Vascular Dysfunction in Heart Failure with Preserved Ejection Fraction

Abstract

Heart failure (HF) with preserved ejection fraction (HFPEF) is the fastest growing form of HF and is nearly exclusively found in older persons, particularly women, in whom 90% of new HF cases are HFPEF.1Gottdiener J.S. Arnold A.M. Aurigemma G.P. Polak J.F. Tracy R.P. Kitzman D.W. et al.Predictors of congestive heart failure in the elderly: the Cardiovascular Health Study.J Am Coll Cardiol. 2000; 35: 1628-1637Abstract Full Text Full Text PDF PubMed Scopus (740) Google Scholar Although these patients often have frequent episodes of acute decompensation, even when stable and compensated, the primary symptom in chronic HFPEF is severe exercise intolerance, which can be measured objectively as decreased pulmonary oxygen uptake during peak aerobic exercise (peak VO2), and is associated with their severely reduced quality of life.2Haykowsky M.J. Tomczak C.R. Scott J.M. Patterson D.I. Kitzman D.W. Determinants of exercise intolerance in patients with heart failure and reduced or preserved ejection fraction.J Appl Physiol (1985). 2015; 119: 739-744Crossref PubMed Scopus (124) Google Scholar, 3Haykowsky M.J. Brubaker P.H. John J.M. Stewart K.P. Morgan T.M. Kitzman D.W. Determinants of exercise intolerance in elderly heart failure patients with preserved ejection fraction.J Am Coll Cardiol. 2011; 58: 265-274Abstract Full Text Full Text PDF PubMed Scopus (291) Google Scholar, 4Kitzman D.W. Little W.C. Brubaker P.H. Anderson R.T. Hundley W.G. Marburger C.T. et al.Pathophysiological characterization of isolated diastolic heart failure in comparison to systolic heart failure.JAMA. 2002; 288: 2144-2150Crossref PubMed Scopus (712) Google Scholar In accordance with the Fick principle (VO2 = cardiac output [CO] × arterial venous oxygen content difference [a-vO2diff]), the reduced peak VO2 in HFPEF patients may be due to impairments in cardiac, vascular, and/or skeletal muscle function that result in decreased oxygen delivery to and/or utilization by the active skeletal muscles.2Haykowsky M.J. Tomczak C.R. Scott J.M. Patterson D.I. Kitzman D.W. Determinants of exercise intolerance in patients with heart failure and reduced or preserved ejection fraction.J Appl Physiol (1985). 2015; 119: 739-744Crossref PubMed Scopus (124) Google Scholar, 3Haykowsky M.J. Brubaker P.H. John J.M. Stewart K.P. Morgan T.M. Kitzman D.W. Determinants of exercise intolerance in elderly heart failure patients with preserved ejection fraction.J Am Coll Cardiol. 2011; 58: 265-274Abstract Full Text Full Text PDF PubMed Scopus (291) Google Scholar, 5Upadhya B. Haykowsky M.J. Eggebeen J. Kitzman D.W. Sarcopenic obesity and the pathogenesis of exercise intolerance in heart failure with preserved ejection fraction.Curr Heart Fail Rep. 2015; 12: 205-214Crossref PubMed Scopus (45) Google Scholar, 6Haykowsky M.J. Kitzman D.W. Exercise physiology in heart failure and preserved ejection fraction.Heart Fail Clin. 2014; 10: 445-452Abstract Full Text Full Text PDF PubMed Scopus (38) Google Scholar, 7Haykowsky M. Brubaker P. Kitzman D. Role of physical training in heart failure with preserved ejection fraction.Curr Heart Fail Rep. 2012; 9: 101-106Crossref PubMed Scopus (39) Google Scholar, 8Sarma S. Levine B.D. Soothing the sleeping giant: improving skeletal muscle oxygen kinetics and exercise intolerance in HFpEF.J Appl Physiol (1985). 2015; 119: 734-738Crossref PubMed Scopus (14) Google Scholar Understanding the relative contributions of these factors to reduced exercise capacity requires their measurement during exercise along with VO2. Using upright exercise with expired gas analysis and simultaneous echocardiographic measurement of left ventricular volumes, our group reported that the lower peak VO2 in older HFPEF patients vs age-matched healthy subjects was due not only to reduced exercise cardiac output, but also to an equal contribution of reduced systemic a-vO2diff.2Haykowsky M.J. Tomczak C.R. Scott J.M. Patterson D.I. Kitzman D.W. Determinants of exercise intolerance in patients with heart failure and reduced or preserved ejection fraction.J Appl Physiol (1985). 2015; 119: 739-744Crossref PubMed Scopus (124) Google Scholar, 3Haykowsky M.J. Brubaker P.H. John J.M. Stewart K.P. Morgan T.M. Kitzman D.W. Determinants of exercise intolerance in elderly heart failure patients with preserved ejection fraction.J Am Coll Cardiol. 2011; 58: 265-274Abstract Full Text Full Text PDF PubMed Scopus (291) Google Scholar, 9Kitzman D.W. Higginbotham M.B. Cobb F.R. Sheikh K.H. Sullivan M.J. Exercise intolerance in patients with heart failure and preserved left ventricular systolic function: failure of the Frank-Starling mechanism.J Am Coll Cardiol. 1991; 17: 1065-1072Abstract Full Text PDF PubMed Scopus (585) Google Scholar Moreover, the rest to peak exercise change in a-vO2diff was the strongest independent predictor of peak VO2 for both healthy subjects and HFPEF patients.3Haykowsky M.J. Brubaker P.H. John J.M. Stewart K.P. Morgan T.M. Kitzman D.W. Determinants of exercise intolerance in elderly heart failure patients with preserved ejection fraction.J Am Coll Cardiol. 