients and controls at rest, the ability to enhance the time to peak filling was mark-edly attenuated in HFpEF.13 Intriguingly, those authors also observed impaired cardiac energetics on nuclear magnetic resonance spectroscopy, which may contribute to this loss of diastolic reserve.

Systolic LimitationsAlthough EF is the measure that is used most often clinically to assess systolic function, it is a rather poor measure of LV contractility, because of its high load-dependence.25 Numerous

Figure 4. Endothelial dysfunction in heart failure with preserved ejection fraction (HFpEF). (A) The hyperemic increase in digital blood flow in response to upper arm cuff occlusion is impaired in HFpEF patients (red) compared to healthy controls (blue). (B) Nearly half of the patients with HFpEF showed evidence of endothelial dysfunction. Subjects with endothelial dysfunction (ED) reported more severe symptoms of fatigue (C) and dyspnea (E) at low-level, submaximal exercise than subjects with normal en-dothelial function, and the reactive hyperemia index (a measure of endothelial function) inversely correlated with symptom sever-ity during exercise (D,F) and directly correlated with peak VO2 (P<0.0001, not shown). HTN, hypertension. (Adapted with permis-sion from Borlaug et al.15)


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viding further evidence of inadequate vasodilation.15 The in-ability to adequately dilate, coupled with the inability to enhance contractility, leads to dynamic abnormalities in ventricular-arterial coupling with exercise in HFpEF.13,15,59

Central and conduit vessel stiffening is common in HFpEF and contributes to exercise limitation and blood pressure labil-ity.59–62 Beyond vascular stiffening, the mechanisms for abnor-mal exercise vasodilation remain unclear. Borlaug et al re-ported that HFpEF patients commonly display endothelial dysfunction, and the extent of dysfunction directly correlated with greater symptoms of dyspnea and fatigue during sub-maximal exercise and inversely correlated with peak VO2 in HFpEF (Figure 4).15 Recently, Akiyama et al reported that the presence of endothelial function predicts increased risk of HF hospitalization in patients with HFpEF.63 In an elegant study, Guazzi et al administered the phosphodiesterase inhibitor sildenafil to patients with HFrEF, and noted improvements in endothelial function that closely paralleled decreases in venti-latory responses to stress, supporting the notion that there is cross-talk between microvascular function in skeletal muscle and symptoms of effort intolerance.44 However, not all studies have observed endothelial dysfunction in HFpEF. Haykowsky et al observed no difference in endothelial function in HFpEF

Similar impairments in systolic reserve in HFpEF have been described with dobutamine infusion17,19 and rapid pacing57 in HFpEF patients, though not all studies have observed systolic limitations.20,48 Even subtle impairment of contractility at rest may indicate marked limitations in reserve, which may ex-plain why impaired resting myocardial contractility (despite normal EF) predicts increased mortality in HFpEF.12 Systolic reserve limitation in HFpEF affects diastole as well, because the ability to contract to smaller LV volumes at end-systole enhances the recoil and suction forces during early diastole,52 which are also known to be impaired in HFpEF.14,58

Vascular Stiffening and DysfunctionIn addition to impaired contractile reserve, inadequate vasodi-lation appears to contribute to the inability to reduce ESV in HFpEF. Borlaug et al first reported attenuated reductions in mean SVR during matched and peak exercise in HFpEF,10 and most,15,49,50,55,59 though not all18 subsequent studies have cor-roborated this finding. In another HFpEF population, Borlaug et al performed direct assessment of peripheral blood flow during exercise using a finger-tip plethysmographic device and observed impaired increases in digital flow in HFpEF patients compared to hypertensive and non-hypertensive controls, pro-

