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Determinants of exercise capacity in patients with heart failure without left ventricular hypertrophy

Published:October 01, 2022DOI:https://doi.org/10.1016/j.jjcc.2022.09.004

      Highlights

      • We evaluated the mechanisms of exercise intolerance in HFpEF without LVH.
      • In this population, PH and RV to PA uncoupling were associated with exercise capacity.
      • PA distensibility might affect exercise intolerance in HFpEF patients without LVH.

      Abstract

      Background

      Determinants of exercise intolerance in a phenotype of heart failure with preserved ejection fraction (HFpEF) with normal left ventricular (LV) structure have not been fully elucidated.

      Methods

      Cardiopulmonary exercise testing and exercise-stress echocardiography were performed in 44 HFpEF patients without LV hypertrophy. Exercise capacity was determined by peak oxygen consumption (peak VO2). Doppler-derived cardiac output (CO), transmitral E velocity, systolic (LV-s′) and early diastolic mitral annular velocities (e′), systolic pulmonary artery (PA) pressure (SPAP), tricuspid annular plane systolic excursion (TAPSE), and peak systolic right ventricular (RV) free wall velocity (RV-s′) were measured at rest and exercise. E/e′ and TAPSE/SPAP were used as an LV filling pressure parameter and RV-PA coupling, respectively.

      Results

      During exercise, CO, LV-s′, RV-s′, e′, and SPAP were significantly increased (p < 0.05 for all), whereas E/e′ remained unchanged and TAPSE/SPAP was significantly reduced (p < 0.001). SPAP was higher and TAPSE/SPAP was lower at peak exercise in patients showing lower-half peak VO2. In univariable analyses, LV-s′ (R = 0.35, p = 0.022), SPAP (R = −0.40, p = 0.008), RV-s′ (R = 0.47, p = 0.002), and TAPSE/SPAP (R = 0.42, p = 0.005) were significantly correlated with peak VO2. In multivariable analyses, not only SPAP, but also TAPSE/SPAP independently determined peak VO2 even after the adjustment for clinically relevant parameters.

      Conclusions

      In HFpEF patients without LV hypertrophy, altered RV-PA coupling by exercise could be associated with exercise intolerance, which might not be caused by elevated LV filling pressure.

      Graphical abstract

      Keywords

      Introduction

      Limited exercise capacity is a major symptom in patients with chronic heart failure (HF) regardless of the left ventricular (LV) ejection fraction (EF) [
      • Del Buono M.G.
      • Arena R.
      • Borlaug B.A.
      • Carbone S.
      • Canada J.M.
      • Kirkman D.L.
      • et al.
      Exercise intolerance in patients with heart failure: JACC state-of-the-art review.
      ]. Over the past decade, contributors to the reduced exercise capacity are being gradually elucidated in HF with preserved LV EF (HFpEF), that is, abnormal increase in LV filling pressure, blunted heart rate response, peripheral factors, and impaired right ventricular (RV) to pulmonary artery (PA) coupling during exercise [
      • Abudiab M.M.
      • Redfield M.M.
      • Melenovsky V.
      • Olson T.P.
      • Kass D.A.
      • Johnson B.D.
      • et al.
      Cardiac output response to exercise in relation to metabolic demand in heart failure with preserved ejection fraction.
      ,
      • Guazzi M.
      • Dixon D.
      • Labate V.
      • Beussink-Nelson L.
      • Bandera F.
      • Cuttica M.J.
      • et al.
      RV contractile function and its coupling to pulmonary circulation in heart failure with preserved ejection fraction: stratification of clinical phenotypes and outcomes.
      ,
      • Haykowsky 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.
      ,
      • Reddy Y.N.V.
      • Olson T.P.
      • Obokata M.
      • Melenovsky V.
      • Borlaug B.A.
      Hemodynamic correlates and diagnostic role of cardiopulmonary exercise testing in heart failure with preserved ejection fraction.
      ]. Among the contributing factors, elevated LV filling pressure caused by increased LV stiffness manifests the characteristics of HFpEF patients [
      • Reddy Y.N.V.
      • Olson T.P.
      • Obokata M.
      • Melenovsky V.
      • Borlaug B.A.
      Hemodynamic correlates and diagnostic role of cardiopulmonary exercise testing in heart failure with preserved ejection fraction.
      ,
      • Zile M.R.
      • Gaasch W.H.
      • Carroll J.D.
      • Feldman M.D.
      • Aurigemma G.P.
      • Schaer G.L.
      • et al.
      Heart failure with a normal ejection fraction: is measurement of diastolic function necessary to make the diagnosis of diastolic heart failure?.
      ,
      • Shah A.M.
      • Claggett B.
      • Sweitzer N.K.
      • Shah S.J.
      • Anand I.S.
      • O'Meara E.
      • et al.
      Cardiac structure and function and prognosis in heart failure with preserved ejection fraction: findings from the echocardiographic study of the treatment of preserved cardiac function heart failure with an aldosterone antagonist (TOPCAT) trial.
      ]. And in general, the changes in LV properties are assumed to result from LV hypertrophy or concentric remodeling [
      • Zile M.R.
      • Gaasch W.H.
      • Carroll J.D.
      • Feldman M.D.
      • Aurigemma G.P.
      • Schaer G.L.
      • et al.
      Heart failure with a normal ejection fraction: is measurement of diastolic function necessary to make the diagnosis of diastolic heart failure?.
      ]. On the other hand, a substantial proportion of HFpEF patients are reported to lack abnormal cardiac morphology [
      • Lam C.S.
      • Roger V.L.
      • Rodeheffer R.J.
      • Bursi F.
      • Borlaug B.A.
      • Ommen S.R.
      • et al.
      Cardiac structure and ventricular-vascular function in persons with heart failure and preserved ejection fraction from Olmsted CountyMinnesota.
      ,
      • Zile M.R.
      • Gottdiener J.S.
      • Hetzel S.J.
      • McMurray J.J.
      • Komajda M.
      • McKelvie R.
      • et al.
      Prevalence and significance of alterations in cardiac structure and function in patients with heart failure and a preserved ejection fraction.
      ]. They are considered a subset of patients with minor cardiac loads and degeneration, but little is known what leads to impaired exercise tolerance in LV properties. We thought that by focusing on this specific subset, we might approach the mechanisms that lead to impaired exercise capacity in HFpEF without LV hypertrophy.

