Exercise In Heart Failure With Preserved Ejection Fraction Research Articles

Pulmonary gas exchange in relation to exercise pulmonary hypertension in patients with heart failure with preserved ejection fraction.

Exercise pulmonary hypertension (ePH), defined as a mean pulmonary artery pressure (mPAP)/cardiac output (Qc) slope >3 WU during exercise, is common in patients with heart failure with preserved ejection fraction (HFpEF). However, the pulmonary gas exchange-related effects of an exaggerated ePH (EePH) response are not well-defined, especially in relation to dyspnea on exertion (DOE) and exercise intolerance. 48 HFpEF patients underwent invasive (pulmonary and radial artery catheters) constant-load (20W) and maximal incremental cycle testing. Hemodynamic measurements (mPAP and Qc), arterial blood and expired gases, and ratings of breathlessness (RPB, Borg 0-10) were obtained. The mPAP/Qc slope was calculated from rest-to-20W. Those with a mPAP/Qc slope >4.2 (median) were classified as HFpEF+EePH (n=24) and those with a mPAP/Qc slope <4.2 were classified as HFpEF (without EePH) (n=24). The A-aDO2, VD/VT (Bohr equation), and the VE/VCO2 slope (from rest-to-20W) were calculated. PaO2 was lower (p=0.03), and VD/VT was higher (p=0.03) at peak exercise in HFpEF+EePH compared with HFpEF. A-aDO2 was similar at peak exercise between groups (p=0.14); however, HFpEF+EePH achieved the peak A-aDO2 at a lower peak work rate (p<0.01). The VE/VCO2 slope was higher in HFpEF+EePH compared with HFpEF (p=0.01). RPB was ≥1-unit higher at 20W and VO2peak was lower (p<0.01) in HFpEF+EePH compared with HFpEF. These data suggest that EePH contributes to pulmonary gas exchange impairments during exercise by causing a V/Q mismatch that provokes both ventilatory inefficiency and hypoxemia, both of which seem to contribute to DOE and exercise intolerance in patients with HFpEF.

Addressing the enigma of treating heart failure with preserved ejection fraction with P2X3 receptor antagonism

Heart failure with preserved ejection fraction (HFpEF) is a major health burden and a primary cause of death globally, yet there remains no curative treatment. Previous studies have indicated an important role for P2X3 receptors (P2X3R) in mediating high levels of sympathetic drive in hypertension (1). Given the high sympathetic drive in HFpEF(2), we investigated whether P2X3R antagonism would improve this condition. We tested the hypotheses that in HFpEF, P2X3R activation causes high levels of blood pressure and excessive vasoconstriction in the hindlimb vasculature during exercise. Following unilateral renal artery clipping, an ovine model of HFpEF was established in female sheep displaying hypertension and diastolic dysfunction. A sham-operated group acted as a control. Mean arterial pressure (MAP), heart rate (HR), and hindlimb blood flow (HLBF) were recorded before and during treadmill exercise, and the effect of either a P2X3R antagonist (L227, 10mg/kg) or vehicle was assessed. The clipping of one renal artery increased MAP (91±5 vs. 131±6, p≤0.05). The administration of the P2X3R antagonist reduced both MAP (-6±7 mmHg, p≤0.05) and HR (-6±6 bpm, p&lt;0.05) in HFpEF sheep but no effect in sham-operated animals. HLBF during exercise was attenuated in the HFpEF model compared to sham-operated sheep (an increase of 2±1 vs. 4±2 L/min, respectively, p&lt;0.05). Importantly, P2X3R blockade improved the change in HLBF during exercise from 1±0.1 to 2±0.4 L/min in HFpEF sheep, but there was no change in the sham-operated animals. There was no change in the MAP or HR response to the exercise with the P2X3R blockade. P2X3R plays a role in the aetiology of hypertension and in the attenuation of HLBF responses during exercise in HFpEF. P2X3R antagonism may provide a novel target to alleviate symptoms of HFpEF and improve exercise tolerance through increased HLBF. 1. Pijacka W, Moraes DJ, Ratcliffe LE, Nightingale AK, Hart EC, da Silva MP, Machado BH, McBryde FD, Abdala AP, Ford AP and Paton JFR. Purinergic receptors in the carotid body as a new drug target for controlling hypertension. Nature medicine 22: 1151-1159, 2016. 2. Seravalle G, Quarti-Trevano F, Dell’Oro R, Gronda E, Spaziani D, Facchetti R, Cuspidi C, Mancia G, and Grassi G. Sympathetic and baroreflex alterations in congestive heart failure with preserved, midrange and reduced ejection fraction. Journal of Hypertension 37: 443-448, 2019. Health Research Council of New Zealand and Sidney Taylor Trust. This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

Normal sympathetic neural but blunted cardiovascular responses during static handgrip exercise in heart failure with preserved ejection fraction