Figure 5. Chronotropic incompetence in heart failure with preserved ejection fraction (HFpEF). (A) Compared with controls (red), patients with HFpEF (black) display markedly lower increases in heart rate (∆HR) during maximal effort exercise. (B) The increase in HR with exercise correlates with exercise capacity (peak VO2) in both groups (bivariate P<0.0001), but for any increase in VO2, there was less enhancement of HR in HFpEF patients compared to controls. This difference persisted after adjusting for age and β-blocker use. Heart rate acceleration during the onset of exercise (C) and deceleration during early recovery (D) were abnormal in HFpEF compared to controls. (Data taken from Borlaug et al.15 and Abudiab et al.23)



minants of exercise capacity.76 Intriguingly, the presence of AF in HFpEF was found to be an independent predictor of RV dysfunction, which may additionally explain the adverse out-come and greater impairment in exercise capacity in subjects with AF.24 However, at this time it remains unclear whether AF causes the RV dysfunction or vice versa.

Right Heart, Pulmonary Vasculature and the PericardiumPulmonary hypertension (PH) is common in HFpEF,77 particu-larly during exercise,49 because downstream elevations in left heart pressures add in series with components of pressure-re-lated resistance and QP.22 The presence of PH increases the risk of death in HFpEF,77 and recent studies have shown that pro-gression in pulmonary vascular disease in HFpEF is associated with a deterioration in RV function that is potently associated with adverse outcome, independent of other established pre-dictors of mortality.24 Tedford et al have shown that increases in PCWP are associated with lower PA compliance at any given resistance, increasing the oscillatory load on the RV, and this effect occurs even acutely during exercise in patients with HFpEF.78 Because they are connected in series, inadequate RV output could contribute to exercise limitation by promoting “underfilling” of the left heart during stress. Although this phenomenon has been demonstrated in HFrEF,79 it has not been documented in patients with HFpEF.

Complicating this assessment is the fact that right-sided chamber and left atrial enlargement in HFpEF with RV failure creates the substrate for increased pericardial restraint and dia-stolic ventricular interaction,80 where the right heart influences the left in parallel.22 In this circumstance, left heart filling pres-sures may be elevated even if LVEDV is normal or reduced.81 Janicki observed that a significant number of patients with advanced HFrEF display this phenomenon of enhanced dia-stolic ventricular interaction during exercise, whereby PCWP and right atrial pressure increase in tandem with no further enhancement in SV, because of the restraining effects of the pericardium that prevent additional preload recruitment.82 Fur-ther study is required to determine whether this phenomenon contributes to exercise intolerance in HFpEF, or perhaps whether surgical mitigation of pericardial restraint might im-prove exercise capacity.

Peripheral FactorsThere are numerous lines of evidence to support the notion that true maximal VO2 is limited by central (QC) rather than peripheral (AVO2diff) determinants. These include the obser-vations that (1) VO2 max is achieved by activation of only 50% of total body muscle mass, and activation of additional muscle does not increase QC or VO2 beyond this level, (2) when ad-ditional muscles are activated at VO2 max, arterial blood pres-sure is maintained by vasoconstriction to exercising muscles, and (3) the capacity of skeletal muscle to consume O2 greatly exceeds what the heart can deliver.27 However, true VO2 max is rarely achieved in patients with HF, and VO2 max is not equiva-lent to what is routinely measured in practice (peak VO2).

Recently, Haykowsky et al examined the determinants of peak VO2 in patients with HFpEF and age-matched controls free of HF. Although they observed that peak VO2 was tightly correlated with both QC and AVO2diff, in both their HFpEF and control groups, the change in AVO2diff with exercise was the strongest independent predictor of peak VO2.18 In a sepa-rate study, this group examined body composition in the same cohort and observed a decrease in the percent of lean total body and leg mass.83 Although peak VO2 increased with increasing lean mass in healthy controls, this was not observed in HFpEF

compared with healthy age-matched controls, or any correla-tion between endothelial function and peak VO2 in multivari-ate analysis.64 In another study, this group observed no im-provements in vascular stiffness or endothelial function after 16 weeks of exercise training in HFpEF.65 This is in contrast to older studies in non-HF populations where habitual exercise has been associated with improvements in age-associated losses in endothelial function.66 Part of the discrepancy in re-sults between various studies may be related to the methods used to assess endothelial function, which may be performed in larger conduit vessels such as the brachial or femoral arter-ies (as in the Haykowsky study) compared with the microvas-culature (as in the Borlaug and Akiyama studies). Indeed, re-cent work from the Framingham group has shown significant differences in the risk factor associations and overall preva-lence of endothelial dysfunction when assessed using these different methods, suggesting that they may provide distinct information regarding vascular function.67