      Methods

      Study population and protocol

      This study was designed as a prospective observational study of adult HF patients in a single tertiary hospital from September 2019 to July 2021. Patients were included according to echocardiographic criteria: I) normal LV mass index (≤115 g/m2 in men, ≤95 g/m2 in women) and II) preserved LV ejection fraction ≥50 % and met at least one of the following clinical criteria: 1) history of HF hospitalization, 2) presenting any HF symptoms, 3) signs of LV diastolic dysfunction according to the guidelines [
      • Nagueh S.F.
      • Smiseth O.A.
      • Appleton C.P.
      • Byrd 3rd, B.F.
      • Dokainish H.
      • Edvardsen T.
      • et al.
      Recommendations for the evaluation of left ventricular diastolic function by echocardiography: an update from the American Society of Echocardiography and the european Association of Cardiovascular Imaging.
      ], 4) elevated plasma N-terminal brain natriuretic peptide (NT-proBNP) levels (≥125 pg/mL), and 5) those with history of atrial fibrillation (AF). To avoid including AF patients without HFpEF, we excluded AF patients who lacked objective evidence of HFpEF; i.e. HFA-PEFF score < 5 [
      • Pieske B.
      • Tschope C.
      • de Boer R.A.
      • Fraser A.G.
      • Anker S.D.
      • Donal E.
      • et al.
      How to diagnose heart failure with preserved ejection fraction: the HFA-PEFF diagnostic algorithm: a consensus recommendation from the heart failure association (HFA) of the european Society of Cardiology (ESC).
      ]. Other exclusion criteria were set at known cardiomyopathy or myocardial diseases, significant left-sided valvular heart disease (≥moderate regurgitation, ≥mild stenosis), prior cardiac surgery, congenital heart disease, left-to-right shunt, unstable coronary artery disease, and constrictive pericarditis. Also, patients with lung disease were carefully excluded based on the findings of chest X-rays and spirometry. Accordingly, 52 patients were included in the final analysis. After written informed consent was obtained, blood samples were stored, and exercise-stress echocardiography (ESE), cardiopulmonary exercise testing (CPET), and cardiac magnetic resonance (CMR) were examined within 7 days. When the patient was given a β blocker, exercise testing was done under its continuation. The study was performed in accordance with the declaration of Helsinki, and our institutional review board approved the protocol.

      Data collection

      We collected the following data from all study participants: body mass index, vital signs, comorbidities, medications, New York Heart Association (NYHA) functional class, clinical frailty scale (CFS), HFA-PEFF score, and laboratory analysis. Systemic hypertension was defined as elevated resting blood pressure (systolic blood pressure ≥ 140 mm Hg) or taking medication including calcium channel blockers, angiotensin-converting enzyme inhibitors (ACEI), angiotensin II receptor blockers (ARB), or beta-blockers. HFA-PEFF score was calculated using the recently proposed algorithm using Step 2 [
      • Pieske B.
      • Tschope C.
      • de Boer R.A.
      • Fraser A.G.
      • Anker S.D.
      • Donal E.
      • et al.
      How to diagnose heart failure with preserved ejection fraction: the HFA-PEFF diagnostic algorithm: a consensus recommendation from the heart failure association (HFA) of the european Society of Cardiology (ESC).
      ], accounting for e′, E/e′, TR peak velocity, LAVI, LVMI, and serum NT-proBNP level. In addition, serum levels of procollagen-III-peptide (P-III-P) were measured on the immunoradiometric assay (BML, Tokyo, Japan) to obtain a marker of myocardial fibrosis.

      Cardiopulmonary exercise testing

      A symptom-limited CPET was performed using an upright electromechanical bicycle ergometer (Aerobike 75XLII; Combi Wellness, Tokyo, Japan) using a ramp protocol. Oxygen consumption (VO2), carbon dioxide production (VCO2), and minute ventilation (VE) were measured using simultaneous respiratory gas analysis with a breathing apparatus (Aeromonitor AE-300S; Minato Medical Science, Osaka, Japan). Exercise capacity was assessed by the highest value of maximum VO2 (peak VO2). The maximum work and anaerobic threshold (AT) determined by the V-slope method were also measured [
      • Beaver W.L.
      • Wasserman K.
      • Whipp B.J.
      A new method for detecting anaerobic threshold by gas exchange.
      ]. Ventilatory efficiency was expressed by the slope of VE/VCO2.

      Exercise stress echocardiography

      ESE was performed by using a supine bicycle ergometer (Angio V2; Lode BV, Groningen, Netherlands) and an iE33 ultrasound system with an S5-1 transducer (Philips Ultrasound, Bothell WA, USA). To adjust the workload among the patients, we defined submaximal workload as the level of AT and the peak workload as 80 % of the peak load (AT and peak load were adapted from the result of CPET) [
      • Tsujinaga S.
      • Iwano H.
      • Sarashina M.
      • Hayashi T.
      • Murayama M.
      • Ichikawa A.
      • et al.
      Diastolic intra-left ventricular pressure difference during exercise: strong determinant and predictor of exercise capacity in patients with heart failure.
      ]. The workload was increased to the level of AT in a minute and two-dimensional, Doppler, and color M-mode Doppler (CMMD) echocardiographic images at submaximal exercise were acquired within 3 min. After that, the workload was further increased to the peak level in the following 2 min, and images at peak exercise were obtained. Standard measurements of the LV and left atrial (LA) chambers were obtained in accordance with current recommendations [
      • Lang R.M.
      • Badano L.P.
      • Mor-Avi V.
      • Afilalo J.
      • Armstrong A.
      • Ernande L.
      • et al.
      Recommendations for cardiac chamber quantification by echocardiography in adults: an update from the American Society of Echocardiography and the European Association of Cardiovascular Imaging.
      ]. Stroke volume (SV) was calculated from the time velocity integral of the LV ejection flow and the diameter of the LV outflow tract. Cardiac output was calculated as SV times heart rate. Transmitral Doppler flow was recorded, and peak early-diastolic velocity (E) was measured. Peak systolic (s′) and early-diastolic (e′) septal mitral annular velocities were measured from the apical 4-chamber view and the ratio of E to septal e′ (E/e′) was calculated. CMMD images were recorded with the cursor parallel to LV inflow in the apical 4-chamber view to analyze intraventricular pressure difference (IVPD). Tricuspid regurgitation pressure gradient (TRPG) was estimated by continuous Doppler image and systolic pulmonary artery pressure (SPAP) was estimated by adding right atrial pressure of 10 mm Hg [
      • Ha J.W.
      • Choi D.
      • Park S.
      • Shim C.Y.
      • Kim J.M.
      • Moon S.H.
      • et al.
      Determinants of exercise-induced pulmonary hypertension in patients with normal left ventricular ejection fraction.
      ]. In 5 patients whose TRPG was not available, SPAP was assumed to be 20 mm Hg [
      • Harada T.
      • Obokata M.
      • Omote K.
      • Iwano H.
      • Ikoma T.
      • Okada K.
      • et al.
      Independent and incremental prognostic value of semiquantitative measures of tricuspid regurgitation severity in heart failure with preserved ejection fraction.
      ]. Mean pulmonary artery pressure was estimated by using the following formula: Mean pulmonary artery pressure = 0.61 × SPAP + 2 mm Hg [
      • Chemla D.
      • Castelain V.
      • Humbert M.
      • Hébert J.L.
      • Simonneau G.
      • Lecarpentier Y.
      • et al.
      New formula for predicting mean pulmonary artery pressure using systolic pulmonary artery pressure.
      ]. Total pulmonary resistance (TPR) was calculated as mean pulmonary artery pressure divided by cardiac output. RV functional indices including tricuspid annular plane systolic excursion (TAPSE), peak systolic RV free wall velocity (RV-s′), and RV fractional area change (RVFAC) were measured according to the current guideline [
      • Lang R.M.
      • Badano L.P.
      • Mor-Avi V.
      • Afilalo J.
      • Armstrong A.
      • Ernande L.
      • et al.
      Recommendations for cardiac chamber quantification by echocardiography in adults: an update from the American Society of Echocardiography and the European Association of Cardiovascular Imaging.
      ]. RV-PA coupling was assessed by TAPSE/SPAP [
      • Guazzi M.
      • Dixon D.
      • Labate V.
      • Beussink-Nelson L.
      • Bandera F.
      • Cuttica M.J.
      • et al.
      RV contractile function and its coupling to pulmonary circulation in heart failure with preserved ejection fraction: stratification of clinical phenotypes and outcomes.
      ]. In patients with AF at the time of evaluation, all measurements were repeated at least three times and averaged.