2011; 58: 265-274Abstract Full Text Full Text PDF PubMed Scopus (291) Google Scholar In a subsequent report, we found that following exercise training (to date, the only intervention shown to improve exercise intolerance in HFPEF), the increased peak VO2 occurred nearly entirely via increased a-vO2diff.10Haykowsky M.J. Brubaker P.H. Stewart K.P. Morgan T.M. Eggebeen J. Kitzman D.W. 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: 120-128Abstract Full Text Full Text PDF PubMed Scopus (230) Google Scholar, 11Kitzman D.W. Brubaker P.H. Herrington D.M. Morgan T.M. Stewart K.P. Hundley W.G. 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: 584-592Abstract Full Text Full Text PDF PubMed Scopus (239) Google Scholar The strong contribution of peripheral, “noncardiac” factors (expressed as reduced a-vO2diff during peak exercise) to the reduced peak VO2 in HFPEF was confirmed by an elegant invasive exercise study reported by Dhakal et al12Dhakal B.P. Malhotra R. Murphy R.M. Pappagianopoulos P.P. Baggish A.L. Weiner R.B. et al.Mechanisms of exercise intolerance in heart failure with preserved ejection fraction: the role of abnormal peripheral oxygen extraction.Circ Heart Fail. 2015; 8: 286-294Crossref PubMed Scopus (254) Google Scholar and more recently by another group using noninvasive measures during exercise.13Shimiaie J. Sherez J. Aviram G. Megidish R. Viskin S. Halkin A. et al.Determinants of effort intolerance in patients with heart failure: combined echocardiography and cardiopulmonary stress protocol.JACC Heart Fail. 2015; 3: 803-814Crossref PubMed Scopus (59) Google Scholar Taken together, the studies performed to date suggest that peripheral noncardiac factors play an important role in limiting peak VO2 in HFPEF patients. The 2 principle “noncardiac” factors that compose a-vO2diff and that can limit peak VO2 in HFPEF patients are arterial and skeletal muscle function. The arterial functional impairments include phasic and intrinsic stiffness, reduced responsiveness to vasodilatory stimuli, and reduced microvascular perfusion. These can affect any combination of the 3 segmental arterial compartments: large, central arteries (such as the aorta); peripheral arteries (mainly the large conduit arteries such as femoral and brachial); and the microvasculature. These impairments at these various locations can ultimately result in reduced blood flow to working skeletal muscle units, leading to early fatigue and exhaustion.2Haykowsky M.J. Tomczak C.R. Scott J.M. Patterson D.I. Kitzman D.W. Determinants of exercise intolerance in patients with heart failure and reduced or preserved ejection fraction.J Appl Physiol (1985). 2015; 119: 739-744Crossref PubMed Scopus (124) Google Scholar Several studies have examined the role that central arterial stiffness may play in limiting exercise performance in HFPEF. The first of these was from Hundley et al,14Hundley W.G. Kitzman D.W. Morgan T.M. Hamilton C.A. Darty S.N. Stewart K.P. et al.Cardiac cycle-dependent changes in aortic area and distensibility are reduced in older patients with isolated diastolic heart failure and correlate with exercise intolerance.J Am Coll Cardiol. 2001; 38: 796-802Abstract Full Text Full Text PDF PubMed Scopus (323) Google Scholar who reported that proximal thoracic aortic distensibility, which has a disproportionate impact on left ventricular afterload, is severely reduced in older HFPEF patients compared with healthy older or younger subjects. Hundley et al further showed that this was positively related to peak VO2 in HFPEF (Table 1). Desai and colleagues18Desai A.S. Mitchell G.F. Fang J.C. Creager M.A. Central aortic stiffness is increased in patients with heart failure and preserved ejection fraction.J Card Fail. 2009; 15: 658-664Abstract Full Text Full Text PDF PubMed Scopus (101) Google Scholar found that carotid-femoral pulse wave velocity (PWV) was significantly increased (denoting increased arterial stiffness) in older HFPEF patients vs age-matched hypertensive and healthy control subjects. In another study, carotid-femoral PWV velocity was also shown to be significantly greater in HFPEF patients with underlying coronary artery disease (CAD) vs both HF with reduced EF (HFREF) patients with CAD or individuals with CAD and preserved systolic function without HF.16Balmain S. Padmanabhan N. Ferrell W.R. Morton J.J. McMurray J.J. Differences in arterial compliance, microvascular function and venous capacitance between patients with heart failure and either preserved or reduced left ventricular systolic function.Eur J Heart Fail. 2007; 9: 865-871Crossref PubMed Scopus (57) Google Scholar Finally, our group showed that carotid distensibility, assessed by high-resolution ultrasound, is significantly reduced in HFPEF patients vs healthy older subjects (Table 1).21Kitzman D.W. Herrington D.M. Brubaker P.H. Moore J.B. Eggebeen J. Haykowsky M.J. Carotid arterial stiffness and its relationship to exercise intolerance in older patients with heart failure and preserved ejection fraction.Hypertension. 2013; 61: 112-119Crossref PubMed Scopus (78) Google ScholarTable 1Studies of Resting Vascular Function in HFPEF Patients and ControlsStudy/ySubjectsNo.Age (y)Sex (F)Imaging Modality or DeviceVascular MeasureMain FindingRelationship Between Vascular Function and Peak VO2Hundley,14Hundley W.G. Kitzman D.W. Morgan T.M. Hamilton C.A. Darty S.N. Stewart K.P. et al.Cardiac cycle-dependent changes in aortic area and distensibility are reduced in older patients with isolated diastolic heart failure and correlate with exercise intolerance.J Am Coll Cardiol. 