Exercise Intolerance In Heart Failure Research Articles

Association of Active and Passive Components of LV Diastolic Filling With Exercise Intolerance in Heart Failure With Preserved Ejection Fraction: Mechanistic Insights From Spironolactone Response

ObjectivesThis study sought to investigate the association of left ventricular (LV) untwisting rate (UT) and E/e’ ratio with the response of exercise capacity to spironolactone in heart failure with preserved ejection fraction (HFpEF). BackgroundIn most patients with HFpEF, LV filling abnormalities represent a central component in the development of dyspnea. LV diastolic filling is determined by the interplay of passive (LV stiffness and myocardial collagen content, reflected by E/e’ ratio) and active myocardial properties (UT, a precursor to isovolumic pressure decay and contributor to diastolic suction). MethodsIn 194 patients with HFpEF (64 ± 8 years), a complete echocardiogram (including assessment of myocardial deformation and rotational mechanics) was performed. Echocardiography following maximal exercise was undertaken to assess LV systolic and diastolic responses to stress. A subset of 105 patients with an exercise-induced increase in estimated LV filling pressure were randomly assigned to spironolactone 25 mg (n = 51) or placebo (n = 54) for 6 months. ResultsBaseline peak Vo2 was associated with UT (β = 0.19; p = 0.01) and E/e’ (β = −0.16; p = 0.03), independent of clinical data and exercise reserve in longitudinal deformation and ventricular-arterial coupling. An increase in peak Vo2 with treatment was independently associated with changes in UT (β = 0.28; p = 0.003) and exertional increase in E/e′ (β = −0.23; p = 0.01) from baseline to follow-up. A significant interaction with the use of spironolactone on peak Vo2 was found for E/e′ (p = 0.02) but not for UT (p = 0.62). ConclusionsBoth active and passive determinants of LV filling, as reflected by UT and E/e′, contribute to reduced exercise capacity in HFpEF. Improvement in functional capacity with a 6-month therapy with spironolactone is associated with improvements in both indices. However, the possible mediating effect of this medication is observed only on E/e′.

Therapeutic Targets for the Multi-system Pathophysiology of Heart Failure: Exercise Training.

Adult chronic heart failure (HF) is a terminal syndrome. While the HF phenotype is inhomogeneous across the ejection fraction spectrum, exercise intolerance remains a cardinal feature of all HF patients. Impairment of a single organ system cannot independently account for exercise intolerance in HF. Thus, the multi-system integrative pathophysiology of HF leads to challenges in identifying an effective medical therapy aimed at targeting a single mechanism to improve exercise tolerance. This unresolved medical care approach raises a number of points for discussion in this field as it is well-recognized that exercise intolerance is accompanied by increased hospitalizations and mortality across the HF spectrum. Practitioner-guided individualized exercise training represents an intrinsic multi-level therapeutic approach that inclusively "targets" integrated physiological systems. A rapidly evolving body of evidence provides firm support that structured exercise therapy is safe while leading to improved exercise tolerance (peak oxygen uptake [V̇O2]) followed by reduced hospitalizations and cardiovascular mortality across the HF spectrum. The benefits of guided exercise therapy in HF have been directly attributed to integrative improvements in peak V̇O2, skeletal muscle strength, cardiac function, micro- to macro-vascular function, circulation/organ perfusion, and nervous system function, among others. Despite the sound clinical evidence in support of exercise-based medical care, there remains an appreciable gap in translation of current scientific evidence and implementation of this therapeutic paradigm into routine clinical practice as well as universal insurance coverage for HF patients. In the following review, the theme of discussion is framed in a manner that carries a sense of urgency for the need to increase awareness of the up-to-date evidence-based support for the clinical implementation of structured exercise therapy as a necessary routine component of primary medical care practices for reducing hospitalizations, morbidity, and mortality in all HF patients.