Background: Exercise intolerance is a hallmark of heart failure, which significantly impacts activities of daily living and quality of life. In heart failure with reduced ejection fraction, exercise intolerance is associated with sympathetic nervous system hyperactivity during exercise. Whether this is also true in heart failure with preserved ejection fraction (HFpEF) is unknown. Therefore, we hypothesized that patients with HFpEF would have augmented sympathetic neural responses to exercise. Methods: Thirty-four patients with HFpEF (19 women, 70±7 [SD] yrs) and 24 age-matched healthy controls (14 women, 70±6 yrs) were studied. Mean arterial pressure (MAP; finger photoplethysmography calibrated with brachial blood pressure [BP]), heart rate (HR; lead II electrocardiogram), cardiac output (CO; derived from the Windkessel model), total peripheral resistance (TPR=MAP/CO), and muscle sympathetic nerve activity (MSNA, microneurography) were measured during 3 min of supine baseline, static handgrip (SHG) exercise at 40% of maximal voluntary contraction (MVC) force until fatigue, and 2 min of post-exercise circulatory arrest (PECA). Sympathetic transduction was estimated using diastolic BP divided by MSNA burst incidence. Results: Patients with HFpEF had a smaller MVC (24±8 vs. 30±9 kg, P=0.020) and a shorter time to fatigue during SHG (162±67 vs. 210±80 sec, P=0.012) than controls. However, there were consistent results across subgroups analyzed according to matched MVC or time to fatigue during SHG. Baseline MSNA burst frequency was higher in HFpEF patients compared with controls (36±16 vs. 24±13 bursts/min, P=0.005); however, there were no differences in MSNA responses (Δ) to SHG and PECA between the groups (SHG peak: 19±14 in HFpEF vs. 19±12 bursts/min in controls, P=0.984; PECA: 8±13 vs. 6±7 bursts/minute, P=0.596). Increases in MAP, HR, and TPR from baseline to peak SHG were smaller in patients with HFpEF than in controls (all P&lt;0.05), while the increase in CO was not different between the groups ( P=0.101). In contrast, ΔMAP, ΔHR and ΔCO from baseline to PECA were not different between the groups (all P&gt;0.05), but ΔTPR remained lower in patients with HFpEF than controls ( P=0.023). The transduction of MSNA burst incidence into diastolic BP was lower in patients with HFpEF compared with controls throughout data collection ( P=0.010). Conclusions: Contrary to our hypothesis, patients with HFpEF have normal sympathetic neural reactivity during SHG exercise despite a higher baseline. The blunted pressor response may be attributed to impaired sympathetic transduction to stress rather than a change in sympathetic neural responsiveness during exercise in HFpEF. Supported by the National Institutes of Health (P01HL137630 and R01HL091078) This is the full abstract presented at the American Physiology Summit 2023 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

Impact of severe secondary tricuspid regurgitation on rest and exercise hemodynamics of patients with heart failure and a preserved left ventricular ejection fraction.

Both secondary tricuspid regurgitation (STR) and heart failure with preserved ejection fraction (HFpEF) are relevant public health problems in the elderly population, presenting with potential overlaps and sharing similar risk factors. However, the impact of severe STR on hemodynamics and cardiorespiratory adaptation to exercise in HFpEF remains to be clarified. To explore the impact of STR on exercise hemodynamics and cardiorespiratory adaptation in HFpEF. We analyzed invasive hemodynamics and gas-exchange data obtained at rest and during exercise from HFpEF patients with severe STR (HFpEF-STR), compared with 1:1 age-, sex-, and body mass index (BMI)- matched HFpEF patients with mild or no STR (HFpEF-controls). Twelve HFpEF with atrial-STR (mean age 72 years, 92% females, BMI 28 Kg/m2) and 12 HFpEF-controls patients were analyzed. HFpEF-STR had higher (p < 0.01) right atrial pressure than HFpEF-controls both at rest (10 ± 1 vs. 5 ± 1 mmHg) and during exercise (23 ± 2 vs. 14 ± 2 mmHg). Despite higher pulmonary artery wedge pressure (PAWP) at rest in HFpEF-STR than in HFpEF-controls (17 ± 2 vs. 11 ± 2, p = 0.04), PAWP at peak exercise was no more different (28 ± 2 vs. 29 ± 2). Left ventricular transmural pressure and cardiac output (CO) increased less in HFpEF-STR than in HFpEF-controls (interaction p-value < 0.05). This latter was due to lower stroke volume (SV) values both at rest (48 ± 9 vs. 77 ± 9 mL, p < 0.05) and at peak exercise (54 ± 10 vs. 93 ± 10 mL, p < 0.05). Despite these differences, the two groups of patients laid on the same oxygen consumption isophlets because of the increased peripheral oxygen extraction in HFpEF-STR (p < 0.01). We found an inverse relationship between pulmonary vascular resistance and SV, both at rest and at peak exercise (R 2 = 0.12 and 0.19, respectively). Severe STR complicating HFpEF impairs SV and CO reserve, leading to pulmonary vascular de-recruitment and relative left heart underfilling, undermining the typical HFpEF pathophysiology.

588 EXPLORING THE IMPACT OF SEVERE SECONDARY TRICUSPID REGURGITATION ON REST AND EXERCISE HEMODYNAMICS OF PATIENTS WITH HEART FAILURE AND A PRESERVED LEFT VENTRICULAR EJECTION FRACTION

