Exercise In Heart Failure Patients Research Articles

Therapeutic Efficacy of Shexiang Baoxin Pill Combined with Exercise in Patients with Heart Failure with Preserved Ejection Fraction: A Single-Center, Double-Blind, Randomized Controlled Trial.

To evaluate the therapeutic efficacy of Shexiang Baoxin Pill combined with exercise in heart failure patients with preserved ejection fraction (HFpEF). Sixty patients with HFpEF were randomly divided into group A (n=20), receiving Shexiang Baoxin Pill combined with home-based exercise training based on conventional drugs for 12 weeks; group B (n=20), receiving conventional drugs combined with home-based exercise training for 12 weeks; and group C (n=20), receiving conventional drug treatment only. Peak oxygen uptake (peakVO2), anaerobic threshold (AT), 6-min walking test (6MWT), Pittsburgh Sleep Quality Index (PSQI), and SF-36 questionnaire (SF-36) results before and after treatment were compared among groups. After the 12-week intervention, patients in group C showed significant declines in peakVO2, AT, 6MWT, PSQI, and SF-36 compared with pre-treatment (P<0.01), while groups A and B both showed significant improvements in peakVO2, AT, 6MWT, PSQI, and SF-36 results compared with pre-treatment (P<0.01). Compared with group C, patients in groups A and B showed significant improvements in peakVO2, AT, 6MWT, PSQI, and SF-36 (P<0.01). In addition, patients in group A showed more significant improvements in physical function, role-physical, vitality, and mental health scores on the SF-36 questionnaire, and PSQI scores than those in group B (P<0.01). Exercise training improved exercise tolerance, sleep quality and quality of life (QoL) in patients with HFpEF. Notably, Shexiang Baoxin Pill played an active role in sleep quality and QoL of patients with HFpEF. (The trial was registered in the Chinese Clinical Trial Registry (No. ChiCTR2100054322)).

Abstract 13286: Symptoms in Heart Failure Improve With More Intense Physical Activity

Purpose. RCTs have demonstrated the benefits of exercise in heart failure (HF) including improved functional status and quality of life, with fewer hospitalizations. Little is known about how changes in physical activity (PA) over time may influence physical and psychological symptoms. This study examined the extent to which changes in PA over time were associated with changes in physical and psychological symptoms in HF. Methods. A secondary analysis was conducted using an RCT of exercise in HF patients (N=86) who received an initial ICD. Data were collected at baseline and 2 months. Physical activity was measured over 5 consecutive days using the StepWatch PA Monitor (Orthocare Innovations TM ) for total PA (mean steps/day) and intensity (mean steps/min for most intense 30 minutes/day). Other measures included: physical symptoms (Patient Concerns Assessment (PCA); fatigue and pain (SF-36 Vitality &amp; Bodily Pain subscales, respectively), and symptoms of depression (Patient Health Questionnaire-9, PHQ9) and anxiety (State-Trait Anxiety Index, STAI). Multivariate regression was used to examine for associations between increased and decreased PA and changes in physical and psychological symptoms, adjusting for age, co-morbidities, body mass index, ejection fraction (EF), and study group. Results. Patients were male (82%), 55.3±12.1 years of age, white (79%), with multiple co-morbidities (Charlson Co-morbidity: 2.1±1.3), BMI of 30.0±5.1, with reduced EF (31.0±10.1%). An increase in PA intensity from baseline to 2 months was associated with significant improvement in psychological symptoms (PHQ9:β= -0.13, p=0.030; STAI:β= -0.26,p=0.026) and fatigue (β= 0.55,p=0.023). An increase in total PA (steps/day) was associated with improvement in anxiety only (β= -1.23, p=0.045). A decrease in PA (total and intensity) was not associated with changes in any symptoms. Conclusion. For patients with HF and an initial ICD, increased intensity of PA over 2 months was associated with improved psychological symptoms and reduced fatigue. Decreases in PA (total and intensity) were not associated with symptoms. These findings warrant further investigation as interventions focused on PA intensity rather than quantity may be more effective in reducing symptoms in HF.

A Cardiac Rehabilitation Program Increases the Acute Response of Endothelial Progenitor Cells to Maximal Exercise in Heart Failure Patients.