P6-1 - Protein Acetylation in Skeletal Muscle Impairs Mitochondrial Fatty Acid Oxidation and Limits Exercise Capacity in Post-Infarct Heart Failure in Mice

Background: Exercise intolerance is a major clinical manifestation in heart failure (HF) patients, due largely to skeletal muscle (SKM) abnormalities. Lysine Acetylation is a reversible post-translational modification involved in regulating mitochondrial metabolic enzymes. We investigated whether mitochondrial acetylation in SKM could contribute to impaired fatty acid oxidation and exercise intolerance associated with HF. Methods and Results: MI was created in male C57BL/6J mice by ligating the left coronary artery (n = 7), and a sham operation was performed in other mice (n = 7). After 4 weeks, the work and peak oxygen uptake (VO2) was significantly reduced in MI mice compared to sham mice (work 11 ± 1 vs 23 ± 1 J; peak VO2 143 ± 5 vs 159 ± 3 mL⋅kg−1⋅min−1). Mitochondrial proteins that include TCA cycle enzymes, electron transport chain, and fatty acid β-oxidation enzymes such as enoyl-CoA hydratase and 3-ketoacyl-CoA thiolase were hyperacetylated in SKM from MI mice, in conjunction with a decrease in mitochondrial fatty acid respiratory capacity rates. In addition, metabolomic analysis revealed that plasma N6-acetyl-lysine level was increased in HF patients compared to controls (15.0 ± 3.2 × 10−5 vs 9.8 ± 2.4 × 10−5, P < .01) and negatively correlated with peak VO2 measured by cardiopulmonary exercise test (r2 = 0.52, P < .01). Conclusions: Mitochondrial acetylation is associated with impaired fatty acid oxidation and reduced exercise capacity in HF. These results provide a novel pathophysiological insight into the mechanism of exercise intolerance in HF.

O44-2 - Incremental Value of Early Diastolic Flow to Global Longitudinal Strain Ratio for the Prediction of Exercise Intolerance in Heart Failure

O44-2 - Incremental Value of Early Diastolic Flow to Global Longitudinal Strain Ratio for the Prediction of Exercise Intolerance in Heart Failure

Effect of Cardiac Resynchronization Therapy on Arterial-Ventricular Coupling during Exercise in Heart Failure with Reduced Ejection Fraction

Exercise intolerance in heart failure with reduced ejection fraction (HFrEF) is mediated, in part, by an impairment in arterial-ventricular coupling. Cardiac resynchronization therapy (CRT) improves resting and paced arterial-ventricular coupling. The effect of chronic CRT on arterial-ventricular coupling during exercise in HFrEF has not been studied. PURPOSE: To study the effects of 6 months of CRT on arterial-ventricular coupling during exercise in patients with HFrEF. METHODS: Seven patients with HFrEF (59 ± 9 yrs; m/f: 5/2; NYHA III/IV = 6/1; EF = 18 ± 3%; peak VO2 = 12.5 ± 3.6 ml/kg/min) were studied pre-CRT and 6 months following (post-CRT). After resting measurements, subjects performed cycle ergometry at 22 ± 8 W (70 ± 13% of peak VO2) for 4 min. Left ventricular volumes were determined using contrast enhanced echocardiography. Blood pressure was measured manually at the brachium. End-systolic pressure (ESP) was approximated as 0.9 × systolic blood pressure. Effective arterial elastance (Ea) was calculated as ESP/stroke volume and end-systolic elastance (Ees) was calculated as ESP/end-systolic volume. Arterial-ventricular coupling was calculated as Ea/Ees. Comparisons were made with a 2 (rest, exercise) × 2 (pre-CRT, post-CRT) repeated measures factorial ANOVA and t-tests. Data are mean ± SD and P < 0.05 was significant. RESULTS: There was a main effect of CRT on Ea, where the pre-CRT Ea increased 0.28 ± 0.45 mmHg/mL during exercise and the post-CRT Ea decreased 0.12 ± 0.25 mmHg/mL (P < 0.05). There was no main effect of CRT on Ees, as both the pre-CRT (0.04 ± 0.03 mmHg/mL) and post-CRT (0.08 ± 0.04 mmHg/mL) increase in Ees from rest to exercise was not significant (P > 0.05). However, resting and exercise Ees tended to be higher post-CRT. Lastly, there was a main effect of CRT on Ea/Ees, where Ea/Ees increased 0.40 ± 1.35 mmHg/mL from rest to exercise pre-CRT and Ea/Ees decreased 0.69 ± 0.35 mmHg/mL from rest to exercise post-CRT (P < 0.05). CONCLUSION: The improvement in arterial-ventricular coupling during exercise following chronic CRT in HFrEF can be attributed to improvements in arterial loading on the left ventricle, as contractility changes related to CRT were modest.