Abstract Background Both secondary tricuspid regurgitation (STR) and heart failure with preserved ejection fraction (HFpEF) are relevant public health problem in the elderly population, presenting with potential overlaps and sharing similar risk factors. However, the impact of severe STR on hemodynamics and cardiorespiratory adaptation to exercise in HFpEF remains to be clarified. Aim To explore the impact of severe STR on exercise hemodynamics and cardiorespiratory adaptation in HFpEF. Methods We analyzed invasive hemodynamics and gas-exchange data obtained at rest and during exercise from HFpEF patients with severe STR (HFpEF-STR), compared with 1:1 age, sex and body mass index matched HFpEF patients with mild or no STR (HFpEF-controls). Results 13 HFpEF-STR (mean age 72 years, 85% females, BMI 28 Kg/m2) and 13 age-, sex-, and BMI-matched HFpEF-controls patients were included. HFpEF-STR had higher (p&amp;lt;0.01) right atrial pressure than HFpEF-controls both at rest (10±1 vs 5±1 mmHg) and during exercise (23±2 vs 14±2). During exercise, pulmonary artery wedge pressure as well as left ventricular transmural pressure increased less in HFpEF-STR than in HFpEF-controls (interaction p-value&amp;lt;0.05). Similarly, cardiac output (CO) increased less in HFpEF-STR than in HFpEF-controls (interaction p-value&amp;lt;0.05) during exercise, due to the lower stroke volume (SV) values both at rest (49±8 vs 78±8, p&amp;lt;0.05) and at peak exercise (55±9 vs 92±9 mL, p&amp;lt;0.05). Despite these differences, the two groups of patients laid on the same oxygen consumption isophlets because of the increased peripheral oxygen extraction in HFpEF-STR (p&amp;lt;0.01). An inverse relationship was found between pulmonary vascular resistance and SV, both at rest and at peak exercise (R2=0.12 and 0.19, respectively). Conclusions Severe STR complicating HFpEF impairs SV and CO reserve, leading to pulmonary vascular de-recruitment and relative left heart underfilling, mining the typical HFpEF pathophysiology. Exercise pathophysiology of secondary tricuspid regurgitation (STR) in heart failure with preserved ejection fraction (HFpEF).

Dynamic aspects of ventricular interaction during exercise in HFpEF and in pre-capillary pulmonary hypertension.

The contribution of adverse ventricular interdependence remains undervalued in heart failure or pulmonary vascular disease, and not much is known about its dynamic nature during exercise and respiration. In this study, we evaluated ventricular interaction during exercise in patients with heart failure with preserved ejection fraction (HFpEF) and patients with chronic thromboembolic pulmonary hypertension (CTEPH) as compared with healthy controls. Forty-six subjects (10 controls, 19 CTEPH patients, and 17 HFpEF patients) underwent cardiac magnetic resonance imaging during exercise. Ventricular interaction was determined through analysis of the septal curvature (SC) of a mid-ventricular short-axis slice at end-diastole, end-systole, and early-diastole, both in expiration and inspiration. Exercise amplified ventricular interaction in CTEPH patients and to a lesser extent in HFpEF patients (P<0.05 for decrease in SC with exercise). Adverse interaction was most profound in early-diastole and most pronounced in CTEPH patients (P<0.05 interaction group*exercise) because of a disproportionate increase RV afterload (P<0.05 to both controls and HFpEF) and diastolic pericardial restraint (P<0.001 for interaction group*exercise) during exercise. Inspiration enhanced diastolic interdependence in CTEPH and HFpEF patients (P<0.05 vs. expiration). Both at rest and during exercise, SC strongly correlated with RV volumes and pulmonary artery pressures (all P<0.05). Exercise amplifies adverse right-left ventricular interactions in CTEPH, while a more moderate effect is observed in isolated post-capillary HFpEF. Given the strong link with RV function and pulmonary hemodynamic, assessing ventricular interaction with exCMR might be valuable from a diagnostic or therapeutic perspective.

Low-dose dopamine improves ventilatory efficiency during exercise in heart failure with preserved ejection fraction through inhibition of tonic activity of peripheral chemoreceptors

Abstract Introduction Peripheral chemoreceptors (PChRs) play an important role in adequate oxygenation by 1) maintaining baseline ventilation (tonic activity) and 2) providing hyperventilation in response to acute hypoxia (reflexia). It has been previously shown that in patients with heart failure with reduced ejection fraction hypertonicity and/or hyperreflexia of PChRs contribute to exercise intolerance (ExIn). It is unknown whether similar mechanisms are present in heart failure with preserved ejection fraction (HFpEF) and which component of PChR functionality has a decisive role in this matter. Purpose The aim of this study was to evaluate the role of PChRs in ExIn in patients with HFpEF. Methods All patients underwent assessment of PChRs which included measurements of: 1) tonic activity (TA, decrease in ventilation following pharmacological inhibition of PChRs), 2) reflex response (RR; an increase in ventilation in the response to acute hypoxia). The inhibition of PChRs was achieved with low-dose dopamine infusion (3 μg kg–1 min–1) and the acute hypoxia was produced with brief nitrogen gas administrations. Enrolled patients underwent symptom-limited cardiopulmonary exercise test using cycle ergometer from which peak oxygen consumption (peakVO2) and the slope relating ventilation to carbon dioxide (VE/VCO2 slope) were derived. All measurements (including PChRs' function tests and cardiopulmonary exercise test) were performed twice in a randomized, double-blinded and placebo-controlled manner (dopamine vs normal saline). Results We included 12 stable patients with HFpEF (age: 73±7 years, LVEF: 58±3%). During exercise the inhibition of PChRs with dopamine resulted in the improvement (decrease) in VE/VCO2 slope comparing to placebo (36±3.6 vs 34.3±3.7, p=0.04) but no change regarding peakVO2. There was a correlation between TA and relative magnitude of improvement in VE/VCO2 following PChRs inhibition (R=0.76, p=0.005). We also found a trend for correlation between RR and VE/VCO2 measured during placebo (R=0.56, p=0.059). There was no correlation between TA and RR (p=0.24). Conclusion Both TA and RR of PChRs are involved in ventilatory inefficacy during exercise in HFpEF – but in different ways. While augmented RR is likely an indicator of high VE/VCO2, the elevated TA indicates the magnitude of the improvement in exercise tolerance following PChRs deactivation. Thus, further interventions aimed at the modulation of PChRs should enroll patients based on TA rather than RR. Funding Acknowledgement Type of funding sources: Public grant(s) – National budget only. Main funding source(s): National Science Centre, PRELUDIUM grant