Just as systolic dysfunction begets diastolic dysfunction by impairing elastic recoil during early diastole, vascular stiffen-ing may also impair diastolic function.25 Increases in arterial afterload prolong relaxation, particularly in the failing heart.68 Loading sequence appears to also be important, with later-systolic afterload increases having more deleterious effects upon LV ejection and relaxation.69–71 This provides another mechanism whereby vascular stiffening and elevated afterload contribute to elevation in filling pressures observed with stress in HFpEF.60

Heart Rate and RhythmAs discussed earlier, enhancement in HR plays a critical role in allowing for adequate QC reserve, and several studies have identified impairments in chronotropic reserve in HFpEF (Figure 5).3,9,10,15,18,23,49,72,73 Borlaug et al observed significant-ly depressed peak HR in HFpEF patients compared to con-trols, which was coupled with abnormalities in cardioaccel-eration and HR recovery after cessation of exercise.10 The latter is a marker of autonomic health, which is associated with longevity, even after controlling for the presence or absence of cardiovascular diseases. Other groups have also observed im-paired HR recovery in HFpEF, even when accounting for β-blocker usage,73 and abnormal arterial baroreflex sensitivity has also been documented,10 further supporting a role for au-tonomic dysfunction in HFpEF. Although not all studies have observed abnormal HR reserve in HFpEF,50 it has been found to be extremely common in several large recent studies, ranging from as high as 56% to 78%.15,72 This observation, coupled with the tight correlation between HR reserve and peak VO2,9,10,15 suggests that restoration of chronotropic competence may en-hance exercise capacity in HFpEF. However, increases in HR may compromise LV filling in patients with prolonged relax-ation, and a recent small study reported dramatic improve-ments in peak VO2 after just 7 days of treatment with the nega-tive chronotropic drug, ivabradine.74 Clearly, further research is needed regarding the management of HR responses to exer-cise in HFpEF patients, and a prospective trial testing the ef-fects of rate-adaptive pacing in patients with chronotropic in-competence is currently being planned.

In addition to HR reserve, heart rhythm appears to be im-portant in HFpEF. A recent study has shown the presence of atrial fibrillation (AF) portends greater risk of death in HFpEF patients.75 In an ancillary study from the RELAX trial, Zakeri et al demonstrated that despite similar HR responses to exer-cise, HFpEF patients with AF displayed much more severe exercise intolerance, even after adjusting for other key deter-


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study, for any increase in VO2, there was on average a 20% lower increase in QC in the HFpEF patients (Figure 6), indi-cating that limited cardiac output reserve, rather than periph-eral dysfunction, was the dominant contributor to the reduc-tion in peak VO2. When contemplating the reasons for the divergent findings between this study and those of Haykowsky and Bhella, it is important to consider that HFpEF is a hetero-geneous disease, and it is highly likely that there are subgroups of patients in whom exercise capacity is more or less con-strained by central vs. peripheral mechanisms. Further efforts to subtype these categories may be helpful in the classification and individualization of treatment of HFpEF.23,84