      Speckle tracking method

      LV global longitudinal strain (GLS) were assessed using the speckle tracking method. Two-dimensional echocardiographic images were analyzed offline by using vendor-independent software (2D Strain Analysis software version TTA2.4, TomTec Imaging Systems, Unterschleissheim, Germany) as previously reported [
      • Mor-Avi V.
      • Lang R.M.
      • Badano L.P.
      • Belohlavek M.
      • Cardim N.M.
      • Derumeaux G.
      • et al.
      Current and evolving echocardiographic techniques for the quantitative evaluation of cardiac mechanics: ASE/EAE consensus statement on methodology and indications endorsed by the Japanese Society of Echocardiography.
      ]. LV endocardial border was manually traced in the apical four-, two-, and three-chamber views to determine LV global longitudinal strain (GLS). GLS was then averaged and expressed as an absolute value.

      Analysis of the IVPD with the use of CMMD images

      For the estimation of early-diastolic IVPD, CMMD images were analyzed using an automated analysis algorithm based on Matlab (The Mathworks, Natick, MA, USA). Briefly, the temporal profile of the IVPD from the mitral annulus to the LV apex was determined to integrate the Euler equation, and the early-diastolic peak of the IVPD was measured [
      • Tsujinaga S.
      • Iwano H.
      • Sarashina M.
      • Hayashi T.
      • Murayama M.
      • Ichikawa A.
      • et al.
      Diastolic intra-left ventricular pressure difference during exercise: strong determinant and predictor of exercise capacity in patients with heart failure.
      ,
      • Stewart K.C.
      • Kumar R.
      • Charonko J.J.
      • Ohara T.
      • Vlachos P.P.
      • Little W.C.
      Evaluation of LV diastolic function from color M-mode echocardiography.
      ]. This method has been validated by comparison with direct measurements with micromanometers [
      • Greenberg N.L.
      • Vandervoort P.M.
      • Firstenberg M.S.
      • Garcia M.J.
      • Thomas J.D.
      Estimation of diastolic intraventricular pressure gradients by doppler M-mode echocardiography.
      ].

      Cardiac magnetic resonance imaging

      CMR was performed using a 3T whole-body scanner (Ingenia Elision X or Achieva TX; Philips Medical Systems, Best, the Netherlands) with dS Torso/dS Posterior coil or a 32-channel phased-array receiver torso-cardiac coil with a breath-holding expiration. Gadolinium-enhanced CMR was performed with intravenous gadobutrol administration (0.1 mmol/kg, Gadovist; Bayer Yakuhin, Osaka, Japan). Ten minutes after the contrast injection, inversion recovery-prepared, three-dimensional turbo field echo pulse sequence with electrocardiogram gating was performed to obtain a delayed-enhancement image with fat saturation. The imaging parameters were as follows: slice thickness = 10 mm; FOV = 380 mm; matrix size = 212 × 160 or 256 × 167; TR/TE = 3.6/1.7 or 3.7/2.3 ms; flip angle = 15° or 10°. Look–Locker sequence was performed prior to myocardial delayed-enhancement imaging to null the signal intensity of normal myocardium. Hyper-enhanced (late gadolinium enhancement; LGE) lesions were visually evaluated in the whole LV wall by an experienced radiologist (S.T.). For pre- and post-contrast T1-mapping, LV short-axis image at midventricular level was obtained using a modified Look-Locker inversion recovery sequence with the following parameters: slice thickness = 10 mm; FOV = 300 mm; matrix size = 152 × 150 or 160 × 158; TR/TE = 2.3 ms/1.0 ms; flip angle = 20°. Pre- (native) and post-contrast T1 values were measured by setting oval region of interest (ROI) (larger than 10 mm2) in the septum of mid-LV using a standard DICOM viewer (XTREK view, J-MAC SYSTEM Inc., Sapporo, Japan). Areas of LGE lesions were visually excluded from the ROI to avoid artificially elevated values. These measurements were performed by an experienced radiologist (S.T.). Extracellular volume fraction (ECV) was calculated using pre- and post-contrast T1 values of myocardium and blood pool (T1 myo pre, T1 myo post, T1 blood pre, and T1 blood post, respectively) as follows: ECV (%) = (100 − hematocrit (%)) × (1/T1 myo post − 1/T1 myo pre)/(1/T1 blood post − 1/T1 blood pre) [
      • Messroghli D.R.
      • Moon J.C.
      • Ferreira V.M.
      • Grosse-Wortmann L.
      • He T.
      • Kellman P.
      • et al.
      Clinical recommendations for cardiovascular magnetic resonance mapping of T1, T2, T2* and extracellular volume: a consensus statement by the Society for Cardiovascular Magnetic Resonance (SCMR) endorsed by the European Association for Cardiovascular Imaging (EACVI).
      ]. Venous blood samples for hematocrit were measured on the same day as the CMR study.

      Statistical analysis

      Continuous data were expressed as mean ± standard deviation or median (interquartile range) as appropriate. Paired t-test was used to compare continuous variables between the two groups. Categorical variables were presented as numbers (%) and compared between different groups by using chi-square test. ESE indices were summarized according to peak VO2 upper or lower than median value (17.4 mL/min/kg), and unpaired t-test was performed. Pearson's or Spearman's correlation analyses were used to examine the relationship between them. Multivariable regression analysis was used to identify the independent determinant of peak VO2 in which variables showing a significant correlation in univariable analyses were incorporated as explanatory variables. For all tests, values of p < 0.05 were considered significant. All statistical analyses were performed using JMP version 16.0 (SAS Institute Inc., Cary, NC, USA).