2001; 38: 796-802Abstract Full Text Full Text PDF PubMed Scopus (323) Google Scholar 2001HFPEFHOHY101010777124856MRIADAMVHFPEF sig ↓ vs HO and HY; HO sig ↓ vs HYHFPEF sig ↓ vs HOAfter controlling for age and gender, AD was significant predictor of peak VO2Borlaug, 200615Borlaug B.A. Melenovsky V. Russell S.D. Kessler K. Pacak K. Becker L.C. et al.Impaired chronotropic and vasodilator reserves limit exercise capacity in patients with heart failure and a preserved ejection fraction.Circulation. 2006; 114: 2138-2147Crossref PubMed Scopus (510) Google ScholarHFPEFAGCM171965651616RV + BPEAESVRNo sig diff between groupsNo sig diff between groupsNot assessedBalmain, 200716Balmain S. Padmanabhan N. Ferrell W.R. Morton J.J. McMurray J.J. Differences in arterial compliance, microvascular function and venous capacitance between patients with heart failure and either preserved or reduced left ventricular systolic function.Eur J Heart Fail. 2007; 9: 865-871Crossref PubMed Scopus (57) Google ScholarHFPEF (PCAD)HFREF (PCAD)CON (PCAD + PSF)12121277 74 70847App TonLDIFVCCF-PWVCPVOPHFPEF sig ↑ vs HFREF and CONACH: CON Sig ↑ vs HFPEF & HFREFNitro: CON Sig ↑ vs HFPEF & HFREFHFPEF sig ↓ vs HFREFNot assessedHundley, 200717Hundley W.G. Bayram E. Hamilton C.A. Hamilton E.A. Morgan T.M. Darty S.N. et al.Leg flow-mediated arterial dilation in elderly patients with heart failure and normal left ventricular ejection fraction.Am J Physiol Heart Circ Physiol. 2007; 292: H1427-34Crossref PubMed Scopus (68) Google ScholarHFPEFHFREFHO98810747371645MRILeg FMDHFPEF and HO Sig ↑ vs HFREFAfter controlling for age and gender, leg FMD was a significant predictor of peak VO2 in HO and HFREFDesai, 200918Desai A.S. Mitchell G.F. Fang J.C. Creager M.A. Central aortic stiffness is increased in patients with heart failure and preserved ejection fraction.J Card Fail. 2009; 15: 658-664Abstract Full Text Full Text PDF PubMed Scopus (101) Google ScholarHFPEFHYP-no HFCON1623146266667129App TonCIPACAIFPWCF-PWVCR-PWVHFPEF sig ↑ vs CONHFPEF and HYP Sig ↓ vs CONNo sig difference between groupsHFPEF and HYP sig ↑ vs CONHFPEF sig ↑ vs HYP and CON, CON sig ↑ vs HYPNo sig difference between groupsNot assessedBorlaug, 201019Borlaug B.A. Olson T.P. Lam C.S. Flood K.S. Lerman A. Johnson B.D. et al.Global cardiovascular reserve dysfunction in heart failure with preserved ejection fraction.J Am Coll Cardiol. 2010; 56: 845-854Abstract Full Text Full Text PDF PubMed Scopus (515) Google ScholarHFPEFHYP-no HFCON21191067656216147EndopatEcho + BPDPATAEaSVRReactive hyperemic index sig ↓ in HFPEF and HYP-NoHF vs CONNo sig diff between groupsNo sig diff between groupsPeak VO2 significantly associated with change in reactive hyperemic indexHaykowsky,201320Haykowsky M.J. Herrington D.M. Brubaker P.H. Morgan T.M. Hundley W.G. Kitzman D.W. Relationship of flow-mediated arterial dilation and exercise capacity in older patients with heart failure and preserved ejection fraction.J Gerontol A Biol Sci Med Sci. 2013; 68: 161-167Crossref PubMed Scopus (54) Google ScholarHFPEFHOHY663116707025512110USBA FMDHFPEF & HO sig ↓ vs YHAfter controlling for age, gender, and BSA, no significant relationship between BAFMD and peak VO2Kitzman, 201321Kitzman D.W. Herrington D.M. Brubaker P.H. Moore J.B. Eggebeen J. Haykowsky M.J. Carotid arterial stiffness and its relationship to exercise intolerance in older patients with heart failure and preserved ejection fraction.Hypertension. 2013; 61: 112-119Crossref PubMed Scopus (78) Google ScholarHFPEFOHYH693824706924522512USCDCCPEMYEMBeta IndexHFPEF sig ↓ vs OHOH sig ↓ vs YHOH sig ↑ vs YHHFPEF sig ↑ vs OH, OH sig ↑ vs YHOH sig ↑ vs YHCD was directly and YEM, PEM, and beta index were was inversely related to peak VO2Farrero, 201422Farrero M. Blanco I. Batlle M. Santiago E. Cardona M. Vidal B. et al.Pulmonary hypertension is related to peripheral endothelial dysfunction in heart failure with preserved ejection fraction.Circ Heart Fail. 2014; 7: 791-798Crossref PubMed Scopus (41) Google ScholarHFPEFHYP-no HF284271682321USBAFMDHFPEF sig ↓ vs HYP. In subset of HFPEF patients with pulmonary hypertension, a sig inverse correlation with BA FMD and PVR was reported.Not assessedMarechaux, 201623Marechaux S. Samson R. van Belle E. Breyne J. de Monte J. Dédrie C. et al.Vascular and microvascular endothelial function in heart failure with preserved ejection fraction.J Card Fail. 2016; 22: 3-11Abstract Full Text Full Text PDF Scopus (54) Google ScholarHFPEFAGCM454570703635App TonUSLDRHCF-PWVAIAPTTRRWBAFMDPUNo sig diff between groupsNo sig diff between groupsHFPEF sig ↓ vs ACCMNo sig diff between groupsHFPEF sig ↓ vs ACCMHFPEF sig ↓ vs ACCMNot assessedAD, aortic distensibility; AGCM, age-, gender-, and comorbidity-matched control; AI, augmentation index; AMV, aortic maximal velocity; App Ton, applanation tonometry; AP, augmentation pressure; BAFMD, brachial artery flow-mediated dilation; CON, control; CC, carotid compliance; CD; carotid distensibility; CF-PWV, carotid-femoral pulse wave velocity; CI, characteristic impedance; CP, cutaneous perfusion; CR-PWV, carotid-radial pulse