Trimetazidine in heart failure with preserved ejection fracton: a randomized, double-blind cross-over trial

Abstract Introduction Impaired myocardial mitochondrial function plays an import role in the pathophysiology of heart failure with preserved ejection fraction (HFpEF). Left ventricular relaxation has a high energy demand, and there is evidence indicative of a causal relationship between observed impaired energy homeostasis and diastolic dysfunction. Improvement of mitochondrial function with metabolism-modulating drugs may be a promising novel therapeutic approach in HFpEF. Trimetazidine – a fatty acid oxidation inhibitor – shifts mitochondrial metabolism towards glucose oxidation, which results in higher mitochondrial oxygen efficiency. In this study we investigated whether trimetazidine improves diastolic function during exercise in HFpEF by improving the myocardial energy homeostasis. Methods The DoPING-HFpEF trial was a phase II single-center, double-blind, placebo-controlled, randomized cross-over trial. The study consisted of two treatment periods of three months separated by a 2-week wash-out period (Figure 1). Patients were treated with placebo or trimetazidine three times a day (or twice daily in case of an impaired kidney function). The primary endpoint was change in pulmonary capillary wedge pressure (PCWP) measured with right heart catheterization at multiple stages of exercise. Secondary endpoint was change in phosphocreatine (PCr)/adenosine triphosphate (ATP) ratio, an index of the myocardial energy status, measured with phosphorus-31 magnetic resonance (MR) spectroscopy. Additional exploratory endpoints were 6-minute-walking-distance, diastolic and systolic parameters measured with echocardiography or cardiac MR, NT-proBNP levels, and quality of life. Results Twenty-five HFpEF patients were included and completed the trial, 80% of which were included based on previously established elevated (exercise) PCWP, and 20% were included based on diastolic dysfunction grade ≥II on echocardiography and elevated NT-proBNP levels. There was no effect on the primary outcome PCWP at multiple levels of exercise, with an average change in PCWP of 0±4 (SD) mmHg (Figure 2A, P=0.97). Myocardial PCr/ATP in the trimetazidine arm was similar to placebo (Figure 2B, P=0.08). There was no change by trimetazidine in the exploratory parameters 6-minute walking distance, NT-proBNP, overall quality of life, or other parameters for diastolic function measured with echocardiography and cardiac MR. There was no indication of period or cross over effect. Conclusion Trimetazidine did not improve diastolic function or myocardial energy homeostasis in patients with HFpEF. Funding Acknowledgement Type of funding sources: Foundation. Main funding source(s): Dutch Heart Foundation (DHF) and “Out-of-the-Box” grant from the Amsterdam Cardiovascular Sciences (ACS) Institute, Amsterdam, The Netherlands.

Exercise training ameliorates myocardial phenotypes in heart failure with preserved ejection fraction by changing N6-methyladenosine modification in mice model.

Heart failure with preserved ejection fraction (HFpEF) shows complicated and not clearly defined etiology and pathogenesis. Although no pharmacotherapeutics have improved the survival rate in HFpEF, exercise training has become an efficient intervention to improve functional outcomes. Here, we investigated N6-methyladenosine (m6A) RNA methylation modification in a “two-hit” mouse model with HFpEF and HFpEF with exercise (HFpEF + EXT). The manner of m6A in HFpEF and HFpEF + EXT hearts was explored via m6A-specific methylated RNA immunoprecipitation followed by high-throughput and RNA sequencing methods. A total amount of 3992 novel m6A peaks were spotted in HFpEF + EXT, and 426 differently methylated sites, including 371 hypermethylated and 55 hypomethylated m6A sites, were singled out for further analysis (fold change >2, p < 0.05). According to gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analyses, unique m6A-modified transcripts in HFpEF + EXT were associated with apoptosis-related pathway and myocardial energy metabolism. HFpEF + EXT had higher total m6A levels and downregulated fat mass and obesity-related (FTO) protein levels. Overexpression of FTO cancels out the benefits of exercise in HFpEF + EXT mice by promoting myocyte apoptosis, myocardial fibrosis and myocyte hypertrophy. Totally, m6A is a significant alternation of epitranscriptomic processes, which is also a potentially meaningful therapeutic target.

Abstract 12146: Acute Nitroglycerin Treatment Improves Exercise Hemodynamics, but Not Ventilation-Perfusion Matching in Patients With Heart Failure With Preserved Ejection Fraction