The purpose of this study was to investigate the effect of a cardiac rehabilitation program on the acute response on endothelial progenitor cells and circulating endothelial cells after maximal exercise in patients with chronic heart failure of different severity. Forty-four chronic heart failure patients were enrolled in a 36-session cardiac rehabilitation program. All patients underwent an initial maximal cardiopulmonary exercise test before and a final maximal cardiopulmonary exercise test after the cardiac rehabilitation program. The patients were divided in two groups of severity according to the median value of peak VO2. Blood was collected at 4 time points; 2 time points at rest, and 2 time points after each cardiopulmonary exercise test. Five endothelial cellular populations were quantified by flow cytometry. Although there was a higher increase in the mobilization of subgroups of endothelial progenitor cells and circulating endothelial cells after the final cardiopulmonary exercise test compared to the initial test within each severity group (p < 0.05), no significant differences between severity groups were observed (p > 0.05). A 36-session cardiac rehabilitation program had similar beneficial effects on the acute response of endothelial progenitor cells and circulating endothelial cells after maximal exercise in patients with chronic heart failure of different severity.

Exercise: a molecular tool to boost muscle growth and mitochondrial performance in heart failure?

Impaired exercise capacity is the key symptom of heart failure (HF) and is associated with reduced quality of life and higher mortality rates. Unfortunately, current therapies, although generally lifesaving, have only small or marginal effects on exercise capacity. Specific strategies to alleviate exercise intolerance may improve quality of life, while possibly improving prognosis as well. There is overwhelming evidence that physical exercise improves performance in cardiac and skeletal muscles in health and disease. Unravelling the mechanistic underpinnings of exercise‐induced improvements in muscle function could provide targets that will allow us to boost exercise performance in HF. With the current review we discuss: (i) recently discovered signalling pathways that govern physiological muscle growth as well as mitochondrial quality control mechanisms that underlie metabolic adaptations to exercise; (ii) the mechanistic underpinnings of exercise intolerance in HF and the benefits of exercise in HF patients on molecular, functional and prognostic levels; and (iii) potential molecular therapeutics to improve exercise performance in HF. We propose that novel molecular therapies to boost adaptive muscle growth and mitochondrial quality control in HF should always be combined with some form of exercise training.

The role of left ventricular remodeling in functional mitral regurgitation: functional and prognostic implications in patients with heart failure

Abstract Background Left ventricular (LV) dilatation plays a key role on functional mitral regurgitation (MR) in patients with heart failure (HF) and exercise MR causes an additional LV remodeling. This study sought to investigate the different phenotypes and prognostic impact of LV end-diastolic volume (EDV) and MR during exercise in HF patients of any left ventricular ejection fraction (LVEF) categorization. Methods 201 HF patients with reduced (n=119), mildly-reduced (n=46), and preserved (n=36) EF underwent exercise with gas exchange analysis combined with echocardiography for assessment of MR and were divided by 3 groups according to EDV index tertiles (T1 &amp;lt;70.1, T2 70.1–95.6, T3 &amp;gt;95.6 ml/m2). Results There was no significant difference in age (67±12 years) and peak oxygen consumption (VO2: 13.1±3.7 ml/kg/min) among the 3 groups but VE/VCO2 slope was higher in T3 group (T1 31±7, T2 31±5, T3 37±11, P&amp;lt;0.05). EDV index was positively correlated with VE/VCO2 slope (R=0.33, P&amp;lt;0.001) and effective regurgitant orifice area (EROA) of MR at rest (R=0.27, P=0.01) and exercise (R=0.45, P&amp;lt;0.001). During follow up, 48 patients had the composite end point of all cause death or HF hospitalization. The age and gender adjusted hazard ratio for the events in patients with MR &amp;gt;2+ was 1.8 (P=0.049) at rest and 1.9 (P=0.026) at exercise. The age, gender, peak VO2, VE/VCO2 slope, and exercise MR &amp;gt;2+ adjusted hazard ratio of EDV index 10 ml/m2 increase was 1.1 (P=0.041) and the ratio in patients with EDV index &amp;gt;95.6 ml/m2, derived by ROC curve (AUC=0.69, P&amp;lt;0.05), was 2.0 (P&amp;lt;0.033, figure). Conclusions Functional MR with LV dilation combines with the worse exercise gas exchange phenotype. Given also the predictive role of a EDV index cutoff of 95.6 ml/m2 attention for chamber geometry during exercise might become an indicator of mitral valve reparation. Funding Acknowledgement Type of funding sources: None.