wave velocity; DPATA, digital peripheral arterial tonometer amplitude; EAE, effective arterial elastance; Echo, echocardiography; FMD, femoral artery flow-mediated dilation; FPW, forward pressure wave; FVC, forearm venous capacitance; HFPEF, heart failure with preserved ejection fraction; HFREF, heart failure with reduced ejection fraction; HO, healthy old; HY, healthy young; HYP-no HF, hypertension with no heart failure; LDI, laser Doppler imaging coupled with inotophoresis using acetylcholine (ACH) and sodium nitroprusside (nitro); LDRH, laser Doppler imaging during reactive hyperemia; MRI, magnetic resonance imaging; PAC, proximal aortic compliance; PCAD, presence of coronary artery disease; PCAD + PSF, presence of coronary artery disease and preserved systolic function with no evidence of HF; PEM, Peterson elastic modulus; PU, perfusion units; PVR, pulmonary vascular resistance; PWV, pulse wave velocity; RV + BP, radionuclide ventriculography and blood pressure; Sig, significantly; SVR, systemic vascular resistance; TTRRW, time to return reflected wave; US, ultrasound; VOP, venous occlusion plythesmography; YEM, Young elastic modulus. Open table in a new tab AD, aortic distensibility; AGCM, age-, gender-, and comorbidity-matched control; AI, augmentation index; AMV, aortic maximal velocity; App Ton, applanation tonometry; AP, augmentation pressure; BAFMD, brachial artery flow-mediated dilation; CON, control; CC, carotid compliance; CD; carotid distensibility; CF-PWV, carotid-femoral pulse wave velocity; CI, characteristic impedance; CP, cutaneous perfusion; CR-PWV, carotid-radial pulse wave velocity; DPATA, digital peripheral arterial tonometer amplitude; EAE, effective arterial elastance; Echo, echocardiography; FMD, femoral artery flow-mediated dilation; FPW, forward pressure wave; FVC, forearm venous capacitance; HFPEF, heart failure with preserved ejection fraction; HFREF, heart failure with reduced ejection fraction; HO, healthy old; HY, healthy young; HYP-no HF, hypertension with no heart failure; LDI, laser Doppler imaging coupled with inotophoresis using acetylcholine (ACH) and sodium nitroprusside (nitro); LDRH, laser Doppler imaging during reactive hyperemia; MRI, magnetic resonance imaging; PAC, proximal aortic compliance; PCAD, presence of coronary artery disease; PCAD + PSF, presence of coronary artery disease and preserved systolic function with no evidence of HF; PEM, Peterson elastic modulus; PU, perfusion units; PVR, pulmonary vascular resistance; PWV, pulse wave velocity; RV + BP, radionuclide ventriculography and blood pressure; Sig, significantly; SVR, systemic vascular resistance; TTRRW, time to return reflected wave; US, ultrasound; VOP, venous occlusion plythesmography; YEM, Young elastic modulus. A few studies have measured peripheral arterial endothelial function in HFPEF patients. Our group showed that brachial artery flow-mediated dilation (FMD) measured using high-resolution ultrasound in response to pressure cuff–induced ischemia, an endothelial-dependent stimulus, is not significantly different in HFPEF patients rigorously screened to exclude the confounding effects of atherosclerosis, compared with age-matched healthy controls (Table 1).20Haykowsky M.J. Herrington D.M. Brubaker P.H. Morgan T.M. Hundley W.G. Kitzman D.W. Relationship of flow-mediated arterial dilation and exercise capacity in older patients with heart failure and preserved ejection fraction.J Gerontol A Biol Sci Med Sci. 2013; 68: 161-167Crossref PubMed Scopus (54) Google Scholar Hundley et al, using phase contrast magnetic resonance imaging of the femoral artery in response to cuff-ischemia, showed that FMD in this key arterial compartment is also not reduced in HFPEF compared with healthy, age-matched controls, in stark contrast to the severely reduced femoral FMD they observed in matched patients with HFREF.17Hundley W.G. Bayram E. Hamilton C.A. Hamilton E.A. Morgan T.M. Darty S.N. et al.Leg flow-mediated arterial dilation in elderly patients with heart failure and normal left ventricular ejection fraction.Am J Physiol Heart Circ Physiol. 2007; 292: H1427-34Crossref PubMed Scopus (68) Google Scholar Both of these studies also measured peak exercise VO2, which, as expected, was reduced in HFPEF to an equal degree as HFREF, indicating that severe exercise intolerance in HFPEF can occur without impaired FMD. Farrero et al recently reported that brachial artery FMD was significantly reduced in HFPEF patients vs age-matched hypertensive controls.22Farrero M. Blanco I. Batlle M. Santiago E. Cardona M. Vidal B. et al.Pulmonary hypertension is related to peripheral endothelial dysfunction in heart failure with preserved ejection fraction.Circ Heart Fail. 2014; 7: 791-798Crossref PubMed Scopus (41) Google Scholar In a subset of HFPEF patients with pulmonary hypertension, in whom right heart catheterization was performed, there was an inverse relationship between brachial artery FMD and pulmonary vascular resistance.22Farrero M. Blanco I. Batlle M. Santiago E. Cardona M. Vidal B. et al.Pulmonary hypertension is related to peripheral endothelial dysfunction in heart failure with preserved ejection fraction.Circ Heart Fail. 2014; 7: 791-798Crossref PubMed Scopus (41) Google Scholar Finally, HFPEF patients have also been shown to have impaired microvascular function, which is associated with reduced exercise capacity and also is an independent predictor of HF events.16Balmain S. Padmanabhan N. Ferrell W.R. Morton J.J. McMurray J.J. Differences in arterial compliance, microvascular function and venous capacitance between patients with heart failure and either preserved or reduced left ventricular systolic function.Eur J Heart Fail. 2007; 9: 865-871Crossref PubMed Scopus (57) Google Scholar, 19Borlaug B.A. Olson T.P. Lam C.S. Flood K.S. Lerman A. Johnson B.D. et al.Global cardiovascular reserve dysfunction in heart failure with preserved ejection fraction.J Am Coll Cardiol. 