Regardless of the primacy of peripheral and skeletal muscle abnormalities in limiting peak VO2 in HFpEF, they could be highly viable therapeutic targets.85 Haykowsky et al noted that improved peak VO2 in HFpEF patients after 4 months of ex-ercise training was predominantly related to higher AVO2diff at peak exercise, with no significant change in QC.86 It may be that there is greater plasticity and potential for rejuvenation in peripheral factors such as blood flow distribution, microvas-cular function, capillary density, skeletal muscle function, energetic stores and mitochondrial oxidative capacity as com-pared with cardiac properties.87 Although some groups have noted improvements in the LV diastolic function of HFpEF

patients, suggesting that impaired skeletal muscle perfusion or oxidative capacity might be present. An alternative possibility might be that increased QC during exercise is inappropriately directed to non-exercising tissues, such as adipose.83 In a dif-ferent cohort, Bhella et al found that while QC reserve was depressed in HFpEF (as previously demonstrated by other groups), when normalized to VO2, HFpEF patients displayed an overly exuberant increase in QC, with markedly impaired AVO2diff reserve.20 Those authors proposed the provocative conclusion that exercise capacity in HFpEF is limited by pre-mature skeletal muscle fatigue and/or by metabolic/neural sig-nals originating in muscle that stimulate excessive QC respons-es to exercise.

However, in a subsequently published, invasive study in which arterial and mixed venous O2 contents were directly measured, no differences in maximal exercise AVO2diff were observed between HFpEF patients and controls (Figure 6).23 Furthermore, when AVO2diff was normalized to peak VO2 achieved, it was higher rather than lower in patients with HFpEF. The authors speculated that this represents a chronic adaptation to inadequate QC, citing the fact that with a lower QC, there is greater time available for gas exchange in the capillaries, which may serve to counterbalance any potential abnormalities in convective and diffusive O2 transfer.23 In that

Figure 6. Central vs. peripheral mechanisms of exercise impairment in heart failure with preserved ejection fraction (HFpEF). (A) Compared to controls (red), patients with HFpEF (black) display less increase in cardiac output (∆CO) during exercise. (B) This cardiac limitation is maintained when normalizing ∆CO to metabolic demands (∆VO2). (C) Total increases in arterial-venous O2 content differences (∆AVO2diff) with maximal exercise were similar in HFpEF patients and controls, but when normalized to ∆VO2, there was greater reliance in the HFpEF subjects on enhanced peripheral O2 extraction and utilization (D), likely to compensate for inadequate skeletal muscle perfusion because of CO limitation. (Adapted with permission from Abudiab et al.23)



therapies failed to detect an improvement in submaximal ex-ercise capacity (6-min walk distance) of HFpEF patients, de-spite a significant increase in hemoglobin while on treatment.90 Figure 7 summarizes the roles of multiple mechanisms in the pathogenesis of HFpEF as has been described.

Exercise Reserve, HFpEF and Normal AgingLV diastolic stiffness increases with normal aging,91 and the age-related increase is greater in women than in men and cor-relates with increases in body mass, all consistent with the typical demographic characteristics of HFpEF: older, hyperten-sive, obese females.92,93 In addition, the ability to tolerate vol-ume loading without excessive increase in LVFP decreases in older women.94 Given these observations, together with the foregoing findings, therapies targeting age-related LV diastolic stiffening would appear to hold promise to help improve exer-cise capacity and outcomes in HFpEF.95 Indeed, better under-standing of the reasons for age-related reductions in cardiac reserve96 and exercise capacity97 may allow for the develop-ment of novel therapies to improve outcome in both HFpEF patients and the broader population of older adults without HF but with deterioration in functional capacity related to normal aging.

patients doing exercise training,88 a more recent study ob-served no changes in cardiovascular mechanics.89 Although the latter study (n=11) reported no change in peak VO2 with exercise training, 2 much larger randomized trials (n=64 and 46, respectively) have demonstrated fairly substantial im-provements in aerobic capacity with training (2.6–3.3 ml · min–1