Exercise intolerance in heart failure with preserved ejection fraction: time to scrutinize diuretic therapy?

Exercise intolerance in heart failure with preserved ejection fraction: time to scrutinize diuretic therapy?

Resveratrol improves exercise performance and skeletal muscle oxidative capacity in heart failure.

We investigated whether treatment of mice with established pressure overload-induced heart failure (HF) with the naturally occurring polyphenol resveratrol could improve functional symptoms of clinical HF such as fatigue and exercise intolerance. C57Bl/6N mice were subjected to either sham or transverse aortic constriction surgery to induce HF. Three weeks postsurgery, a cohort of mice with established HF (%ejection fraction <45) was administered resveratrol (~450 mg·kg-1·day-1) or vehicle for 2 wk. Although the percent ejection fraction was similar between both groups of HF mice, those mice treated with resveratrol had increased total physical activity levels and exercise capacity. Resveratrol treatment was associated with altered gut microbiota composition, increased skeletal muscle insulin sensitivity, a switch toward greater whole body glucose utilization, and increased basal metabolic rates. Although muscle mass and strength were not different between groups, mice with HF had significant declines in basal and ADP-stimulated O2 consumption in isolated skeletal muscle fibers compared with sham mice, which was completely normalized by resveratrol treatment. Overall, resveratrol treatment of mice with established HF enhances exercise performance, which is associated with alterations in whole body and skeletal muscle energy metabolism. Thus, our preclinical data suggest that resveratrol supplementation may effectively improve fatigue and exercise intolerance in HF patients.NEW & NOTEWORTHY Resveratrol treatment of mice with heart failure leads to enhanced exercise performance that is associated with altered gut microbiota composition, increased whole body glucose utilization, and enhanced skeletal muscle metabolism and function. Together, these preclinical data suggest that resveratrol supplementation may effectively improve fatigue and exercise intolerance in heart failure via these mechanisms.

Exercise Intolerance In Heart Failure With Preserved Ejection Fraction.

More than 50% of Americans with heart failure have preserved ejection fraction (HFpEF). Exercise intolerance is a hallmark of HFpEF, but the pathophysiology is not well understood. Diverse etiologies and incomplete mechanistic understanding have resulted in ineffective management strategies to improve the outcomes of HFpEF. Traditional therapies that have been beneficial in the treatment of heart failure with reduced ejection fraction (HFrEF), neurohormonal blockade in particular, have not been effective in treating HFpEF. In this review, we address underlying mechanisms of HFpEF and present the rationale supporting exercise as a component of comprehensive management.