      Results

      Patients' characteristics

      Of the 52 patients, 3 patients were excluded because of inadequate workload based on low peak respiratory exchange ratio (RER) ≤1.05, and 5 AF patients were also excluded due to HFA-PEFF score lower than 5. Accordingly, the final study population consisted of 44 patients. The baseline characteristics of the studied patients are summarized in Table 1. Roughly half of the cases were complicated by hypertension or chronic kidney disease along with mild HF symptoms. LV mass index was distributed within the normal range because LV hypertrophy was excluded. Besides, 6 patients (14 %) showed concentric LV remodeling defined by relative wall thickness ≥ 0.42, whereas no patients showed enlarged LV defined by indexed LV end-diastolic diameter > 36 mm/m2 (male) or >37 mm/m2 (female) [
      • Yamanaka S.
      • Sakata Y.
      • Nochioka K.
      • Miura M.
      • Kasahara S.
      • Sato M.
      • et al.
      Prognostic impacts of dynamic cardiac structural changes in heart failure patients with preserved left ventricular ejection fraction.
      ]. There were two patients with moderate functional tricuspid regurgitation, whereas no patient showed severe tricuspid regurgitation. LA volume index was increased. There were 6 patients with history of AF, and all of them presented AF rhythm at the time of the echocardiographic evaluation.
      Table 1Patients' characteristics.
      Variables (n = 44)
      Age, years69 ± 10
      Male27 (61)
      Body mass index, kg/m224.4 ± 3.9
      Systolic blood pressure, mm Hg121 ± 20
      Heart rate, bpm68 ± 13
      Comorbidity
      Hypertension39 (89)
      Dyslipidemia11 (25)
      Diabetes mellitus5 (11)
      CKD ≥ stage 3 (eGFR ≤ 60 mL/min/1.73 m2)25 (57)
      Atrial fibrillation6 (14)
      Medications
      ACEI or ARB, n (%)19 (43)
      Beta-blocker, n (%)23 (52)
      Diuretics, n (%)10 (23)
      NYHA
      I21 (48)
      II23 (52)
      CFS
      123 (52)
      218 (41)
      33 (7)
      HFA-PEFF score
      Definite HFpEF (≥5 points)20 (45)
      Intermediate score (2–4 points)20 (45)
      HFpEF unlikely (≤1 point)4 (9)
      Laboratory data
      Hemoglobin, g/dL13.2 ± 1.6
      Albumin, g/dL4.1 ± 0.3
      Creatinine, mg/dL0.9 (0.8–1.1)
      eGFR, mL/min/1.73 m258.3 ± 15.1
      NT-proBNP level, pg/mL179 (67–485)
      P-III-P, U/mL0.6 (0.5–0.9)
      Echocardiographic data
      LV end-diastolic volume, mL81.1 ± 22.6
      LV end-systolic volume, mL37.5 ± 15.8
      LV ejection fraction, %63 ± 6
      LV mass index, g/m279.1 (65.4–90.1)
      Relative wall thickness0.36 ± 0.06
      LA volume index, mL/m243.6 ± 24.8
      E wave velocity, cm/s69.7 ± 20.8
      Deceleration time, ms210 ± 62
      E/A (n = 38)1 ± 0.5
      Medial e′, cm/s6.4 ± 2.2
      Lateral e′, cm/s8.7 ± 3.3
      E/e′10.9 ± 6.9
      TAPSE, mm20 ± 4
      RV-s′, cm/s11.3 ± 1.8
      RVFAC, %42 ± 6.4
      TRPG, mm Hg (n = 36)24 ± 5
      Moderate tricuspid regurgitation2 (5)
      CPET data
      Peak RER1.2 ± 0.1
      AT Load, watts61 ± 20
      AT, mL/min/kg12.1 ± 2.7
      Peak Load, watts95 ± 29
      Peak VO2, mL/min/kg17.5 ± 4.4
      VE/VCO2 slope32.7 ± 5.2
      CMR data
      LGE (n = 34)17 (50)
      Native T1, ms (n = 36)1286 ± 43.4
      ECV, % (n = 34)29.1 ± 3.1
      Data are expressed as mean ± SD, median (IQR), or n (%).
      CKD, chronic kidney disease; eGFR, estimated glomerular filtration rate; ACEI, angiotensin-converting enzyme inhibitors; ARB, angiotensin-receptor blockers; NYHA, New York Heart Association; CFS, clinical frailty scale; HFpEF, heart failure with preserved ejection fraction; NT-proBNP, N-terminal pro-B-type natriuretic peptide; P-III-P, procollagen III propeptide; LV, left ventricular; LA, left atrial; E, early-diastolic transmitral flow velocity; e′, early-diastolic mitral annular velocity; E/e′, ratio of E to e′; TAPSE, tricuspid annular plane systolic excursion; RV-s′, peak systolic right ventricular free wall velocity; RVFAC, RV fractional area change; CPET, cardiopulmonary exercise test; RER, respiratory exchange ratio; AT, anaerobic threshold; VO2, oxygen consumption; VE/VCO2, minute ventilation/carbon dioxide production; CMR, cardiovascular magnetic resonance; LGE, late gadolinium enhancement; ECV, extracellular volume fraction.