Comparison between PtCO2 and PaCO2 and Derived Parameters in Heart Failure Patients during Exercise: A Preliminary Study.

Evaluation of arterial carbon dioxide pressure (PaCO2) and dead space to tidal volume ratio (VD/VT) during exercise is important for the identification of exercise limitation causes in heart failure (HF). However, repeated sampling of arterial or arterialized ear lobe capillary blood may be clumsy. The aim of our study was to estimate PaCO2 by means of a non-invasive technique, transcutaneous PCO2 (PtCO2), and to verify the correlation between PtCO2 and PaCO2 and between their derived parameters, such as VD/VT, during exercise in HF patients. 29 cardiopulmonary exercise tests (CPET) performed on a bike with a ramp protocol aimed at achieving maximal effort in ≈10 min were analyzed. PaCO2 and PtCO2 values were collected at rest and every 2 min during active pedaling. The uncertainty of PCO2 and VD/VT measurements were determined by analyzing the error between the two methods. The accuracy of PtCO2 measurements vs. PaCO2 decreases towards the end of exercise. Therefore, a correction to PtCO2 that keeps into account the time of the measurement was implemented with a multiple regression model. PtCO2 and VD/VT changes at 6, 8 and 10 min vs. 2 min data were evaluated before and after PtCO2 correction. PtCO2 overestimates PaCO2 for high timestamps (median error 2.45, IQR −0.635–5.405, at 10 min vs. 2 min, p-value = 0.011), while the error is negligible after correction (median error 0.50, IQR = −2.21–3.19, p-value > 0.05). The correction allows removing differences also in PCO2 and VD/VT changes. In HF patients PtCO2 is a reliable PaCO2 estimation at rest and at low exercise intensity. At high exercise intensity the overall response appears delayed but reproducible and the error can be overcome by mathematical modeling allowing an accurate estimation by PtCO2 of PaCO2 and VD/VT.

Circulating long chain acylcarnitines and outcomes in diabetic heart failure: an HF-ACTION clinical trial substudy

BackgroundWhether differences in circulating long chain acylcarnitines (LCAC) are seen in heart failure (HF) patients with and without diabetes mellitus (DM), and whether these biomarkers report on exercise capacity and clinical outcomes, remains unknown. The objective of the current study was to use metabolomic profiling to identify biomarkers that report on exercise capacity, clinical outcomes, and differential response to exercise in HF patients with and without DM.MethodsTargeted mass spectrometry was used to quantify metabolites in plasma from participants in the heart failure: a controlled trial investigating outcomes of exercise training (HF-ACTION) trial. Principal components analysis was used to identify 12 uncorrelated factors. The association between metabolite factors, diabetes status, exercise capacity, and time to the primary clinical outcome of all-cause mortality or all-cause hospitalization was assessed.ResultsA total of 664 participants were included: 359 (54%) with DM. LCAC factor levels were associated with baseline exercise capacity as measured by peak oxygen consumption (beta 0.86, p = 2 × 10−7, and were differentially associated in participants with and without DM (beta 1.58, p = 8 × 10−8 vs. 0.67, p = 9 × 10−4, respectively; p value for interaction = 0.012). LCAC levels changed to a lesser extent in participants with DM after exercise (mean ∆ 0.09, p = 0.24) than in those without DM (mean ∆ 0.16, p = 0.08). In univariate and multivariate modeling, LCAC factor levels were associated with time to the primary outcome (multivariate HR 0.80, p = 2.74 × 10−8), and were more strongly linked to outcomes in diabetic participants (HR 0.64, p = 3.21 × 10−9 v. HR 0.90, p = 0.104, p value for interaction = 0.001). When analysis was performed at the level of individual metabolites, C16, C16:1, C18, and C18:1 had the greatest associations with both exercise capacity and outcomes, with higher levels associated with worse outcomes. Similar associations with time to the primary clinical outcome were not found in a control group of patients without HF from the CATHeterization GENetics (CATHGEN) study.ConclusionsLCAC biomarkers are associated with exercise status and clinical outcomes differentially in HF patients with and without DM. Impaired fatty acid substrate utilization and mitochondrial dysfunction both at the level of the skeletal muscle and the myocardium may explain the decreased exercise capacity, attenuated response to exercise training, and poor clinical outcomes seen in patients with HF and DM.Trial Registration clinicaltrials.gov Identifier: NCT00047437.