The Factors Improve Peak Oxygen Consumption are Different between Heart Failure with Reduced Ejection Fraction and with Preserved Ejection Fraction

Several factors contribute to exercise intolerance in heart failure (HF), abnormalities of cardiac systolic and diastolic reserve, chronotropic incompetence, vascular dysfunction and skeletal muscle dysfunction. However, the different mechanisms of exercise intolerance may exist between HF with reduced Ejection Fraction (HFrEF) and HF with preserved EF (HFpEF). In this preliminary study, we aimed to investigate the differences of factors influence peak oxygen consumption (VO2peak) between HFrEF and HFpEF. Forty-five patients with HFrEF and forty-eight patients with HFpEF (mean age; 60±11 vs. 63±15 [years], male; 38 vs. 37, EF; 27.1±7.6 vs. 52.0±10.2 [%]) underwent laboratory measurements, echocardiography, cardiopulmonary exercise testing (CPX) and measurements of lower limb muscle strength and calf circumference on the same day. CPX and other examinations were performed two times at interval of six months post-discharge. In HFrEF and HFpEF, mean values of increase in VO2peak (Δ VO2peak) were 1.6±3.0 vs. 1.8±3.7 [ml/min/kg]. In multiple linear regression analysis, calf circumference (β=0.513, p=0.001), Δ E/e′ (β=-0.401, p=0.007) and ischemic etiology (β=-0.390, p=0.009) were selected as independent variables of Δ VO2peak in HFrEF, whereas Δ hemoglobin (β=0.441, p=0.002), Δ logBNP (β=-0.421, p=0.003), Δ chronotropic index (β=0.373, p=0.004) were selected in HFpEF. Our study suggests that the mechanisms of exercise intolerance may be different due to not only cardiac but also non-cardiac factors between in HFrEF and HFpEF.

The role of muscle sympathetic nerve activity in limiting exercise capacity in heart failure.

The role of muscle sympathetic nerve activity in limiting exercise capacity in heart failure.

Skeletal Muscle Afferent Inhibition Improves Exercise Tolerance in Heart Failure

BACKGROUNDIncreased activation of Group III/IV skeletal muscle afferents is suggested to play a role in exercise intolerance in heart failure (HF).PURPOSEThe purpose of this study was to examine if skeletal muscle afferent feedback inhibition improves exercise tolerance in HF.METHODS8 HF patients [59±8 yr, mean±SD] participated in two randomized incremental recumbent cycling exercise sessions to peak capacity (peak oxygen consumption, VO2). Session 1: The synthetic opioid fentanyl (50 mcg), known to block afferent feedback, was injected intrathecally (INJ) in the lumbar spine (L3‐L4 intervertebral space) prior to exercise. Session 2: Participants were prepared similarly with a sham injection (placebo, PLA). Gas exchange, dyspnea and RPE were measured.RESULTSHF patients exercised for a longer duration (Δ3±3 min, p=0.02) and reached a higher power output (PLA:109±30 vs. INJ:128±34 W, p=0.02) with locomotor afferent inhibition. Additionally, peak VO2 was non‐significantly greater (PLA:18.7±3.3 vs. INJ:21.8±4.4 ml/kg/min, p=0.10). With INJ workload matched to peak PLA workload, RPE was reduced (PLA:18±2 vs. INJ:15±2, respectively, p=0.005) and dyspnea was lower (PLA:7.5±2 vs. INJ:4.2±1, p=0.003) with no difference in VO2 (p&gt;0.05).CONCLUSIONInhibition of group III/IV locomotor muscle afferent feedback contributes to improved exercise tolerance and exertional symptoms in HF patients.

Sarcopenic obesity and the pathogenesis of exercise intolerance in heart failure with preserved ejection fraction.

Heart failure with preserved ejection fraction (HFpEF) is the most common form of heart failure (HF) in older adults. The primary chronic symptom in patients with HFpEF, even when well compensated, is severe exercise intolerance. Cardiac and peripheral functions contribute equally to exercise intolerance in HFpEF, though the latter has been the focus of fewer studies. Of note, multiple studies with exercise training have shown that exercise intolerance can improve significantly in the absence of improvements in exercise cardiac output, indicating a role of peripheral, noncardiac adaptations. In addition, clinical drug trials performed to date in HFpEF, all of which have focused on influencing cardiovascular function, have not been positive on primary clinical outcomes and most have not improved exercise capacity. Mounting evidence indicates that sarcopenic obesity, characterized by the coexistence of excess fat mass and decreased muscle mass, could contribute to the pathophysiology of exercise intolerance in older HFpEF patients and may provide avenues for novel treatments.