2010; 56: 845-854Abstract Full Text Full Text PDF PubMed Scopus (515) Google Scholar, 24Matsue Y. Suzuki M. Nagahori W. Ohno M. Matsumura A. Hashimoto Y. et al.Endothelial dysfunction measured by peripheral arterial tonometry predicts prognosis in patients with heart failure with preserved ejection fraction.Int J Cardiol. 2013; 168: 36-40Abstract Full Text Full Text PDF PubMed Scopus (48) Google Scholar These microvascular function impairments are in accord with our group's finding of reduced capillary density in skeletal muscle in HFPEF and its relation to reduced peak VO2.25Kitzman D.W. Nicklas B. Kraus W.E. Lyles M.F. Eggebeen J. Morgan T.M. et al.Skeletal muscle abnormalities and exercise intolerance in older patients with heart failure and preserved ejection fraction.Am J Physiol Heart Circ Physiol. 2014; 306: H1364-70Crossref PubMed Scopus (215) Google Scholar In summary, prior studies have established that HFPEF patients have abnormalities in function in multiple segments of the arterial tree, and that these contribute to their severe exercise intolerance. In this issue of Journal of Cardiac Failure, Marechaux et al23Marechaux S. Samson R. van Belle E. Breyne J. de Monte J. Dédrie C. et al.Vascular and microvascular endothelial function in heart failure with preserved ejection fraction.J Card Fail. 2016; 22: 3-11Abstract Full Text Full Text PDF Scopus (54) Google Scholar provide new data on arterial function in HFPEF. This study is the first to simultaneously assess function in all 3 major arterial compartments in HFPEF patients. The authors measured carotid-femoral PWV, brachial artery FMD in response to 5 minutes of cuff ischemia, laser Doppler–derived skin (thenar region) perfusion at rest and during reactive hyperemia in 45 older (mean age, 70 years) HFPEF patients, and 45 sedentary hypertensive control subjects without a history or evidence of HF matched for age, sex, body mass index, and diabetes. Despite this matching, a significantly greater number of HFPEF patients had a history of CAD (4.5-fold greater prevalence) as well as using beta-blockers and loop diuretics compared with controls (Table 1). The authors reported that brachial artery FMD, reactive hyperemia skin perfusion (including both the first and second rise in perfusion units), and estimated aortic diastolic pressure were significantly lower, whereas estimated aortic pulse pressure and augmentation pressure were significantly increased in HFPEF patients compared with controls (Table 1). Unexpectedly, no significant difference was found between groups for carotid-femoral PWV, estimated aortic systolic blood pressure, augmentation index, time-to-return of reflected wave, and basal skin perfusion. Differences between groups for brachial FMD and reactive hyperemia-mediated second slope of the rise in skin perfusion remained significant after adjusting for beta-blocker and diuretic therapy and history of CAD. The authors are congratulated for performing a comprehensive examination of arterial function and inclusion of older HFPEF patients and sedentary hypertensive control subjects matched for age, sex, gender, and diabetes. Prior studies have measured 1 or several indices of arterial function along the oxygen cascade in HFPEF patients and age-matched healthy or comorbidity-matched controls without HF. As shown in Table 1, a consistent finding across studies is that arterial stiffness and microvascular function are impaired in HFPEF patients (with or without underlying CAD), whereas brachial artery and femoral artery endothelial function are preserved compared with healthy age-matched or comorbidity-matched controls without HF. In the current study, arterial stiffness was preserved, whereas peripheral (brachial artery FMD) endothelial function and microvascular function was impaired in HFPEF patients and age- and comorbidity-matched (except for CAD) controls. The disparity between studies for arterial stiffness data may be due to the HFPEF patients in the current study having more favorable arterial function than that previously reported for HFPEF patients. Specifically, carotid-femoral PWV in HFPEF patients (16.6 m/s) and hypertensive controls (11.4 m/s) studied by Desai et al18Desai A.S. Mitchell G.F. Fang J.C. Creager M.A. Central aortic stiffness is increased in patients with heart failure and preserved ejection fraction.J Card Fail. 2009; 15: 658-664Abstract Full Text Full Text PDF PubMed Scopus (101) Google Scholar are greater than that reported in the current study for HFPEF patients (11.3 m/s) and hypertensive controls (10.1 m/s). Given that central (carotid and aortic stiffness), peripheral (superficial femoral artery FMD), and microvascular function are associated with a lower peak VO2 in HFPEF patients,17Hundley W.G. Bayram E. Hamilton C.A. Hamilton E.A. Morgan T.M. Darty S.N. et al.Leg flow-mediated arterial dilation in elderly patients with heart failure and normal left ventricular ejection fraction.Am J Physiol Heart Circ Physiol. 