Introduction: Heart failure with preserved ejection fraction (HFpEF) patients exhibit a marked rise in PCWP during exercise, which may contribute to ventilation-perfusion (V/Q) mismatch and manifest as an increase in alveolar dead space (alveolar V D ) and alveolar-arterial PO 2 difference (AaPO 2 ). Nitrates reduce PCWP during exercise in HFpEF, but whether nitrates also reduce V/Q mismatch during exercise is unknown. Hypothesis: The increase in PCWP and V/Q mismatch during exercise would be attenuated with acute nitroglycerin (NTG) treatment compared with placebo in HFpEF patients. Methods: 13 patients performed a 6min cycling test at 20W and an incremental cycling test (with right-heart and arterial catheterization) with placebo and NTG treatment. The physiologic dead space to tidal volume (V D /V T ) was calculated using the Enghoff modification of the Bohr equation. Alveolar V D was calculated as: V D /V T x V T - anatomic dead space (anatomic V D , estimated as 2mL/kg lean body mass). AaPO 2 was calculated using the alveolar gas equation. Data were analyzed using a 2-way ANOVA. Results: PCWP decreased with NTG at 20W (placebo: 21.1±6.2 vs. NTG: 16.5±6.1mmHg, p=0.02) and peak exercise (placebo: 33.7±7.1 vs. NTG: 26.2±5.6mmHg, p&lt;0.01). However, alveolar V D did not differ between treatments at rest (placebo: 0.11±0.07 vs. NTG:0.12±0.06L/breath, p=0.91), 20W (placebo: 0.22±0.09 vs. NTG: 0.24±0.10L/breath, p=0.62), or peak exercise (placebo: 0.34±0.14 vs. NTG:0.36±0.16L/breath, p=0.83). Nor did AaPO 2 differ between treatments at rest (placebo: 17.6±4.3 vs. NTG: 18.3±5.7mmHg, p=0.76), 20W (placebo: 22.0±6.9 vs. NTG: 22.1±8.1mmHg, p=0.99), or peak exercise (placebo: 25.1±9.1 vs. NTG: 27.8±9.9mmHg, p=0.41). No significant exercise-by-treatment interaction was detected for V D /V T (p=0.80). Conclusions: This study showed that NTG attenuated the increase in PCWP, but had no effect on the increase in alveolar V D or AaPO 2 during exercise. These findings suggest that the exercise-induced increase in V/Q mismatch may not be exclusively related to abnormal exercise hemodynamics. Further study is required to determine the clinical consequences and the mechanism(s) responsible for the progressive increase in V/Q mismatch during exercise in HFpEF patients.

Left atrial conduit flow rate at baseline and during exercise: an index of impaired relaxation in patients with heart failure and preserved ejection fraction

Abstract Introduction In healthy subjects, adrenergic stimulation augments left ventricular (LV) long-axis shortening/lengthening, and increases left atrial (LA) to LV intracavitary pressure gradients in early diastole. Lower increments are observed in patients with heart failure with preserved ejection fraction (HFpEF). Purpose We hypothesized that exercise in HFpEF would similarly impair passive LV filling in early-mid diastole, during conduit flow from pulmonary veins. Methods Twenty HFpEF patients (67.8±9.8 years; 11 women), diagnosed according to 2007 ESC recommendations, underwent ramped semi-supine bicycle exercise to submaximal target heart rate (∼100) or symptoms. Seventeen asymptomatic subjects (64.3±8.9 years; 7 women) served as controls. Simultaneous LA and LV volumes were measured from pyramidal 3D echocardiographic full-volume datasets acquired from apical window at baseline and during stress, together with brachial arterial pressure. LA conduit function was computed, from minimum LV volume to ECG P wave, as [LV volume (time) – LV minimum volume] – [LA maximum volume – LA volume (time)] and expressed as average flow rate. The slope of the single-beat preload recruitable stroke work (PRSW) quantified LV inotropic state. Results There were divergent responses in conduit flow rate, which increased by 40% during exercise in control subjects (+17.8±37.3 ml/s) but decreased by 18% in patients with HFpEF (−9.6±42.3 ml/s) (p=0.046); increments during stress correlated with PRSW slope changes (p=0.003). Conclusion In HFpEF conduit flow rate decreases when diastolic dysfunction develops during exercise, in parallel with LV inotropic state changes, thereby contributing to impaired stroke volume reserve. Conduit flow can be measured as a marker of LV relaxation. Funding Acknowledgement Type of funding sources: None.

Left atrial conduit flow rate at baseline and during exercise: an index of impaired relaxation in HFpEF patients.

AimsIn healthy subjects, adrenergic stimulation augments left ventricular (LV) long‐axis shortening and lengthening, and increases left atrial (LA) to LV intracavitary pressure gradients in early diastole. Lower increments are observed in patients with heart failure with preserved ejection fraction (HFpEF). We hypothesized that exercise in HFpEF would further impair passive LV filling in early‐mid diastole, during conduit flow from pulmonary veins.Methods and resultsTwenty HFpEF patients (67.8 ± 9.8 years; 11 women), diagnosed using 2007 ESC recommendations, underwent ramped semi‐supine bicycle exercise to submaximal target heart rate (∼100 bpm) or symptoms. Seventeen asymptomatic subjects (64.3 ± 8.9 years; 7 women) were controls. Simultaneous LA and LV volumes were measured from pyramidal 3D‐echocardiographic full‐volume datasets acquired from an apical window at baseline and during stress, together with brachial arterial pressure. LA conduit flow was computed from the increase in LV volume from its minimum at end‐systole to the last frame before atrial contraction (onset of the P wave), minus the reduction in LA volume during the same time interval; the difference was integrated and expressed as average flow rate, according to a published formula. The slope of single‐beat preload recruitable stroke work (PRSW) quantified LV inotropic state. 3D LV torsion (rotation of the apex minus rotation of the base divided by LV length) was also measurable, both at rest and during stress, in 10 HFpEF patients and 4 controls. There were divergent responses in conduit flow rate, which increased by 40% during exercise in controls (+17.8 ± 37.3 mL/s) but decreased by 18% in patients with HFpEF (−9.6 ± 42.3 mL/s) (P = 0.046), along with congruent changes (+1.77 ± 1.13°/cm vs. −1.94 ± 2.73°/cm) in apical torsion (P = 0.032). Increments of conduit flow rate and apical torsion during stress correlated with changes in PRSW slope (P = 0.003 and P = 0.006, respectively).ConclusionsIn HFpEF, conduit flow rate decreases when diastolic dysfunction develops during exercise, in parallel with changes in LV inotropic state and torsion, contributing to impaired stroke volume reserve. Conduit flow is measurable using 3D‐echocardiographic full‐volume atrio‐ventricular datasets, and as a marker of LV relaxation can contribute to the diagnosis of HFpEF.