Mechanisms of exercise intolerance in heart failure with preserved ejection fraction: the role of abnormal peripheral oxygen extraction.

Exercise capacity as measured by peak oxygen uptake (Vo2) is similarly impaired in patients with heart failure with preserved ejection fraction (HFpEF) and heart failure with reduced ejection fraction (HFrEF). However, characterization of how each component of Vo2 changes in response to incremental exercise in HFpEF versus HFrEF has not been previously defined. We hypothesized that abnormally low peripheral o2 extraction (arterio-mixed venous o2 content difference, [C(a-v)o2]) during exercise significantly contributes to impaired exercise capacity in HFpEF. We performed maximum incremental cardiopulmonary exercise testing with invasive hemodynamic monitoring on 104 patients with symptomatic NYHA II to IV heart failure (HFpEF, n=48, peak Vo2=13.9±0.5 mL kg(-1) min(-1), mean±SEM, and HFrEF, n=56, peak Vo2=12.1±0.5 mL kg(-1) min(-1)) and 24 control subjects (peak Vo2 27.0±1.7 mL kg(-1) min(-1)). Peak exercise C(a-v)o2 was lower in HFpEF compared with HFrEF (11.5±0.27 versus 13.5±0.34 mL/dL, respectively, P<0.0001), despite no differences in age, hemoglobin level, peak respiratory exchange ratio, Cao2, or cardiac filling pressures. Peak C(a-v)o2 and peak heart rate emerged as the leading predictors of peak Vo2 in HFpEF. Impaired peripheral o2 extraction was the predominant limiting factor to exercise capacity in 40% of patients with HFpEF and was closely related to elevated systemic blood pressure during exercise (r=0.49, P=0.0005). In the first study to directly measure C(a-v)o2 throughout exercise in HFpEF, HFrEF, and normals, we found that peak C(a-v)o2 was a major determinant of exercise capacity in HFpEF. The important functional limitation imposed by impaired o2 extraction may reflect intrinsic abnormalities in skeletal muscle or peripheral microvascular function, and represents a potential target for therapeutic intervention.

Activation of PPARδ signaling improves skeletal muscle oxidative metabolism and endurance function in an animal model of ischemic left ventricular dysfunction.

Exercise intolerance in heart failure has been linked to impaired skeletal muscle oxidative capacity. Oxidative metabolism and exercise capacity are regulated by PPARδ signaling. We hypothesized that PPARδ stimulation reverts skeletal muscle oxidative dysfunction. Myocardial infarction (MI) was induced in C57BL/6 mice and the development of ventricular dysfunction was monitored over 8 wk. Mice were randomized to the PPARδ agonist GW501516 (5 mg/kg body wt per day for 4 wk) or placebo 8 wk post-MI. Muscle function was assessed through running tests and grip strength measurements. In muscle, we analyzed muscle fiber cross-sectional area and fiber types, metabolic gene expression, fatty acid (FA) oxidation and ATP content. Signaling pathways were studied in C2C12 myotubes. FA oxidation and ATP levels decreased in muscle from MI mice compared with sham- operated mice. GW501516 administration increased oleic acid oxidation levels in skeletal muscle of the treated MI group compared with placebo treatment. This was accompanied by transcriptional changes including increased CPT1 expression. Further, the PPARδ-agonist improved running endurance compared with placebo. Cell culture experiments revealed protective effects of GW501516 against the cytokine-induced decrease of FA oxidation and changes in metabolic gene expression. Skeletal muscle dysfunction in HF is associated with impaired PPARδ signaling and treatment with the PPARδ agonist GW501516 corrects oxidative capacity and FA metabolism and improves exercise capacity in mice with LV dysfunction. Pharmacological activation of PPARδ signaling could be an attractive therapeutic intervention to counteract the progressive skeletal muscle dysfunction in HF.