· kg–1).87,88

Other FactorsThe lungs function as the first step in the transport of O2 from the external environment to the tissues for utilization, and ab-normalities in ventilation or gas exchange (alveolar membrane O2 conductance, capillary blood volume, ventilation-perfusion matching) might be expected to contribute to exercise impair-ment in HF. Pulmonary limitations have not been considered as a significant contributor to reduced peak VO2, given the dramatic reserve capacity of the lungs,27 but pulmonary me-chanics and gas exchange have not been adequately studied in HFpEF, and it is certainly conceivable that with acute in-creases in LVFP, interstitial edema develops, changing the compliance properties of the lungs, possibly leading to greater respiratory muscle fatigue that may discourage further exer-cise. Adequate delivery of O2 from the lungs to muscle and tissues requires hemoglobin, and anemia is common in HFpEF patients. However, a recent trial of erythropoietin-stimulating

Figure 7. Summary of mechanisms of exercise intolerance in heart failure with preserved ejection fraction (HFpEF). “Central” impairments are shown in the ovals and “peripheral” impairments in the rectangles. Arrows indicate where an abnormality di-rectly contributes to another. Question marks indicate theoretical but unproven mechanistic relationships. See text for additional details. AVO2, arterial-venous oxygen content; β-AR, beta-adrenoreceptor; LVFP, left ventricular filling pressures; PA, pulmonary artery; RV, right ventricle; VA, ventricular-arterial.


30 BORLAUG BA

10. Borlaug BA, Melenovsky V, Russell SD, Kessler K, Pacak K, Becker LC, et al. Impaired chronotropic and vasodilator reserves limit exercise capacity in patients with heart failure and a preserved ejection fraction. Circulation 2006; 114: 2138 – 2147.

11. Lam CS, Roger VL, Rodeheffer RJ, Bursi F, Borlaug BA, Ommen SR, et al. Cardiac structure and ventricular-vascular function in per-sons with heart failure and preserved ejection fraction from Olm-sted County, Minnesota. Circulation 2007; 115: 1982 – 1990.

12. Borlaug BA, Lam CS, Roger VL, Rodeheffer RJ, Redfield MM. Contractility and ventricular systolic stiffening in hypertensive heart disease insights into the pathogenesis of heart failure with preserved ejection fraction. J Am Coll Cardiol 2009; 54: 410 – 418.

13. Phan TT, Abozguia K, Nallur Shivu G, Mahadevan G, Ahmed I, Williams L, et al. Heart failure with preserved ejection fraction is characterized by dynamic impairment of active relaxation and con-traction of the left ventricle on exercise and associated with myocar-dial energy deficiency. J Am Coll Cardiol 2009; 54: 402 – 409.

14. Tan YT, Wenzelburger F, Lee E, Heatlie G, Leyva F, Patel K, et al. The pathophysiology of heart failure with normal ejection fraction: Exercise echocardiography reveals complex abnormalities of both systolic and diastolic ventricular function involving torsion, untwist, and longitudinal motion. J Am Coll Cardiol 2009; 54: 36 – 46.

15. Borlaug BA, Olson TP, Lam CS, Flood KS, Lerman A, Johnson BD, et al. Global cardiovascular reserve dysfunction in heart failure with preserved ejection fraction. J Am Coll Cardiol 2010; 56: 845 – 854.

16. Prasad A, Hastings JL, Shibata S, Popovic ZB, Arbab-Zadeh A, Bhella PS, et al. Characterization of static and dynamic left ventricu-lar diastolic function in patients with heart failure with a preserved ejection fraction. Circ Heart Fail 2010; 3: 617 – 626.

17. Lee AP, Song JK, Yip GW, Zhang Q, Zhu TG, Li C, et al. Impor-tance of dynamic dyssynchrony in the occurrence of hypertensive heart failure with normal ejection fraction. Eur Heart J 2010; 31: 2642 – 2649.

18. Haykowsky MJ, Brubaker PH, John JM, Stewart KP, Morgan TM, Kitzman DW. Determinants of exercise intolerance in elderly heart failure patients with preserved ejection fraction. J Am Coll Cardiol 2011; 58: 265 – 274.