Cardiac output changes during exercise in heart failure patients: focus on mid-exercise.

AimsPeak exercise oxygen uptake (VO2) and cardiac output (CO) are strong prognostic indexes in heart failure (HF) but unrelated to real‐life physical activity, which is associated to submaximal effort.Methods and resultsWe analysed maximal cardiopulmonary exercise test with rest, mid‐exercise, and peak exercise non‐invasive CO measurements (inert gas rebreathing) of 231 HF patients and 265 healthy volunteers. HF patients were grouped according to exercise capacity (peak VO2 < 50% and ≥50% pred, Groups 1 and 2). To account for observed differences, data regarding VO2, CO, stroke volume (SV), and artero‐venous O2 content difference [ΔC(a‐v)O2] were adjusted by age, gender, and body mass index. A multiple regression analysis was performed to predict peak VO2 from mid‐exercise cardiopulmonary exercise test and CO parameters among HF patients. Rest VO2 was lower in HF compared with healthy subjects; meanwhile, Group 1 patients had the lowest CO and highest ΔC(a‐v)O2. At mid‐exercise, Group 1 patients achieved a lower VO2, CO, and SV [0.69 (interquartile range 0.57–0.80) L/min; 5.59 (4.83–6.67) L/min; 62 (51–73) mL] than Group 2 [0.94 (0.83–1.1) L/min; 7.6 (6.56–9.01) L/min; 77 (66–92) mL] and healthy subjects [1.15 (0.93–1.30) L/min; 9.33 (8.07–10.81) L/min; 87 (77–102) mL]. Rest to mid‐exercise SV increase was lower in Group 1 than Group 2 (P = 0.001) and healthy subjects (P < 0.001). At mid‐exercise, ΔC(a‐v)O2 was higher in Group 2 [13.6 (11.8–15.4) mL/100 mL] vs. healthy patients [11.6 (10.4–13.2) mL/100 mL] (P = 0.002) but not different from Group 1 [13.6 (12.0–14.9) mL/100 mL]. At peak exercise, Group 1 patients achieved a lower VO2, CO, and SV than Group 2 and healthy subjects. ΔC(a‐v)O2 was the highest in Group 2. At multivariate analysis, a model comprising mid‐exercise VO2, carbon dioxide production (VCO2), CO, haemoglobin, and weight predicted peak VO2, P < 0.001. Mid‐exercise VO2 and CO, haemoglobin, and weight added statistically significantly to the prediction, P < 0.050.ConclusionsMid‐exercise VO2 and CO portend peak exercise values and identify severe HF patients. Their evaluation could be clinically useful.

Event-prediction of right ventricular to pulmonary circulation coupling measured during exercise in patients with heart failure

Abstract Background Right ventricular (RV) contractile function and its coupling with pulmonary circulation (PC) stratify the pattern of clinical phenotypes in heart failure (HF) but its predictive role when measured during exercise is undefined. This study sought to investigate the prognostic impact of RV to PC coupling during exercise in HF patients of any left ventricular ejection fraction (LVEF) categorization. Methods 218 HF patients with reduced (n=120), mid-range (n=55), and preserved (n=43) EF and 51 patients with noncardiac dyspnea underwent exercise with gas exchange analysis combined with echocardiography for assessment of RV-PC coupling assessed by the TAPSE/PASP ratio and left atrial (LA) strain (as a mediator of RV to PC uncoupling). Results TAPSE was negatively correlated with PASP (R=−0.31 and −0.31, P&amp;lt;0.001) both at rest and during exercise. TAPSE/PASP was positively correlated with LA strain (R=0.58 and 0.59, P&amp;lt;0.001) and cardiac output (R=0.28 and 0.58, P&amp;lt;0.001) both at rest and during exercise. The severity of mitral regurgitation was also associated with TAPSE/PASP and LA strain both at rest and during exercise (P for trend &amp;lt;0.001). There was significant difference in peak VO2 and the minute ventilation-carbon dioxide production slope among 3 groups divided by tertile of TAPSE/PASP at exercise. During 5 years follow up, 48 HF patients with reduced (n=34), mid-range (n=8), and preserved (n=6) EF had the composite end point. The age and gender adjusted hazard ratio for the events in HF patients with TAPSE/PASP at exercise &amp;lt;0.33, derived by ROC curve (AUC=0.71, P&amp;lt;0.05), was 2.9 (95% CI: 1.5 to 5.5, figure). Conclusions The impaired RV to PC coupling by TAPSE/PASP ratio during exercise predicts prognosis in patients with HF. The cutoff of 0.33 overlaps with the threshold observed to be predictive at rest in various reports across HF populations. These data further emphasize the usefulness of assessing RV to PC uncoupling in cardiac failure during various clinical conditions. Funding Acknowledgement Type of funding source: None

Respiratory muscle work influences locomotor convective and diffusive oxygen transport in human heart failure during exercise.