Effects of exercise training on neurovascular control and skeletal myopathy in systolic heart failure.

Neurohormonal excitation and dyspnea are the hallmarks of heart failure (HF) and have long been associated with poor prognosis in HF patients. Sympathetic nerve activity (SNA) and ventilatory equivalent of carbon dioxide (VE/VO2) are elevated in moderate HF patients and increased even further in severe HF patients. The increase in SNA in HF patients is present regardless of age, sex, and etiology of systolic dysfunction. Neurohormonal activation is the major mediator of the peripheral vasoconstriction characteristic of HF patients. In addition, reduction in peripheral blood flow increases muscle inflammation, oxidative stress, and protein degradation, which is the essence of the skeletal myopathy and exercise intolerance in HF. Here we discuss the beneficial effects of exercise training on resting SNA in patients with systolic HF and its central and peripheral mechanisms of control. Furthermore, we discuss the exercise-mediated improvement in peripheral vasoconstriction in patients with HF. We will also focus on the effects of exercise training on ventilatory responses. Finally, we review the effects of exercise training on features of the skeletal myopathy in HF. In summary, exercise training plays an important role in HF, working synergistically with pharmacological therapies to ameliorate these abnormalities in clinical practice.

Cardiopulmonary Exercise Testing in Heart Failure

A growing body of literature has underscored the value of ventilatory gas exchange techniques during exercise testing (commonly termed cardiopulmonary exercise testing, or CPX) and their applications in the management of patients with heart failure (HF). The added precision provided by this technology is useful in terms of understanding the physiology and mechanisms underlying exercise intolerance in HF, quantifying the response to therapy, evaluating disability, making activity recommendations, and quantifying the response to exercise training. Importantly, a wealth of data has been published in recent years on the prognostic utility of CPX in patients with HF. These studies have highlighted the concept that indices of ventilatory inefficiency, such as the VE/VCO2 slope and oscillatory breathing, are particularly powerful in stratifying risk in HF. This article provides an overview of the clinical utility of CPX in patients with HF, including the applications of ventilatory inefficiency during exercise, the role of the pulmonary system in HF, respiratory muscle performance (RMP), and the application of CPX as part of a comprehensive clinical and exercise test evaluation.

Exercise Training as Therapy for Heart Failure

Despite a variety of pharmacological and device therapies for persons with chronic heart failure (HF), prognosis and quality of life (QOL) remain poor. The need for new effective strategies to improve outcomes for patients with HF is underscored by persistently high mortality, morbidity, healthcare use, and costs associated with HF, with >1 million US HF hospitalizations at an estimated direct and indirect cost in the US of $40 billion in 2012.1 Exercise intolerance is a primary symptom in patients with chronic HF, both those with preserved ejection fraction (HFpEF) and reduced ejection fraction (HFrEF), and is a strong determinant of prognosis and of reduced QOL.2 Exercise training improves exercise intolerance and QOL in patients with chronic stable HFrEF, and has become an accepted adjunct therapy for these patients (Class B level of evidence) based on a fairly extensive evidence base of randomized trials, mostly small.3 The National Heart, Lung, and Blood Institute–funded Heart Failure: A Controlled Trial Investigating Outcomes of Exercise Training (HF-ACTION) trial compared an individualized, supervised, and home-based aerobic exercise program plus guideline-based pharmacological and device therapy with guideline-based therapy alone in persons with HFrEF. The exercise arm showed a modest reduction in cardiovascular hospitalizations and mortality and improved QOL.4,5 However, problems with adherence in the exercise arm probably dampened the potential benefit. This landmark study leaves several unanswered key questions, including the role of exercise dose; the relative benefit of different types of aerobic exercise, including high-intensity interval training (HIIT), and resistance, training relative to aerobic training; combination of exercise training with other therapies; optimization of adherence; benefit for older patients with HF, those with HFpEF or multiple comorbidities, and those with acute decompensated HF. The National Heart, Lung, and Blood Institute convened a working group of experts on June 11, …