2007; 292: H1427-34Crossref PubMed Scopus (68) Google Scholar, 19Borlaug B.A. Olson T.P. Lam C.S. Flood K.S. Lerman A. Johnson B.D. et al.Global cardiovascular reserve dysfunction in heart failure with preserved ejection fraction.J Am Coll Cardiol. 2010; 56: 845-854Abstract Full Text Full Text PDF PubMed Scopus (515) Google Scholar, 21Kitzman D.W. Herrington D.M. Brubaker P.H. Moore J.B. Eggebeen J. Haykowsky M.J. Carotid arterial stiffness and its relationship to exercise intolerance in older patients with heart failure and preserved ejection fraction.Hypertension. 2013; 61: 112-119Crossref PubMed Scopus (78) Google Scholar it is possible that differences between studies for arterial stiffness may be due to the HFPEF patients in the current study having higher exercise capacity compared with HFPEF patients included in previous investigations. The finding in the current study that brachial artery FMD is significantly lower in HFPEF patients compared with hypertensive controls is consistent with that reported by Farrero et al, who studied similar patient and control subjects (Table 1).22Farrero M. Blanco I. Batlle M. Santiago E. Cardona M. Vidal B. et al.Pulmonary hypertension is related to peripheral endothelial dysfunction in heart failure with preserved ejection fraction.Circ Heart Fail. 2014; 7: 791-798Crossref PubMed Scopus (41) Google Scholar However, these findings contrast with 2 other studies that showed that brachial artery and superficial femoral artery FMD is not significantly different between HFPEF patients and age-matched healthy controls.17Hundley W.G. Bayram E. Hamilton C.A. Hamilton E.A. Morgan T.M. Darty S.N. et al.Leg flow-mediated arterial dilation in elderly patients with heart failure and normal left ventricular ejection fraction.Am J Physiol Heart Circ Physiol. 2007; 292: H1427-34Crossref PubMed Scopus (68) Google Scholar, 20Haykowsky M.J. Herrington D.M. Brubaker P.H. Morgan T.M. Hundley W.G. Kitzman D.W. Relationship of flow-mediated arterial dilation and exercise capacity in older patients with heart failure and preserved ejection fraction.J Gerontol A Biol Sci Med Sci. 2013; 68: 161-167Crossref PubMed Scopus (54) Google Scholar The disparity between the present findings with regard to FMD and those of the 2 prior studies is likely related to atherosclerosis. Given the profound influence of atherosclerosis on endothelial function and FMD,26Celermajer D.S. Sorensen K.E. Bull C. Robinson J. Deanfield J.E. Endothelium-dependent dilation in the systemic arteries of asymptomatic subjects relates to coronary risk factors and their interaction.J Am Coll Cardiol. 1994; 24: 1468-1474Abstract Full Text PDF PubMed Scopus (1121) Google Scholar, 27Anderson T.J. Uehata A. Gerhard M.D. Meredith I.T. Knab S. Delagrange D. et al.Close relation of endothelial function in the human coronary and peripheral circulations.J Am Coll Cardiol. 1995; 26: 1235-1241Abstract Full Text PDF PubMed Scopus (1759) Google Scholar for the Haykowsky et al and Hundley et al studies, both HFPEF patients and healthy subjects were rigorously screened to exclude those at high risk (hyperlipidemia, cigarette smoking) and those with known or suspected coronary, cerebrovascular, and peripheral arterial disease by record review, history, physical examination, exercise echocardiography, and carotid ultrasound. This was done to determine whether any differences in FMD were due to HFPEF rather than from differences in atherosclerosis. These 2 studies indicate that abnormal FMD is not intrinsic to HFPEF and may not be an independent contributor to severe exercise intolerance. All other studies of arterial function in HFPEF, including the present study, included significant numbers of patients with clinically evident (and therefore advanced) atherosclerosis. For instance, in the present study, the 4.5-fold higher prevalence of CAD in the HFPEF patients compared with hypertensive controls in the present study likely contributed to the significantly lower FMD in the HFPEF patients and may account for differences in FMD outcomes between studies. Although statistical adjustments for CAD were made, this technique is not robust for isolating atherosclerosis as a confounder as prospective, comprehensive screening, particularly when the brachial artery is the target vessel. Regardless, the findings by Merechaux et al23Marechaux S. Samson R. van Belle E. Breyne J. de Monte J. Dédrie C. et al.Vascular and microvascular endothelial function in heart failure with preserved ejection fraction.J Card Fail. 2016; 22: 3-11Abstract Full Text Full Text PDF Scopus (54) Google Scholar and Ferraro et al22Farrero M. Blanco I. Batlle M. Santiago E. Cardona M. Vidal B. et al.Pulmonary hypertension is related to peripheral endothelial dysfunction in heart failure with preserved ejection fraction.Circ Heart Fail. 2014; 7: 791-798Crossref PubMed Scopus (41) Google Scholar indicate