IntroductionIt remains unclear if naturally occurring respiratory muscle (RM) work influences leg diffusive O2 transport during exercise in heart failure patients with reduced ejection fraction (HFrEF). In this retrospective study, we hypothesized that RM unloading during submaximal exercise will lead to increases in locomotor muscle O2 diffusion capacity (DMO2) contributing to the greater leg VO2.MethodsTen HFrEF patients and 10 healthy control matched participants performed two submaximal exercise bouts (i.e., with and without RM unloading). During exercise, leg blood flow was measured via constant infusion thermodilution. Intrathoracic pressure was measured via esophageal balloon. Radial arterial and femoral venous blood gases were measured and used to calculate leg arterial and venous content (CaO2 and CvO2, respectively), VO2, O2 delivery, and DMO2.ResultsFrom CTL to RM unloading, leg VO2, O2 delivery, and DMO2 were not different in healthy participants during submaximal exercise (all, p > .15). In HFrEF, leg VO2 (CTL: 0.7 ± 0.3 vs. RM unloading: 1.0 ± 0.4 L/min, p < .01), leg O2 delivery (CTL: 0.9 ± 0.4 vs. RM unloading: 1.4 ± 0.5 L/min, p < .01), and leg DMO2 (CTL: 31.5 ± 11.4 vs. RM unloading: 49.7 ± 18.6 ml min−1 mmHg−1) increased from CTL to RM unloading during submaximal exercise (all, p < .01), whereas CaO2‐CvO2 was not different (p = .51). The degree of RM unloading (i.e., % decrease in esophageal pressure‐time integral during inspiration) was related to the % increase in leg DMO2 with RM unloading (r = −.76, p = .01).ConclusionOur data suggest RM unloading leads to increased leg VO2 due to greater convective and diffusive O2 transport during submaximal exercise in HFrEF patients.

Effects of Interatrial Shunt on Pulmonary Vascular Function in Heart Failure With Preserved Ejection Fraction

BackgroundImplantation of an interatrial shunt device (IASD) in patients with heart failure (HF) reduces left atrial hypertension by shunting oxygenated blood to the right heart and lungs. The attendant increases in pulmonary blood flow (Qp) and oxygen content may alter pulmonary vascular function, while left-to-right shunting might compromise systemic perfusion. ObjectivesThe authors hypothesized that IASD would improve indexes of pulmonary artery (PA) function at rest and during exercise in HF patients without reducing systemic blood flow (Qs). MethodsThis is a pooled analysis from 2 trials assessing the effects of the IASD on resting and exercise hemodynamics in HF patients (n = 79) with EF ≥40% with baseline and repeated hemodynamic evaluation between 1 and 6 months. Patients with pulmonary vascular resistance (PVR) >4 WU or right ventricular dysfunction were excluded. ResultsQp and PA oxygen content increased by 27% and 7% following IASD. These changes were associated with salutary effects on pulmonary vascular function (17% reduction in PVR, 12% reduction in PA elastance [pulmonary Ea], and 24% increase in PA compliance). Qp increased during exercise to a greater extent following IASD compared with baseline, which was associated with reductions in exercise PVR and pulmonary Ea. Patients with increases in PA compliance following IASD experienced greater improvements in supine exercise duration. There was no reduction in Qs following IASD at rest or during exercise. ConclusionsImplantation of an IASD improves pulmonary vascular function at rest and during exercise in selected patients with HF and EF ≥40%, without compromising systemic perfusion. Further study is warranted to identify underlying mechanisms and long-term pulmonary hemodynamic effects of IASD. (REDUCE LAP-HF Trial [REDUCE LAP-HF]; NCT01913613; and REDUCE LAP-HF Randomized Trial I [REDUCE LAP-HF I]; NCT02600234)

Confirming a beneficial effect of the six-minute walk test on exercise confidence in patients with heart failure.