Abstract 12306: Changes of Metabolomic Profiling Are Associated With Reduced Exercise Capacity in Patients With Heart Failure

Background: Exercise intolerance is a major clinical manifestation, and closely related to poor prognosis in heart failure (HF) patients. Metabolic derangements have been shown to play an important role in this phenomenon. Recent metabolomic investigations have highlighted several novel biochemical pathways in HF, however, metabolic profiling associated with exercise capacity has not been elucidated. We thus investigated the metabolites associated with exercise capacity by using global metabolomic analysis of plasma samples in HF patients. Methods: Ten consecutive HF patients with reduced ejection fraction (57 ± 12 years old, New York Heart Association class II - III) and 5 age-matched healthy subjects as controls (56 ± 3 years old) were studied. Charged metabolites in plasma samples were measured by capillary electrophoresis mass spectrometry. Peak oxygen uptake (peak VO 2 ) and VE/VCO 2 slope were measured by cardiopulmonary exercise test. Results: A total of 233 charged metabolites were identified and quantified absolutely using standard chemicals for each metabolite. Significant increases in arginine methylation, phospholipid metabolites, and urea cycle metabolites were observed in HF patients compared to controls (Figure). Peak VO 2 was negatively correlated with methylarginine including asymmetric dimethylarginine (ADMA) (r=-0.77, P&lt;0.001) and symmetric dimethylarginine (SDMA) (r=-0.65, P=0.040) levels, and phospholipid metabolites including choline (r=-0.63, P=0.049) and N,N -dimethylglycine (r=-0.75, P=0.011) levels in HF patients. VE/VCO 2 slope was positively correlated with N,N -dimethylglycine (r=0.72, P=0.026) and Urea (r=0.82, P=0.006) levels. Conclusions: Increases in metabolites of arginine methylation, phospholipid metabolism, and urea cycle were associated with exercise intolerance in HF. These results provide mechanistic insights into exercise intolerance associated with HF.

Profound lung remodeling in heart failure, a poorly understood phenomenon with a significant impact (715.6)

Exercise intolerance, characterized by dyspnea and early onset of exertional fatigue, is a chief complaint among patients with heart failure (HF). Limb muscle dysfunction is a known contributor to exercise intolerance, however, this phenomena does not explain dyspnea. Lung remodeling has been reported in end‐stage HF patients which could contribute to dyspnea and exercise intolerance, underscoring the importance and urgent need to better understand its role in HF. Our aim is to characterize the development of lung remodeling and its impact on exercise intolerance in HF. We hypothesize that lung remodeling occurs early in the development of HF, causing exercise‐induced hemoglobin (Hb) desaturation, affecting exercise performance. Methods: Male CD1 mice were subject to either transverse aortic constriction (TAC) or sham surgery. Exercise tolerance and Hb saturation were measured during a graded exercise test. The animals were sacrificed and lungs excised and fixed for histological evaluation. Results: Time to exhaustion was decreased by 40% in TAC. Hb saturation in TAC decreased during exercise while sham remained unchanged (p&lt;0.05). Hb levels were similar between sham and TAC animals. Lung compliance was significantly reduced in 9 week TAC compared to sham (p&lt;0.05), which further declined by 18 weeks (p&lt;0.01). Histological assessment revealed significant remodeling including a 43% increase in fibrosis (p&lt;0.01), marked inflammation and distended alveoli. Conclusions: Lung remodeling plays a significant yet under acknowledged role in exercise intolerance in HF patients. Grant Funding Source: Ontario Thoracic Society

Mechanisms of Exercise Intolerance in Heart Failure With Preserved Ejection Fraction

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