Simultaneous Measurement of Lung Diffusing Capacity and Pulmonary Hemodynamics Reveals Exertional Alveolar-Capillary Dysfunction in Heart Failure With Preserved Ejection Fraction.

BackgroundHemodynamic perturbations in heart failure with preserved ejection fraction (HFpEF) may alter the distribution of blood in the lungs, impair gas transfer from the alveoli into the pulmonary capillaries, and reduce lung diffusing capacity. We hypothesized that impairments in lung diffusing capacity for carbon monoxide (DLCO) in HFpEF would be associated with high mean pulmonary capillary wedge pressures during exercise.Methods and ResultsRebreathe DLCO and invasive hemodynamics were measured simultaneously during exercise in patients with exertional dyspnea. Pulmonary pressure waveforms and breath‐by‐breath pulmonary gas exchange were recorded at rest, 20 W, and symptom‐limited maximal exercise. Patients with HFpEF (n=20; 15 women, aged 65±11 years, body mass index 36±8 kg/m2) achieved a lower symptom‐limited maximal workload (52±27 W versus 106±42 W) compared with controls with noncardiac dyspnea (n=10; 7 women, aged 55±10 years, body mass index 30±5 kg/m2). DLCO was lower in patients with HFpEF compared with controls at rest (DLCO 10.4±2.9 mL/min per mm Hg versus 16.4±6.9 mL/min per mm Hg, P<0.01) and symptom‐limited maximal exercise (DLCO 14.6±4.7 mL/min per mm Hg versus 23.8±10.8 mL/min per mm Hg, P<0.01) because of a lower alveolar‐capillary membrane conductance in HFpEF (rest 16.8±6.6 mL/min per mm Hg versus 28.4±11.8 mL/min per mm Hg, P<0.01; symptom‐limited maximal exercise 25.0±6.7 mL/min per mm Hg versus 45.5±22.2 mL/min per mm Hg, P<0.01). DLCO was lower in HFpEF for a given mean pulmonary artery pressure, mean pulmonary capillary wedge pressure, pulmonary arterial compliance, and transpulmonary gradient.ConclusionsLung diffusing capacity is lower at rest and during exercise in HFpEF due to impaired gas conductance across the alveolar‐capillary membrane. DLCO is impaired for a given pulmonary capillary wedge pressure and pulmonary arterial compliance. These data provide new insight into the complex relationships between hemodynamic perturbations and gas exchange abnormalities in HFpEF.

Obesity, venous capacitance, and venous compliance in heart failure with preserved ejection fraction.

Circulating blood volume is functionally divided between the unstressed volume, which fills the vascular space, and stressed blood volume (SBV), which generates vascular wall tension and intravascular pressure. With decreases in venous capacitance, blood functionally shifts to the SBV, increasing central venous pressure and pulmonary venous pressures. Obesity is associated with both elevated venous pressure and heart failure with preserved ejection fraction (HFpEF). To explore the mechanisms underlying this association, we evaluated relationships between blood volume distribution, venous compliance, and body mass in patients with and without HFpEF. Subjects with HFpEF (n= 62) and non-cardiac dyspnoea (NCD) (n= 79) underwent invasive haemodynamic exercise testing with echocardiography. SBV was estimated (eSBV) from measured haemodynamic variables fit to a comprehensive cardiovascular model. Compared to NCD, patients with HFpEF displayed a leftward-shifted central venous pressure-dimension relationship, indicating reduced venous compliance. eSBV was 81% higher at rest and 69% higher during exercise in HFpEF than NCD (both P< 0.0001), indicating reduced venous capacitance. Despite greater augmented eSBV with exercise, the increase in cardiac output was reduced in HFpEF, suggesting operation on the plateau of the Starling curve. Exercise eSBV was directly correlated with higher body mass index (r=0.77, P< 0.0001) and inversely correlated with right ventricular-pulmonary arterial coupling (r=-0.57, all P< 0.0001). Patients with HFpEF display reductions in systemic venous compliance and increased eSBV related to reduced venous capacitance, abnormalities in right ventricular-pulmonary artery interaction, and increased body fat. These data provide new evidence supporting an important role of venous dysfunction in obesity-related HFpEF and suggest that therapies that improve venous function may hold promise to improve clinical status in this cohort.