Low confidence to exercise is a barrier to engaging in exercise in heart failure patients. Participating in low to moderate intensity exercise, such as the six-minute walk test, may increase exercise confidence. To compare the effects of a six-minute walk test with an educational control condition on exercise confidence in heart failure patients. This was a prospective, quasi-experimental design whereby consecutive adult patients attending an out-patient heart failure clinic completed the Exercise Confidence Scale prior to and following involvement in the six-minute walk test or an educational control condition. Using a matched pairs, mixed model design (n=60; 87% male; Mage=58.87±13.16), we identified a significantly greater improvement in Total exercise confidence (F(1,54)=4.63, p=0.036, partial η2=0.079) and Running confidence (F(1,57)=4.21, p=0. 045, partial η2=0.069) following the six-minute walk test compared to the educational control condition. These benefits were also observed after adjustment for age, gender, functional class and depression. Heart failure patients who completed a six-minute walk test reported greater improvement in exercise confidence than those who read an educational booklet for 10 min. The findings suggest that the six-minute walk test may be used as a clinical tool to improve exercise confidence. Future research should test these results under randomized conditions and examine whether improvements in exercise confidence translate to greater engagement in exercise behavior.

Improvement of functional capacity in sacubitril-valsartan treated patients assessed by cardiopulmonary exercise test

Neprilisin and angiotensin receptor inhibition (Sacubitril/Valsartan, i.e. ARNI) is recommended in heart failure guidelines for patients in NYHA class II-III with reduced left ventricular ejection fraction (LVEF). ARNI increase survival and quality of life; due to their hemodynamic effects, ARNI could also affect exercise tolerance. We studied the effects of ARNI on cardiopulmonary test (CPET) after six months of treatment in 35 patients [67 ± 11 years; LVEF 31 ± 6%; NT-proBNP 1822 ± 1651 pg/ml; ICD/CRT since at least 6 months in 26/35], treated with increasing doses of Sacubitril/Valsartan up to 318 ± 36 mg/die. In addition, levels of NT-proBNP, renal function, electrolytes, and echocardiocolorDoppler were assessed in the same time periods. No variations of renal function and/or potassium levels were observed; NT-proBNP decreased. Most CPET variables were improved by ARNI (p < .05): peak VO2 and O2 pulse increased (from 15.8 ± 3.4 to 17.0 ± 4.0 ml/kg/min and from 11.5 ± 2.5 to 12.6 ± 2.4 ml/beat, respectively), while VEVCO2 slope decreased from 35.2 ± 11.2 to 33.1 ± 12.3. A significant relationship (p < .05) was observed between the amount of increase in LVEF and that of O2 pulse in all patients, and between the amount of decrease in PAPs and that of VEVCO2 slope in patients showing pulmonary hypertension in baseline. In a subgroup of 22 patients who already completed A 1 year follow-up, overall CPET improvement was maintained. In conclusion, already in the short term ARNI favourably affect cardiopulmonary response to exercise in heart failure patients; such a change seems to be preserved on a longer period.

TCT-339 Partial Inferior Vena Cava Occlusion During Exercise in Heart Failure Patients Prevents Left Ventricular Pressure Overload, Improves Exercise Times, and Reduces Respiratory Rate: Mechanical “Balancing” of Biventricular Function as a Novel Therapy for Heart Failure Qualify of Life

Interatrial shunt devices off-load the left ventricle by shunting blood from the left to right atrium and are associated with improvements in exercise capacity and quality of life in heart failure patients. The authors hypothesize that controlling right ventricular stroke volume through partial