that in the general population of typical HFPEF patients, which includes a significant percentage of patients with CAD and atherosclerosis, FMD is reduced and may be a target for intervention. An important limitation of the present Merechaux et al23Marechaux S. Samson R. van Belle E. Breyne J. de Monte J. Dédrie C. et al.Vascular and microvascular endothelial function in heart failure with preserved ejection fraction.J Card Fail. 2016; 22: 3-11Abstract Full Text Full Text PDF Scopus (54) Google Scholar study is that exercise capacity was not measured. In addition, assessments of FMD arterial and microvascular function were performed only in the arm, which does not participate significantly in endurance exercise. Thus, it is not possible to determine the roles that the vascular abnormalities they observed play in limiting exercise capacity and producing symptoms in HFPEF. However, prior studies that included cardiopulmonary exercise testing in concert with testing of arterial function have established a clear link between exercise capacity and all 3 aspects of arterial function, including arterial stiffness, arterial dilation, and microvascular function.14Hundley W.G. Kitzman D.W. Morgan T.M. Hamilton C.A. Darty S.N. Stewart K.P. et al.Cardiac cycle-dependent changes in aortic area and distensibility are reduced in older patients with isolated diastolic heart failure and correlate with exercise intolerance.J Am Coll Cardiol. 2001; 38: 796-802Abstract Full Text Full Text PDF PubMed Scopus (323) Google Scholar, 15Borlaug B.A. Melenovsky V. Russell S.D. Kessler K. Pacak K. Becker L.C. et al.Impaired chronotropic and vasodilator reserves limit exercise capacity in patients with heart failure and a preserved ejection fraction.Circulation. 2006; 114: 2138-2147Crossref PubMed Scopus (510) Google Scholar, 19Borlaug B.A. Olson T.P. Lam C.S. Flood K.S. Lerman A. Johnson B.D. et al.Global cardiovascular reserve dysfunction in heart failure with preserved ejection fraction.J Am Coll Cardiol. 2010; 56: 845-854Abstract Full Text Full Text PDF PubMed Scopus (515) Google Scholar, 21Kitzman D.W. Herrington D.M. Brubaker P.H. Moore J.B. Eggebeen J. Haykowsky M.J. Carotid arterial stiffness and its relationship to exercise intolerance in older patients with heart failure and preserved ejection fraction.Hypertension. 2013; 61: 112-119Crossref PubMed Scopus (78) Google Scholar, 25Kitzman D.W. Nicklas B. Kraus W.E. Lyles M.F. Eggebeen J. Morgan T.M. et al.Skeletal muscle abnormalities and exercise intolerance in older patients with heart failure and preserved ejection fraction.Am J Physiol Heart Circ Physiol. 2014; 306: H1364-70Crossref PubMed Scopus (215) Google Scholar It is noteworthy that studies of arterial function in patients with HFREF have shown profound abnormalities in arterial function in all 3 arterial compartments (stiffness, vasodilation, and microvascular).28Rerkpattanapipat P. Hundley W.G. Link K.M. Brubaker P.H. Hamilton C.A. Darty S.N. et al.Relation of aortic distensibility determined by magnetic resonance imaging in patients > or =60 years of age to systolic heart failure and exercise capacity.Am J Cardiol. 2002; 90: 1221-1225Abstract Full Text Full Text PDF PubMed Scopus (81) Google Scholar, 29Hornig B. Maier V. Drexler H. Physical training improves endothelial function in patients with chronic heart failure.Circulation. 1996; 93: 210-214Crossref PubMed Scopus (539) Google Scholar, 30Zelis R. Sinoway L.I. Musch T.I. Davis D. Just H. Regional blood flow in congestive heart failure: concept of compensatory mechanisms with short and long time constants.Am J Cardiol. 1988; 62: 2E-8EAbstract Full Text PDF PubMed Scopus (56) Google Scholar Further, in HFREF, these abnormalities are present even in patients without known atherosclerosis, a distinction from HFPEF.2Haykowsky M.J. Tomczak C.R. Scott J.M. Patterson D.I. Kitzman D.W. Determinants of exercise intolerance in patients with heart failure and reduced or preserved ejection fraction.J Appl Physiol (1985). 2015; 119: 739-744Crossref PubMed Scopus (124) Google Scholar In HFREF, arterial dysfunction in each of these compartments contributes significantly to their severe exercise intolerance.2Haykowsky M.J. Tomczak C.R. Scott J.M. Patterson D.I. Kitzman D.W. Determinants of exercise intolerance in patients with heart failure and reduced or preserved ejection fraction.J Appl Physiol (1985). 2015; 119: 739-744Crossref PubMed Scopus (124) Google Scholar Further, FMD improves with exercise training and contributes to the training-related improvement in peak VO2,29Hornig B. Maier V. Drexler H. Physical training improves endothelial function in patients with chronic heart failure.Circulation. 1996; 93: 210-214Crossref PubMed Scopus (539) Google Scholar another distinction from HFPEF.11Kitzman D.W. Brubaker P.H. Herrington D.M. Morgan T.M. Stewart K.P. Hundley W.G. 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: 584-592Abstract Full Text Full Text PDF PubMed Scopus (239) Google Scholar Of the 3 vascular function abnormalities identified to date in HFPEF, microvascular function may be the most consequential. First, perfusion is critical to skeletal muscle function and thus most relevant to exercise.2Haykowsky M.J. Tomczak C.R. Scott J.M. Patterson D.I. Kitzman D.W. Determinants of exercise intolerance in patients with heart failure and reduced or preserved ejection fraction.J Appl Physiol (1985). 