      Responses to exercise during ESE

      Changes in hemodynamic and echocardiographic parameters during ESE are summarized according to peak VO2 upper or lower than median value (17.4 mL/min/kg) in Table 2. Overall, there were trends for an increase in LV end-diastolic volume and ejection fraction, increasing SV. In relation to those, the exercise significantly increased LV-s′, GLS, e′, and IVPD. In contrast, E/e′ did not increase during the exercise despite the increase in SPAP. Although TAPSE and RV-s′ were also increased, TAPSE/SPAP was reduced by the exercise (Fig. 1). Precisely, 4 patients (9 %) reached the cut-off value to detect exercise-induced pulmonary hypertension (SPAP ≥60 mm Hg), meanwhile there were another 15 patients (34 %) with unusual elevation of TRPG during exercise (>38 mm Hg) [
      • Lancellotti P.
      • Pellikka P.A.
      • Budts W.
      • Chaudhry F.A.
      • Donal E.
      • Dulgheru R.
      • et al.
      The clinical use of stress echocardiography in non-ischaemic heart disease: recommendations from the European Association of Cardiovascular Imaging and the American Society of Echocardiography.
      ]. Of these, 8 patients (18 %) represented the unusual elevation of SPAP without an increase in E/e′ (≥15) during peak exercise.
      Table 2Changes in hemodynamic and echocardiographic data during exercise-stress echocardiography.
      VariablesOverallPeak VO2 < 17.4 (mL/min/kg) (n = 22)Peak VO2 ≥ 17.4 (mL/min/kg) (n = 22)P value
      Heart rate, bpm
       Baseline71 ± 1370 ± 1372 ± 13NS
       Submaximum102 ± 17
      p < 0.05 versus baseline.
      99 ± 16
      p < 0.05 versus baseline.
      106 ± 18
      p < 0.05 versus baseline.
      NS
       Peak exercise115 ± 18
      p < 0.05 versus baseline.
      110 ± 19
      p < 0.05 versus baseline.
      120 ± 17
      p < 0.05 versus baseline.
      NS
      Systolic blood pressure, mm Hg
       Baseline131 ± 18128 ± 18134 ± 18NS
       Submaximum156 ± 30
      p < 0.05 versus baseline.
      157 ± 32
      p < 0.05 versus baseline.
      156 ± 29
      p < 0.05 versus baseline.
      NS
       Peak exercise174 ± 30
      p < 0.05 versus baseline.
      173 ± 31
      p < 0.05 versus baseline.
      175 ± 30
      p < 0.05 versus baseline.
      NS
      LV end-diastolic volume, mL
       Baseline69.9 ± 22.166.5 ± 25.273.3 ± 18.4NS
       Submaximum72.4 ± 15.769.5 ± 15.975.3 ± 15.2NS
       Peak exercise71.4 ± 18.366.8 ± 17.276.0 ± 18.5NS
      LV end-systolic volume, mL
       Baseline25.7 ± 9.723.2 ± 8.628.2 ± 10.4NS
       Submaximum24.0 ± 8.121.9 ± 5.426.2 ± 9.8NS
       Peak exercise22.7 ± 7.8
      p < 0.05 versus baseline.
      20.5 ± 6.2
      p < 0.05 versus baseline.
      24.9 ± 8.8NS
      LV ejection fraction, %
       Baseline64 ± 665 ± 662 ± 6NS
       Submaximum67 ± 7
      p < 0.05 versus baseline.
      68 ± 6
      p < 0.05 versus baseline.
      66 ± 8
      p < 0.05 versus baseline.
      NS
       Peak exercise68 ± 7
      p < 0.05 versus baseline.
      69 ± 6
      p < 0.05 versus baseline.
      67 ± 7
      p < 0.05 versus baseline.
      NS
      Stroke volume, mL
       Baseline62.3 ± 15.464.9 ± 16.159.8 ± 14.6NS
       Submaximum64.9 ± 14.864.4 ± 15.665.4 ± 14.3
      p < 0.05 versus baseline.
      NS
       Peak exercise64.0 ± 18.264.4 ± 17.263.6 ± 19.5NS
      Cardiac output, L/min
       Baseline4.3 ± 0.94.5 ± 1.04.2 ± 0.9NS
       Submaximum6.6 ± 1.5
      p < 0.05 versus baseline.
      6.3 ± 1.5
      p < 0.05 versus baseline.
      6.8 ± 1.5
      p < 0.05 versus baseline.
      NS
       Peak exercise7.2 ± 1.8
      p < 0.05 versus baseline.
      7.0 ± 1.8
      p < 0.05 versus baseline.
      7.5 ± 1.8
      p < 0.05 versus baseline.
      NS
      LV-s′, cm/s
       Baseline7.5 ± 1.77.2 ± 1.37.9 ± 2.1NS
       Submaximum9.0 ± 1.9
      p < 0.05 versus baseline.
      8.8 ± 1.8
      p < 0.05 versus baseline.
      9.2 ± 2.0
      p < 0.05 versus baseline.
      NS
       Peak exercise9.8 ± 2.0
      p < 0.05 versus baseline.
      9.4 ± 1.4
      p < 0.05 versus baseline.
      10.2 ± 2.4
      p < 0.05 versus baseline.
      NS
      GLS, |%|
       Baseline (n = 48)17.4 ± 3.917.4 ± 4.617.4 ± 3.3NS
       Submaximum (n = 46)20.1 ± 3.5
      p < 0.05 versus baseline.
      20.4 ± 4.4
      p < 0.05 versus baseline.
      19.7 ± 2.3
      p < 0.05 versus baseline.
      NS
       Peak exercise (n = 45)19.5 ± 4.8
      p < 0.05 versus baseline.
      20.1 ± 5.0
      p < 0.05 versus baseline.
      18.7 ± 4.6NS
      E, cm/s
       Baseline73.0 ± 18.176.9 ± 18.569.1 ± 17.2NS
       Submaximum104.9 ± 23
      p < 0.05 versus baseline.
      106.7 ± 20.3
      p < 0.05 versus baseline.
      103.2 ± 25.7
      p < 0.05 versus baseline.
      NS
       Peak exercise112.6 ± 24.1
      p < 0.05 versus baseline.
      117.2 ± 26.7
      p < 0.05 versus baseline.
      107.9 ± 20.8
      p < 0.05 versus baseline.
      NS
      e′, cm/s
       Baseline6.1 ± 1.85.8 ± 1.76.4 ± 1.8NS
       Submaximum8.5 ± 2.5
      p < 0.05 versus baseline.
      8.3 ± 2.7
      p < 0.05 versus baseline.
      8.6 ± 2.3
      p < 0.05 versus baseline.
      NS
       Peak exercise9.6 ± 2.8
      p < 0.05 versus baseline.
      9.7 ± 3.3
      p < 0.05 versus baseline.
      9.6 ± 2.1
      p < 0.05 versus baseline.
      NS
      E/e′
       Baseline13.0 ± 5.314.3 ± 5.711.7 ± 4.5NS
       Submaximum13.5 ± 5.214.4 ± 6.112.6 ± 4.3NS
       Peak exercise12.8 ± 5.513.7 ± 6.511.9 ± 4.1NS
      IVPD, mm Hg
       Baseline (n = 44)3.0 ± 1.03.0 ± 1.02.9 ± 1.0NS
       Submaximum (n = 39)4.6 ± 1.7
      p < 0.05 versus baseline.
      5.1 ± 1.5
      p < 0.05 versus baseline.
      4.0 ± 1.8
      p < 0.05 versus baseline.
      0.049
       Peak exercise (n = 39)5.4 ± 1.6
      p < 0.05 versus baseline.
      5.2 ± 1.5
      p < 0.05 versus baseline.
      5.6 ± 1.7
      p < 0.05 versus baseline.
      NS
      RV-s′, cm/s
       Baseline11.2 ± 2.011 ± 2.111.5 ± 1.9NS
       Submaximum13.4 ± 2.5
      p < 0.05 versus baseline.
      13.3 ± 2.4
      p < 0.05 versus baseline.
      13.6 ± 2.7
      p < 0.05 versus baseline.
      NS
       Peak exercise15.2 ± 3.0
      p < 0.05 versus baseline.
      14.1 ± 2.8
      p < 0.05 versus baseline.
      16.3 ± 2.9
      p < 0.05 versus baseline.
      NS
      TAPSE, mm
       Baseline20.3 ± 3.819.8 ± 4.020.8 ± 3.6NS
       Submaximum22.1 ± 4.9
      p < 0.05 versus baseline.
      21.5 ± 4.222.7 ± 5.6NS
       Peak exercise22.9 ± 4.6
      p < 0.05 versus baseline.
      22.6 ± 4.7
      p < 0.05 versus baseline.
      23.2 ± 4.6
      p < 0.05 versus baseline.
      NS
      SPAP, mm Hg
       Baseline29 ± 630 ± 527 ± 7NS
       Submaximum38 ± 11
      p < 0.05 versus baseline.
      40 ± 9
      p < 0.05 versus baseline.
      36 ± 13
      p < 0.05 versus baseline.
      NS
       Peak exercise43 ± 13
      p < 0.05 versus baseline.
      47 ± 11
      p < 0.05 versus baseline.
      38 ± 13
      p < 0.05 versus baseline.
      0.016
      TPR, mm Hg·min/L
       Baseline4.7 ± 1.54.7 ± 1.34.6 ± 1.8NS
       Submaximum4.1 ± 1.2
      p < 0.05 versus baseline.
      4.2 ± 1.0
      p < 0.05 versus baseline.
      4.0 ± 1.5
      p < 0.05 versus baseline.
      NS
       Peak exercise4.1 ± 1.5
      p < 0.05 versus baseline.
      4.5 ± 1.23.6 ± 1.7
      p < 0.05 versus baseline.
      0.043
      TAPSE/SPAP, mm/mm Hg
       Baseline0.75 ± 0.230.68 ± 0.180.81 ± 0.250.044
       Submaximum0.65 ± 0.27
      p < 0.05 versus baseline.
      0.56 ± 0.15
      p < 0.05 versus baseline.
      0.73 ± 0.33
      p < 0.05 versus baseline.
      0.036
       Peak exercise0.60 ± 0.28
      p < 0.05 versus baseline.
      0.51 ± 0.17
      p < 0.05 versus baseline.
      0.70 ± 0.330.019
      p-values are for the comparisons between the 2 groups.
      LV, left ventricular; LV-s′, systolic mitral annular velocity; GLS, global longitudinal strain; E, early-diastolic transmitral flow velocity; e′, early-diastolic mitral annular velocity; E/e′, ratio of E to e′; IVPD, intraventricular pressure difference; RV-s′, peak systolic right ventricular free wall velocity; TAPSE, tricuspid annular plane systolic excursion; SPAP, systolic pulmonary artery pressure; TPR, total pulmonary resistance; TAPSE/SPAP, ratio of TAPSE to SPAP.
      low asterisk p < 0.05 versus baseline.
      Fig. 1
      Fig. 1Changes in exercise-stress echocardiography parameters during exercise. Changes in indices of left ventricular (LV) contraction, LV diastolic function, and right ventricle (RV)-pulmonary artery (PA) coupling at each stage of exercise. There was no change in E/e′ which reflects LV filling pressure. Note that SPAP plots the cases whose measurements were available.
      pre, at baseline; sub, at submaximal exercise; peak, at peak exercise; LVEF, LV ejection fraction; GLS, global longitudinal strain; IVPD, intraventricular pressure difference; E, early-diastolic transmitral flow velocity; e′, early-diastolic mitral annular velocity; E/e′, ratio of E to e′; SPAP, systolic PA pressure; TAPSE, tricuspid annular plane systolic excursion.
      *p < 0.05 versus baseline.
      When these parameters at peak exercise were compared between patients showing upper half and lower half of peak VO2, the differences between these groups were striking in higher SPAP and lower TAPSE/SPAP in patients with lower peak VO2, whereas markers of LV systolic function, LV diastolic function, and filling pressure were comparable between the groups. Interestingly, TPR reduced during exercise only in patients showing upper half of peak VO2 (Table 2).