19. Norman HS, Oujiri J, Larue SJ, Chapman CB, Margulies KB, Sweitzer NK. Decreased cardiac functional reserve in heart failure with preserved systolic function. J Card Fail 2011; 17: 301 – 308.

20. Bhella PS, Prasad A, Heinicke K, Hastings JL, Arbab-Zadeh A, Adams-Huet B, et al. Abnormal haemodynamic response to exer-cise in heart failure with preserved ejection fraction. Eur J Heart Fail 2011; 13: 1296 – 1304.

21. Guazzi M, Vicenzi M, Arena R, Guazzi MD. Pulmonary hyperten-sion in heart failure with preserved ejection fraction: A target of phosphodiesterase-5 inhibition in a 1-year study. Circulation 2011; 124: 164 – 174.

22. Guazzi M, Borlaug BA. Pulmonary hypertension due to left heart disease. Circulation 2012; 126: 975 – 990.

23. Abudiab MM, Redfield MM, Melenovsky V, Olson TP, Kass DA, Johnson BD, et al. Cardiac output response to exercise in relation to metabolic demand in heart failure with preserved ejection frac-tion. Eur J Heart Fail 2013; 15: 776 – 785.

24. Melenovsky V, Hwang S, Lin G, Redfield MM, Borlaug BA. Right heart dysfunction in heart failure with preserved ejection fraction: The determinants and prognostic impact. Circulation 2013 [Abstract].

25. Borlaug BA, Kass DA. Ventricular-vascular interaction in heart failure. Cardiol Clin 2011; 29: 447 – 459.

26. Borlaug BA, Kass DA. Invasive hemodynamic assessment in heart failure. Cardiol Clin 2011; 29: 269 – 280.

27. Rowell LB. Human cardiovascular control. Oxford: Oxford Univer-sity Press, 1993.

28. Kitzman DW, Groban L. Exercise intolerance. Cardiol Clin 2011; 29: 461 – 477.

29. Higginbotham MB, Morris KG, Williams RS, McHale PA, Coleman RE, Cobb FR. Regulation of stroke volume during submaximal and maximal upright exercise in normal man. Circ Res 1986; 58: 281 – 291.

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Conclusions and Future DirectionsIn summary, numerous recent studies have changed the way we conceptualize the pathophysiology of HFpEF: away from being simply a disorder of diastolic dysfunction to more of a global impairment in the multiple components of cardiovascu-lar15,23 and peripheral18,20 reserves, which limits the ability to cope with physiologic stresses such as exercise. Further re-search is required to refine our understanding, enabling more optimal treatment for patients with HFpEF. A potential area of particular interest might be rigorous phenotyping of the nature of exercise limitation in a given patient (eg, predominant dia-stolic vs. systolic limitation, or peripheral vs. central limita-tion), which may allow for more precise individualization of therapies.23,84 Clearly, better understanding the mechanisms of the age-related reductions in cardiovascular reserve from the cellular to the organ system level needs further probing, and innovative new studies have just begun to make strides in this regard.98 Given the plurality of reserve limitations noted in HFpEF, it begs the question as to whether there are overarch-ing or unifying processes that affect the ventricle, vasculature and periphery that can be treated to improve global reserve, with possibilities including increased nitroso-oxidative stress, abnormal NO/cGMP-dependent signaling pathways,99 or tis-sue deposition of misfolded proteins acquired with senes-cence.100 Finally, although clinical trials in HF have tradition-ally targeted mortality and HF hospitalizations, it is time to think more globally and remember that quality of life is often just as important as quantity in patients with HFpEF. It is an inescapable fact that the number of people with HFpEF is going to increase dramatically during the next 30 years, and further studies examining the determinants and opportunities for improvement of exercise intolerance are critically impor-tant to ensure that these people can enjoy independent, produc-tive and active lifestyles in the years to come.

DisclosuresConflicts: None.

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