2015; 119: 739-744Crossref PubMed Scopus (124) Google Scholar Second, microvascular dysfunction has a proven histological correlate in reduced capillary density in HFPEF.25Kitzman D.W. Nicklas B. Kraus W.E. Lyles M.F. Eggebeen J. Morgan T.M. et al.Skeletal muscle abnormalities and exercise intolerance in older patients with heart failure and preserved ejection fraction.Am J Physiol Heart Circ Physiol. 2014; 306: H1364-70Crossref PubMed Scopus (215) Google Scholar Third, microvascular dysfunction in peripheral tissues is matched by microvascular pruning in the myocardium in HFPEF.31Mohammed S.F. Hussain S. Mirzoyev S.A. Edwards W.D. Maleszewski J.J. Redfield M.M. Coronary microvascular rarefaction and myocardial fibrosis in heart failure with preserved ejection fraction.Circulation. 2015; 131: 550-559Crossref PubMed Scopus (498) Google Scholar Fourth, microvascular dysfunction is the only abnormality that has been shown to be related to mortality in HFPEF.32Akiyama E. Sugiyama S. Matsuzawa Y. Konishi M. Suzuki H. Nozaki T. et al.Incremental prognostic significance of peripheral endothelial dysfunction in patients with heart failure with normal left ventricular ejection fraction.J Am Coll Cardiol. 2012; 60: 1778-1786Abstract Full Text Full Text PDF PubMed Scopus (200) Google Scholar Mechanistically, microvascular dysfunction and reduced capillary density may be driven by systemic inflammation, neurohumoral activation, and other systemic factors, providing a long-sought unifying hypothesis for HFPEF pathophysiology.33Kitzman D.W. Upadhya B. Vasu S. What the dead can teach the living: systemic nature of heart failure with preserved ejection fraction.Circulation. 2015; 131: 522-524Crossref PubMed Scopus (28) Google Scholar These vascular abnormalities have therapeutic implications. The large pharmacological clinical trials in HFPEF have focused on ameliorating cardiac abnormalities and have not shown benefit. The first study to attempt to improve HFPEF by addressing arterial dysfunction was reported in this journal 10 years ago. In a pilot study, Little et al sought to improve aortic distensibility and exercise capacity in HFPEF using a novel glucose cross-link breaker and found no benefit.34Little W.C. Zile M.R. Kitzman D.W. Hundley W.G. O'Brien T.X. Degroof R.C. The effect of alagebrium chloride (ALT-711), a novel glucose cross-link breaker, in the treatment of elderly patients with diastolic heart failure.J Card Fail. 2005; 11: 191-195Abstract Full Text Full Text PDF PubMed Scopus (265) Google Scholar Another trial used a standard angiotensin-converting enzyme inhibitor given for a full year was also unable to improve aortic distensibility.35Kitzman D.W. Hundley W.G. Brubaker P.H. Morgan T.M. Moore J.B. Stewart K.P. et al.A randomized double-blind trial of enalapril in older patients with heart failure and preserved ejection fraction: effects on exercise tolerance and arterial distensibility.Circ Heart Fail. 2010; 3: 477-485Crossref PubMed Scopus (107) Google Scholar Thus, large artery stiffness, which likely developed over decades in a HFPEF patient and is layered on top of age-related changes, may be difficult to modify. As discussed, previous studies indicated that nearly all of the improvement in peak VO2 with exercise training in HFPEF is due to improved peripheral function (increased a-vO2diff)10Haykowsky M.J. Brubaker P.H. Stewart K.P. Morgan T.M. Eggebeen J. Kitzman D.W. 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: 120-128Abstract Full Text Full Text PDF PubMed Scopus (230) Google Scholar but not from improved FMD or arterial stiffness.11Kitzman D.W. Brubaker P.H. Herrington D.M. Morgan T.M. Stewart K.P. Hundley W.G. 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: 584-592Abstract Full Text Full Text PDF PubMed Scopus (239) Google Scholar This leaves, by elimination, microvascular and/or skeletal muscle abnormalities that could have improved with exercise training and produced the substantial improvements observed in peak VO2 in HFPEF.2Haykowsky M.J. Tomczak C.R. Scott J.M. Patterson D.I. Kitzman D.W. Determinants of exercise intolerance in patients with heart failure and reduced or preserved ejection fraction.J Appl Physiol (1985). 2015; 119: 739-744Crossref PubMed Scopus (124) Google Scholar, 10Haykowsky M.J. Brubaker P.H. Stewart K.P. Morgan T.M. Eggebeen J. Kitzman D.W. 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: 120-128Abstract Full Text Full Text PDF PubMed Scopus (230) Google Scholar, 11Kitzman D.W. Brubaker P.H. Herrington D.M. Morgan T.M. Stewart K.P. Hundley W.G. 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: 584-592Abstract Full Text Full Text PDF PubMed Scopus (239) Google Scholar We suggest these may be fruitful areas of focus for future studies to understand pathophysiology and improve outcomes in the important and growing population with HFPEF. Dr Kitzman declares the following relationships: consultant for Abbvie, GSK, Relypsa, Regeneron, Merck, Corvia Medical, and Actavis; grant funding from Novartis; and stock ownership in Gilead Sciences and Relypsa. Dr Haykowsky has no conflicts of interest to declare.