      Determinants of exercise capacity peak VO2

      Results of linear regression analyses to determine peak VO2 are summarized in Table 3. As expected, higher age, lower serum albumin, and lower estimated glomerular filtration rate (eGFR) were associated with lower peak VO2. Additionally, lower peak heart rate and lower peak CO were associated with lower peak VO2. Surprisingly, any parameters of LV systolic and diastolic parameters except for LV-s′ did not determine peak VO2. In contrast, SPAP was negatively, and RV-s′ was positively correlated with peak VO2. Finally, TAPSE/SPAP was positively correlated with peak VO2, suggesting a negative impact of impaired RV-PA coupling during exercise in the studied population (Fig. 2).
      Table 3Determinants of peak VO2.
      VariablesRp-Value
      Age−0.360.017
      Body mass index−0.040.775
      Albumin0.290.052
      eGFR0.55<0.001
      P-III-P(ρ) −0.2690.089
      EXE parameters (peak exercise)
       Heart rate0.430.004
       Stroke volume0.020.886
       Cardiac output0.280.062
       LV end-diastolic volume0.360.017
       LVEF−0.180.256
       GLS (n = 41)−0.070.644
       LV-s′0.350.022
       IVPD (n = 35)0.140.425
       e′0.200.202
       E/e′−0.270.083
       SPAP−0.400.008
       TAPSE0.130.413
       RV-s′0.470.002
       TAPSE/SPAP0.420.005
      CMR findings
       Native T1 (n = 36)−0.270.118
       ECV (n = 34)−0.360.036
      LV, left ventricular; LVEF, left ventricular ejection fraction; GLS, global longitudinal strain; LV-s′, systolic mitral annular velocity; IVPD, intraventricular pressure difference; E, early-diastolic transmitral flow velocity; e′, early-diastolic mitral annular velocity; E/e′, ratio of E to e′; SPAP, systolic pulmonary artery pressure; TAPSE, tricuspid annular plane systolic excursion; RV-s′, peak systolic right ventricular free wall velocity; TAPSE/SPAP, ratio of TAPSE to SPAP; ECV, extracellular volume fraction.
      Fig. 2
      Fig. 2Correlations between exercise-stress echocardiography parameters (at peak exercise) and peak VO2.
      LVEF, left ventricular ejection fraction; GLS, global longitudinal strain; IVPD, intraventricular pressure difference; E, early-diastolic transmitral flow velocity; e′, early-diastolic mitral annular velocity; E/e′, ratio of E to e′; SPAP, systolic pulmonary artery pressure; TAPSE, tricuspid annular plane systolic excursion.
      In multivariable analyses, not only SPAP but also TAPSE/SPAP was selected as an independent determinant of peak VO2 whereas heart rate, LV end-diastolic volume, CO, LV-s′, and E/e′ were not after the adjustment of clinically relevant parameters (Table 4).
      Table 4Unadjusted and adjusted regression coefficients to determine peak VO2.
      VariablesRp-Valueβp-Value
      Heart rate
       Unadjusted0.430.004
       Adjusted
      Adjusted for age, albumin, eGFR.
      0.230.092
      LV end-diastolic volume
       Unadjusted0.360.017
       Adjusted
      Adjusted for age, albumin, eGFR.
      0.240.064
      CO
       Unadjusted0.280.062
       Adjusted
      Adjusted for age, albumin, eGFR.
      0.160.220
      LV-s′
       Unadjusted0.350.022
       Adjusted
      Adjusted for age, albumin, eGFR.
      0.080.226
      E/e′
       Unadjusted−0.270.083
       Adjusted
      Adjusted for age, albumin, eGFR.
      −0.220.077
      TAPSE
       Unadjusted0.130.413
       Adjusted
      Adjusted for age, albumin, eGFR.
      0.020.896
      SPAP
       Unadjusted−0.400.008
       Adjusted
      Adjusted for age, albumin, eGFR.
      −0.310.014
      TAPSE/SPAP
       Unadjusted0.420.005
       Adjusted
      Adjusted for age, albumin, eGFR.
      0.300.025
      LV, left ventricular; CO, cardiac output; LV-s′, systolic mitral annular velocity; E, early-diastolic transmitral flow velocity; e′, early-diastolic mitral annular velocity; E/e′, ratio of E to e′; TAPSE, tricuspid annular plane systolic excursion; SPAP, systolic pulmonary artery pressure; TAPSE/SPAP, ratio of TAPSE to SPAP.
      a Adjusted for age, albumin, eGFR.