IMPROVEMENT OF FUNCTIONAL CAPACITY IN SACUBITRIL-VALSARTAN TREATED PATIENTS ASSESSED BY CARDIOPULMONARY EXERCISE TEST

Objective: The combination of neprilisin and angiotensin receptor inhibition (Sacubitril/Valsartan, i.e. ARNI) is recommended in heart failure guidelines for patients in NYHA class II-III with reduced left ventricular ejection fraction (LVEF). Sacubitril/Valsartan increases survival and quality of life. Moreover, due to its cardiac and hemodynamic effects, it could also affect exercise tolerance. Design and method: We studied the effects of ARNI on cardiopulmonary exercise test (CPET) in 35 patients [67 ± 11 years; Left ventricular ejection fraction (LVEF) 31 ± 6%; NT-proBNP 1822 ± 1651 pg/ml; ICD/CRT 26/35], being treated with increasing doses of Sacubitril/Valsartan up to the maximum tolerated dose (318 ± 36 mg/die) without side effects. In addition to CPET, plasma levels of pro-BNP, renal function, plasma electrolytes, echocardiocolorDoppler were performed at baseline and at 6 months follow-up. Results: No variations of renal function and/or kaliemia were observed, while NT-proBNP levels decreased significantly. Most CPET variables were improved by ARNI: an increase in peak VO2 (from 15.8 ± 3.4 to 17.0 ± 4.0 ml/Kg/min, p < 0.05) and in O2 pulse (from 11.5 ± 2.5 to 12.6 ± 2.4 ml/beat, p < 0.05), together with a decrease in VEVCO2 slope (from 35.2 ± 11.2 to 33.1 ± 12.3, p < 0.05) were observed. In addition, a significant relationship (p < 0.05) was present between the amount of increase in LVEF and that of O2 pulse in all patients (see Figure).Conclusions: Already in the short term, ARNI favourably affect global cardiopulmonary response to exercise in heart failure patients.

Respiratory Muscle Work Constrains Locomotor Convective and Diffusive Transport in Heart Failure during Exercise

IntroductionHeart failure (HF) patients demonstrate augmented ventilation for a given metabolic demand which results in increased respiratory muscle work and subsequent competition for blood flow between the respiratory and locomotor muscle beds. Unloading the respiratory muscles during submaximal exercise has been shown to increase leg oxygen uptake (VO2) in HF patients due increased leg blood flow via increased cardiac output and redistribution of cardiac output from the respiratory to locomotor muscles. It has been suggested that increased leg VO2 following respiratory muscle unloading in HF during submaximal exercise is due to augmented convective O2 transport in HF; however, it is unclear if diffusive O2 transport also increases with respiratory muscle unloading. We hypothesized that respiratory muscle unloading during submaximal exercise will lead to increased leg VO2 due to combined increases in convective and diffusive O2 transport.MethodsTen HF patients with reduced systolic function (6M/4W; 53±15 yrs; BMI: 29±6 kg/m2) were recruited. Patients performed two submaximal exercise bouts (i.e. with and without respiratory muscle unloading (via mechanical ventilator) (RM unloading and control (CTL), respectively)). During exercise, leg blood flow (QL) was measured via thermodilution. Intrathoracic pressure was measured via esophageal balloon. Radial arterial and femoral venous blood gases were measured. Blood gases were used to calculate arterial and venous oxygen content (CaO2 and CvO2, respectively). Leg VO2 was calculated as QL multiplied by the difference between CaO2‐CvO2. Leg O2 delivery was calculated as QL multiplied by CaO2. Leg diffusion capacity (DO2) was calculated as leg VO2 divided by femoral venous partial pressure of O2.ResultsFrom CTL to RM unloading, leg VO2 increased during submaximal exercise (0.7±0.3 vs. 1.0±0.4 L/min, p&lt;0.01, respectively). From CTL to RM unloading, leg O2 delivery increased during submaximal exercise (0.9±0.4 vs. 1.4±0.5 L/min, p&lt;0.01, respectively), whereas CaO2‐CvO2 was not different (14.1±3.0 vs. 14.2±3.2 mL/dL, p=0.57, respectively). From CTL to RM unloading, leg DO2 increased during submaximal exercise (30.4±10.8 vs. 49.7±18.6 mL/mmHg, p&lt;0.01, respectively). There was a negative relationship between the degree of RM unloading (i.e. percent decrease in mean inspiratory esophageal pressure) and percent increase in leg DO2 with RM unloading (r= −0.77, p&lt;0.01).ConclusionOur results demonstrate that unloading the respiratory muscles leads to increased leg VO2 due to convective and diffusive O2 transport during submaximal exercise in HF patients. These findings suggest that the naturally occurring respiratory muscle work in HF compromises convective and diffusive O2 transport and thus constrains leg VO2 during submaximal exercise in HF.Support or Funding InformationNIH HL126638 AHA 18POST3990251This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.

α-Adrenergic receptor regulation of skeletal muscle blood flow during exercise in heart failure patients with reduced ejection fraction.