Exercise Intolerance in Heart Failure With Preserved Ejection Fraction: Arterial Stiffness and Abnormal Left Ventricular Hemodynamic Responses During Exercise

BackgroundArterial stiffness is thought to contribute to the pathophysiology of heart failure with preserved ejection fraction (HFpEF). We sought to examine arterial stiffness in HFpEF and hypertension and investigate associations of arterial and left ventricular hemodynamic responses to exercise. Methods and ResultsA total of 385 symptomatic individuals with an EF of ≥50% underwent upright cardiopulmonary exercise testing with invasive hemodynamic assessment of arterial stiffness and load (aortic augmentation pressure, augmentation index, systemic vascular resistance index, total arterial compliance index, effective arterial elastance index, and pulse pressure amplification) at rest and during incremental exercise. An abnormal hemodynamic response to exercise was defined as a steep increase in pulmonary capillary wedge pressure relative to cardiac output (∆PCWP/∆CO > 2 mm Hg/L/min). We compared rest and exercise measures between HFpEF and hypertension in multivariable analyses. Among 188 participants with HFpEF (mean age 61 ± 13 years, 56% women), resting arterial stiffness parameters were worse compared with 94 hypertensive participants (mean age 55 ± 15 years, 52% women); these differences were accentuated during exercise in HFpEF (all P ≤ .0001). Among all participants, exercise measures of arterial stiffness correlated with worse ∆PCWP/∆CO. Specifically, a 1 standard deviation higher exercise augmentation pressure was associated with 2.15-fold greater odds of abnormal LV hemodynamic response (95% confidence interval 1.52–3.05; P < .001). Further, exercise measures of systemic vascular resistance index, elastance index, and pulse pressure amplification correlated with a lower peak oxygen consumption. ConclusionsExercise accentuates the increased arterial stiffness found in HFpEF, which in turn correlates with left ventricular hemodynamic responses. Unfavorable ventricular–vascular interactions during exercise in HFpEF may contribute to exertional intolerance and inform future therapeutic interventions.

Abstract 13772: Percent Predicted Peak Oxygen Pulse Predicts Vascular Responses to Exercise in HFpEF

Introduction: Cardiopulmonary exercise testing (CPET) can help identify early stages of heart failure with preserved ejection fraction (HFpEF). We sought to determine if percent predicted peak oxygen pulse (%PredO 2 P, as defined by peak oxygen uptake/heart rate), a noninvasive measure combining stroke volume and peripheral oxygen extraction, could serve as a marker of the hemodynamic response to exercise in HFpEF patients. Methods: 154 consecutive patients who underwent maximal CPET (RER&gt;1.05) and were diagnosed with HFpEF (defined as LVEF&gt;50% and PCWP/CO &gt;2 mmHg*min/L or supine resting PCWP &gt;15 mmHg) were included. Exclusion criteria included patients who were taking AV nodal agents, were paced, or had atrial fibrillation. Peak O 2 P and percent predicted were calculated using the Wasserman equation for peak VO2 in conjunction with peak predicted heart rate (220-age). Results: Tertiles of %PredO 2 P were determined with first tertile at 42.1-76.2%, second tertile at 76.2-94.4%, and third tertile at 94.4-139.2%. Baseline parameters differed across %PredO 2 P tertiles ( Table 1 ) with BMI increasing (trend p=0.014). Peak cardiac output (1 st : 10.0±3.0 L/min, 2 nd : 11.1±2.4, 3 rd : 11.5±3.5; p=0.038) and peak stroke volume (1 st : 70.6±20.1 mL, 2 nd : 83.0±16.6, 3 rd : 92.7±20.1; p&lt;0.001) were higher across tertiles, whereas peak HR (1 st : 143±23 bpm, 2 nd : 135±25, 3 rd : 123±26; p&lt;0.001) and peak SVR (1 st : 959±304 dynes*s/cm 5 , 2 nd : 831±187, 3 rd : 810±321; p=0.009) were lower. Exercise PAP/CO slope (1 st : 4.5±2.1 mmHg*min/L, 2 nd : 3.6±1.6, 3 rd : 3.3±1.7; p=0.003) and PCWP/CO slope (1 st : 3.4±1.8 mmHg*min/L, 2 nd : 2.9±1.4, 3 rd : 2.8±2.0; p=0.015) were lower across tertiles of %PredO 2 P. Conclusions: %PredO 2 P is a noninvasive variable that associates with vascular responses to exercise in HFpEF patients. Higher %PredO 2 P was associated with improved vascular responses to exercise with lower SVR, PAP/CO and PCWP/CO slopes.

Inhaled Prostacyclin on Exercise Echocardiographic Cardiac Function in Preserved Ejection Fraction Heart Failure.

Treatments that improve outcomes in patients with heart failure with reduced ejection fraction (HFrEF) have shown no benefits for those with heart failure with preserved ejection fraction (HFpEF). Our study aimed to investigate the effect of inhaled iloprost on myocardial performance during exercise in HFpEF. The study participants were enrolled from the ILO-HOPE trial (NCT03620526), a prospective randomized, double-blind, placebo-controlled study that was designed to investigate the effects of iloprost on cardiovascular hemodynamics during exercise in patients with HFpEF. Subjects were randomized 1:1 to inhalation of iloprost or placebo for 5 min. Two-dimensional transthoracic echocardiography with high temporal resolution was implemented to measure left ventricular (LV) longitudinal strain, LV diastolic function, and RV function both at rest and during supine exercise at 20-W workload. LV global longitudinal strain (GLS) in response to exercise increased more in the iloprost group (LV GLS, -24.96 ± 1.20 vs -20.75 ± 3.00, P < 0.001). Iloprost also resulted in greater increment of LV GLS during exercise (ΔLV GLS, +6.02 ± 1.39 vs +3.44 ± 0.80, P < 0.001). Moreover, iloprost use was associated with enhancement of LV diastolic function, RV systolic function, and relief of pulmonary hypertension during exercise. In patients with HFpEF, inhaled iloprost favorably improved myocardial performance during exercise by increasing LV GLS reserve, decreasing LV diastolic filling load, and reducing stress-induced pulmonary hypertension and thereby improving RV systolic function. Larger studies are needed to validate the result and long-term benefits of iloprost in patients with HFpEF.