      Correlation between LV myocardial fibrosis and exercise capacity

      Among 36 patients who underwent CMR, ECV was slightly elevated (29.1 %) compared to the previously reported normal range [
      • Storz C.
      • Hetterich H.
      • Lorbeer R.
      • Heber S.D.
      • Schafnitzel A.
      • Patscheider H.
      • et al.
      Myocardial tissue characterization by contrast-enhanced cardiac magnetic resonance imaging in subjects with prediabetes, diabetes, and normal controls with preserved ejection fraction from the general population.
      ]. The mean of native T1 value was about the upper limit of a normal range (1286 ms, reference value: 1180–1300 ms). Notably, 12 of the 18 patients (67 %) in lower-half of peak VO2 showed elevated ECV (higher than the institution's normal value), which was more frequent than in patients in upper-half of peak VO2 [5 of 16 (31 %), p = 0.012]. Both ECV and native T1 values were negatively correlated with peak VO2. In contrast, no associations were observed between these parameters and echocardiographic parameters or P-III-P (Online Tables 1, 2).

      Discussion

      In our study, determinants of exercise capacity were tested in HFpEF patients without abnormal LV structure. The findings can be summarized as 1) IVPD, a measure of LV suction, was increased and E/e′ was not increased, whereas SPAP was substantially increased by the exercise, 2) parameters of LV diastolic function during exercise were not associated with exercise capacity, and 3) TAPSE/SPAP at peak exercise was a determinant of exercise capacity independent of clinically relevant factors of exercise capacity. Our result suggests that RV-PA uncoupling induced by pulmonary hypertension, which was not caused by elevated LV filling pressure, might be responsible for reducing exercise capacity in HFpEF patients without a noticeable change in LV morphology.
      The abnormal LV structure as represented by LV hypertrophy has been described as a typical finding in HFpEF patients. The abnormal LV geometry and subsequent LV diastolic dysfunction are found to be associated with increased morbidity and mortality [
      • Shah A.M.
      • Claggett B.
      • Sweitzer N.K.
      • Shah S.J.
      • Anand I.S.
      • O'Meara E.
      • et al.
      Cardiac structure and function and prognosis in heart failure with preserved ejection fraction: findings from the echocardiographic study of the treatment of preserved cardiac function heart failure with an aldosterone antagonist (TOPCAT) trial.
      ,
      • Zile M.R.
      • Gottdiener J.S.
      • Hetzel S.J.
      • McMurray J.J.
      • Komajda M.
      • McKelvie R.
      • et al.
      Prevalence and significance of alterations in cardiac structure and function in patients with heart failure and a preserved ejection fraction.
      ], and as well as a reduction in exercise capacity in HFpEF patients [
      • Kosmala W.
      • Rojek A.
      • Przewlocka-Kosmala M.
      • Mysiak A.
      • Karolko B.
      • Marwick T.H.
      Contributions of nondiastolic factors to exercise intolerance in heart failure with preserved ejection fraction.
      ]. At the same time, a substantial number of patients in the HFpEF population has shown normal cardiac geometry. The most extensive study done on HFpEF patients demonstrated that 46 % of the HFpEF lacked the findings of LV hypertrophy or LV concentric remodeling [
      • Zile M.R.
      • Gottdiener J.S.
      • Hetzel S.J.
      • McMurray J.J.
      • Komajda M.
      • McKelvie R.
      • et al.
      Prevalence and significance of alterations in cardiac structure and function in patients with heart failure and a preserved ejection fraction.
      ]. Another seminal study found normal LV geometry in 31 % of the HFpEF population [
      • Lam C.S.
      • Roger V.L.
      • Rodeheffer R.J.
      • Bursi F.
      • Borlaug B.A.
      • Ommen S.R.
      • et al.
      Cardiac structure and ventricular-vascular function in persons with heart failure and preserved ejection fraction from Olmsted CountyMinnesota.
      ]. As well, a recent study from Japan reported that 56 % of elderly HFpEF patients presented normal range of relative wall thickness, and the proportion was similar to the healthy elderly subjects (54 %) [
      • Seo Y.
      • Ishizu T.
      • Ieda M.
      • Ohte N.
      J-LONG Study Investigators
      Clinical usefulness of the HFA-PEFF diagnostic scoring system in identifying late elderly heart failure with preserved ejection fraction patients.
      ]. Taken together with the longitudinal alteration of LV structure, which contain disappearance of LV hypertrophy over time, reported from the CHART-2 study [
      • Yamanaka S.
      • Sakata Y.
      • Nochioka K.
      • Miura M.
      • Kasahara S.
      • Sato M.
      • et al.
      Prognostic impacts of dynamic cardiac structural changes in heart failure patients with preserved left ventricular ejection fraction.
      ], presence of LV hypertrophy could not necessarily express the early stage of Japanese HFpEF. Although cardiomyocyte cellular hypertrophy and subsequent diastolic dysfunction can occur even when LV hypertrophy is not present [
      • Zile M.R.
      • Gottdiener J.S.
      • Hetzel S.J.
      • McMurray J.J.
      • Komajda M.
      • McKelvie R.
      • et al.
      Prevalence and significance of alterations in cardiac structure and function in patients with heart failure and a preserved ejection fraction.
      ], and increase in LV filling pressure by exercise is the crucial hemodynamic characteristic of HFpEF [
      • Reddy Y.N.V.
      • Olson T.P.
      • Obokata M.
      • Melenovsky V.
      • Borlaug B.A.
      Hemodynamic correlates and diagnostic role of cardiopulmonary exercise testing in heart failure with preserved ejection fraction.
      ], non-cardiac factors were also suggested to contribute the exercise intolerance in this population [
      • Haykowsky 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.
      ,
      • Dhakal 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.
      ,
      • Gorter T.M.
      • Obokata M.
      • Reddy Y.N.V.
      • Melenovsky V.
      • Borlaug B.A.
      Exercise unmasks distinct pathophysiologic features in heart failure with preserved ejection fraction and pulmonary vascular disease.
      ,
      • Nayor M.
      • Houstis N.E.
      • Namasivayam M.
      • Rouvina J.
      • Hardin C.
      • Shah R.V.
      • et al.
      Impaired exercise tolerance in heart failure with preserved ejection fraction: quantification of multiorgan system reserve capacity.
      ]. Haykowsky and coworkers investigated the determinants of aerobic capacity in HFpEF patients and found that arterial-venous oxygen content difference was the strongest predictor of peak aerobic capacity in HFpEF patients, suggesting that peripheral noncardiac factors are essential contributors to exercise intolerance [
      • Haykowsky 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.
      ]. In addition, Gorter and coworkers demonstrated the inability to increase cardiac output associated with RV-PA uncoupling limited exercise capacity of HFpEF patients with combined pre- and post-capillary pulmonary hypertension by using exercise-stress hemodynamic monitoring [
      • Gorter T.M.
      • Obokata M.
      • Reddy Y.N.V.
      • Melenovsky V.
      • Borlaug B.A.
      Exercise unmasks distinct pathophysiologic features in heart failure with preserved ejection fraction and pulmonary vascular disease.
      ]. In line with these observations, we found that exercise-induced pulmonary hypertension and RV-PA uncoupling were independent determinants of exercise capacity in HFpEF patients. Our results underline the importance of non-cardiac factors in maintaining exercise capacity in HFpEF patients.