Stress Echocardiography-Derived E/e’ Predicts Abnormal Exercise Hemodynamics in Heart Failure With Preserved Ejection Fraction

BackgroundThe correlation between echocardiographic parameters and hemodynamics data in patients with heart failure with preserved ejection fraction (HFpEF) is unclear. It is important to find a non-invasive echocardiographic parameter for predicting exercise pulmonary capillary wedge pressure (PCWP).AimThis study sought to determine the correlation between echocardiographic parameters and hemodynamics data at rest and during exercise in HFpEF patients.Methods and ResultsThis study was a cross-sectional cohort exploratory analysis of baseline data from the ILO-HOPE trial. A total of 34 HFpEF patients were enrolled. The average age was 70 ± 12 years, and most (74%) were women. The patients underwent invasive cardiac catheterization and expired gas analysis at rest and during exercise. Echocardiography including tissue Doppler imaging was performed, and global longitudinal strain and other novel diastolic function indexes were analyzed at rest and during exercise. At rest, no significant correlation was noted between resting PCWP and echocardiographic parameters. However, a significant correlation was observed between post-exercise PCWP and stress E/e′ (septal, lateral, and mean) ratio (p = 0.003, 0.031, 0.012). Moreover, post-exercise ΔPCWP showed a good correlation with stress E/e′ (septal, lateral, and mean; all p ≤ 0.001) and global longitudinal strain (GLS) during exercise (p = 0.03). After multivariate regression analysis with adjustment for possible confounding factors including age and sex, there was still a significant correlation between post-exercise ΔPCWP and E/e′ (r = 0.62, p < 0.001 for E/e′mean).ConclusionOnly stress echocardiography derived tissue Doppler E/e′ ratio is closely correlated with abnormal exercise hemodynamics (PCWP and post-exercise ΔPCWP) in HFpEF. This echocardiographic marker is substantially more sensitive than other novel echocardiographic parameters during exercise, and may have significant diagnostic utility for ambulatory HFpEF patients with dyspnea.Clinical Trial Registrationhttps://www.clinicaltrials.gov, identifier NCT03620526.

Exercise Ventilatory Efficiency in Older and Younger Heart Failure Patients With Preserved Ejection Fraction

Patients with heart failure with preserved ejection fraction (HFpEF) exhibit pulmonary abnormalities, but the studies to date have reported wide variability in the ventilatory equivalent for carbon dioxide (V̇E/V̇CO2) slope. It is possible that aging may contribute to that variability. We sought to compare ventilatory efficiency and its components in older and younger HFpEF patients during exercise. Eighteen older (O; 80 ± 4 y) and 19 younger (Y; 59 ± 7 y) HFpEF patients performed cardiopulmonary exercise testing to volitional fatigue. Measurements of arterial blood gases were used to derive VD/VT, dead space ventilation, and alveolar ventilation. V̇E/V̇CO2 slope was greater in older compared with younger HFpEF patients (O 36 ± 7vs Y 31 ± 7; P = .04). At peak exercise, older HFpEF exhibited greater VD/VT compared with younger HFpEF (O 0.37 ± 0.10vs Y 0.28 ± 0.10; P < .01), whereas PaCO2 was not different between groups (P = .58). V̇E and alveolar ventilation were similar (P > .23), but dead space ventilation was greater in older compared with younger HFpEF at peak exercise (P = .04). Older HFpEF patients exhibit greater ventilatory inefficiency resulting from elevated physiologic dead space during peak exercise compared with younger HFpEF patients. These results suggest that aging can worsen the pathophysiologic mechanisms underlying ventilatory efficiency during exercise in HFpEF.

The β-Adrenergic Agonist Albuterol Improves Pulmonary Vascular Reserve in Heart Failure with Preserved Ejection Fraction: A Randomized Controlled Trial

Background Heart failure with preserved ejection fraction (HFpEF) is associated with pulmonary vascular dysfunction, particularly during exercise. Pulmonary vasodilators may favorably reduce pulmonary artery (PA) tone in HFpEF, but this could theoretically worsen left atrial hypertension and pulmonary congestion. Objective To evaluate whether the inhaled β-adrenergic agonist albuterol would improve PA vascular function during exercise in HFpEF. Methods We performed a randomized double blind placebo controlled trial testing the effects of inhaled albuterol on resting and exercise hemodynamics in HFpEF using high fidelity micromanometer catheters and expired gas analysis. The primary end point was pulmonary vascular resistance (PVR) during exercise. Results Subjects with HFpEF (n=30) underwent resting and exercise hemodynamic assessment and were then randomized 1:1 to inhaled, nebulized albuterol or placebo, followed by repeat assessment of rest and exercise hemodynamics. Albuterol improved the primary endpoint of exercise PVR as compared to placebo (−0.6±0.5 vs +0.1±0.7 Wood units, p=0.003). As compared to placebo, albuterol enhanced PA compliance with exercise, improved cardiac output reserve and RV-PA coupling, reduced right atrial and pulmonary artery pressures, and enhanced left ventricular transmural distending pressure during exercise (all p Conclusions Albuterol improves pulmonary vascular function and cardiac hemodynamics with exercise in patients with HFpEF. Further study is warranted to evaluate the chronic efficacy of β-agonists and other pulmonary vasoactive medicines in this population. Clinical Trial Registration: Inhaled Beta-adrenergic agonists to Treat Pulmonary Vascular Disease in Heart Failure with Preserved Ejection Fraction (BEAT HFpEF) - NCT02885636. https://clinicaltrials.gov/ct2/show/NCT02885636