      Surprisingly, pulmonary hypertension was not associated with exercise-induced elevation of LV filling pressure in our population. This result suggests that pulmonary hypertension might have been driven by diminished distensibility of the pulmonary vessels themselves. During exercise, increased volumes of pulmonary blood flow are recruited to the pulmonary vessels [
      • Malhotra R.
      • Dhakal B.P.
      • Eisman A.S.
      • Pappagianopoulos P.P.
      • Dress A.
      • Weiner R.B.
      • et al.
      Pulmonary vascular distensibility predicts pulmonary hypertension severity, exercise capacity, and survival in heart failure.
      ] and thin-walled pulmonary vessels are distended to accommodate this increased blood flow without excessive increase in pulmonary artery pressure. Previous studies reported that pulmonary vascular distensibility was reduced in the circumstances of chronic hypoxia and aging [
      • Reeves J.T.
      • Linehan J.H.
      • Stenmark K.R.
      Distensibility of the normal human lung circulation during exercise.
      ,
      • Forton K.
      • Motoji Y.
      • Caravita S.
      • Faoro V.
      • Naeije R.
      Exercise stress echocardiography of the pulmonary circulation and right ventricular-arterial coupling in healthy adolescents.
      ]. Consistently, we observed the reduction of TPR only in patients showing upper-half of peak VO2. Although the absolute value of non-invasively obtained TPR itself might be somewhat inaccurate, these data would confirm the consideration in which insufficient adaptation of pulmonary vasculature during exercise is associated with reduced exercise capacity. Therefore, some part of the population in clinically diagnosed HFpEF patients without LV hypertrophy might be suffering from abnormal pulmonary vascular response during exercise, which reduces exercise capacity independently of LV diastolic dysfunction. In this study, 8 patients showed unusual elevation of SPAP without an increase in E/e′. Because the studied 44 patients were included from 159 screened HFpEF patients, the actual frequency of this manifestation was 5 % of HFpEF in our institution. Although it might be difficult to extrapolate this frequency to the real world data based on the characteristic of the university hospital, we may need to take into account for this type of hemodynamic characteristics when we manage HFpEF patients without LV hypertrophy.
      On the other hand, we also found the relationship between exercise capacity and LV myocardial fibrosis assessed by ECV and native T1 value. Although elevated ECV and its association with LV stiffness have been observed in HFpEF [
      • Rommel K.P.
      • von Roeder M.
      • Latuscynski K.
      • Oberueck C.
      • Blazek S.
      • Fengler K.
      • et al.
      Extracellular volume fraction for characterization of patients with heart failure and preserved ejection fraction.
      ], this was the first study to find its relationship to exercise capacity in HFpEF patients. Unexpectedly, however, we could not find any associations between ECV and parameters of LV diastolic function. Because ECV may represent the distinct domain of cardiac vulnerability from GLS [
      • Frojdh F.
      • Fridman Y.
      • Bering P.
      • Sayeed A.
      • Maanja M.
      • Niklasson L.
      • et al.
      Extracellular volume and global longitudinal strain both associate with outcomes but correlate minimally.
      ], intercellular fibrosis might have been associated with exercise intolerance not through LV diastolic dysfunction, especially in patients showing normal LV geometry. Further studies are warranted to clarify the underlying mechanism of the relationship between myocardial fibrosis and exercise capacity in this population. In addition, we used TAPSE/SPAP as a simple index of RV-PA coupling that can be evaluated by echocardiography. Although it has been pointed out that TAPSE/SPAP may be more afterload-dependent than invasive measurement, it is well reproducible that can be used even in the evaluation during maximal exercise [
      • Forton K.
      • Motoji Y.
      • Caravita S.
      • Faoro V.
      • Naeije R.
      Exercise stress echocardiography of the pulmonary circulation and right ventricular-arterial coupling in healthy adolescents.
      ,
      • Guazzi M.
      • Naeije R.
      Pulmonary hypertension in heart failure: pathophysiology, pathobiology, and emerging clinical perspectives.
      ].
      We need to acknowledge some limitations in the present study. First, this was a single-center study including a small population and thus more extensive studies are needed to confirm our results.
      Second, although we strictly selected HFpEF patients based on clinical data, the exclusion of patients with LV hypertrophy might be associated with augmented e′ during exercise, therefore, one might have a concern about the diagnosis of HFpEF. In turn, clinically-diagnosed HFpEF patients without LV hypertrophy might include patients with relatively preserved LV relaxation. Furthermore, the inclusion criteria are at risk of including non-HF patients, although we found that all asymptomatic patients without AF showed objective evidence of HF such as elevated NT-pro BNP levels, reduced e′, or enlarged left atrium. Nevertheless, we need to confirm the observed results in a future study including HFpEF patients diagnosed by established criteria [
      • McDonagh T.A.
      • Metra M.
      • Adamo M.
      • Gardner R.S.
      • Baumbach A.
      • Bohm M.
      • et al.
      2021 ESC guidelines for the diagnosis and treatment of acute and chronic heart failure.
      ]. Third, CPET and ESE were performed separately with different protocols used. Fourth, we did not consider peripheral determinants of exercise capacity, such as inactivity, skeletal muscle atrophy, and oxygen metabolism. However, the relationship between TAPSE/SPAP during exercise and peak VO2 in the present results should be consistent regardless of the limiting factors of the exercise. Fifth, some cases might present with subclinical respiratory dysfunction because they did not perform specific evaluations such as spirometry. Sixth, substantial proportion of the enrolled patients used beta-blockers for hypertension and AF. In these patients, beta-blocker might affect their exercise intolerance through chronotropic incompetence [
      • Palau P.
      • Seller J.
      • Dominguez E.
      • Sastre C.
      • Ramon J.M.
      • de La Espriella R.
      • et al.
      Effect of beta-blocker withdrawal on functional capacity in heart failure and preserved ejection fraction.
      ]. However, there was no difference between the patients using beta-blockers and those without in terms of heart rate at peak exercise (117 ± 18 bpm vs 113 ± 19 bpm, p = 0.43) and peak VO2. Finally, because of the evaluation during exercise, the image quality of CMMD of the LV inflow may have been somewhat inappropriate, weakening the relationship between IVPD and peak VO2.

      Conclusions

      In HFpEF patients without LV hypertrophy, altered RV-PA coupling by exercise could be associated with exercise intolerance, which might not be caused by elevated LV filling pressure. The present results are needed to be confirmed in another population diagnosed by established HFpEF criteria.

      Declaration of competing interest

      There is no conflict of interest to disclose relating to the present study.

      Acknowledgments

      This study was funded by the grant from the Japan Society for the Promotion of Science (JSPS) KAKENHI (Grant number 18K07622 ). We thank Kinya Ishizaka for technical assistance.

      Appendix A. Supplementary data

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