Patients suffering from heart failure with reduced ejection fraction (HFrEF) experience impaired limb blood flow during exercise, which may be due to a disease-related increase in α-adrenergic receptor vasoconstriction. Thus, in eight patients with HFrEF (63 ± 4 yr) and eight well-matched controls (63 ± 2 yr), we examined changes in leg blood flow (Doppler ultrasound) during intra-arterial infusion of phenylephrine (PE; an α1-adrenergic receptor agonist) and phentolamine (Phen; a nonspecific α-adrenergic receptor antagonist) at rest and during dynamic single-leg knee-extensor exercise (0, 5, and 10 W). At rest, the PE-induced reduction in blood flow was significantly attenuated in patients with HFrEF (-15 ± 7%) compared with controls (-36 ± 5%). During exercise, the controls exhibited a blunted reduction in blood flow induced by PE (-12 ± 4, -10 ± 4, and -9 ± 2% at 0, 5, and 10 W, respectively) compared with rest, while the PE-induced change in blood flow was unchanged compared with rest in the HFrEF group (-8 ± 5, -10 ± 3, and -14 ± 3%, respectively). Phen administration increased leg blood flow to a greater extent in the HFrEF group at rest (+178 ± 34% vs. +114 ± 28%, HFrEF vs. control) and during exercise (36 ± 6, 37 ± 7, and 39 ± 6% vs. 13 ± 3, 14 ± 1, and 8 ± 3% at 0, 5, and 10 W, respectively, in HFrEF vs. control). Together, these findings imply that a HFrEF-related increase in α-adrenergic vasoconstriction restrains exercising skeletal muscle blood flow, potentially contributing to diminished exercise capacity in this population.

Diastolic Intra–Left Ventricular Pressure Difference During Exercise: Strong Determinant and Predictor of Exercise Capacity in Patients With Heart Failure

Although the enhancement of early-diastolic intra-left ventricular pressure difference (IVPD) during exercise is considered to maintain exercise capacity, little is known about their relationship in heart failure (HF). Cardiopulmonary exercise testing and exercise-stress echocardiography were performed in 50 HF patients (left ventricular [LV] ejection fraction 39 ± 15%). Echocardiographic images were obtained at rest and submaximal and peak exercise. Color M-mode Doppler images of LV inflow were used to determine IVPD. Thirty-five patients had preserved exercise capacity (peak oxygen consumption [VO2] ≥14 mL·kg-1·min-1; group 1) and 15 patients had reduced exercise capacity (group 2). During exercise, IVPD increased only in group 1 (group 1: 1.9 ± 0.9 mm Hg at rest, 4.1 ± 2.0 mm Hg at submaximum, 4.7 ± 2.1 mm Hg at peak; group 2: 1.9 ± 0.8 mm Hg at rest, 2.1 ± 0.9 mm Hg at submaximum, 2.1 ± 0.9 mm Hg at peak). Submaximal IVPD (r = 0.54) and peak IVPD (r = 0.69) were significantly correlated with peak VO2. Peak IVPD determined peak VO2 independently of LV ejection fraction. Moreover, submaximal IVPD could well predict the reduced exercise capacity. Early-diastolic IVPD during exercise was closely associated with exercise capacity in HF. In addition, submaximal IVPD could be a useful predictor of exercise capacity without peak exercise in HF patients.

Abstract 16657: Role of Exercise Induced Mitral Regurgitation and Its Prevalence in Functional Limitation of Heart Failure Patients With Preserved Ejection Fraction

Background: Functional limitation in heart failure (HF) patients recognize multiple mechanisms. Exercise-induced mitral regurgitation (Ex-MR) has been extensively studied in HF population with reduced ejection fraction (HFrEF, EF &lt; 40%), as responsible of right ventricle (RV) to pulmonary circulation (PC) uncoupling phenomenon. The relative role of this hemodynamic determinant has not been investigated so far in HF patients with preserved (HFpEF, EF &gt; 50%) and mid-range EF (HFmrEF, EF 40 - 49%). Aim: To describe functional phenotypes and cardiac response to exercise in HF patients, with respect to the development of Ex-MR. Methods: 179 HF patients and 23 controls were tested with cardiopulmonary exercise test (CPET) combined with exercise-echocardiography. Based on current guidelines, we identified 114 HFrEF, 34 HFmrEF and 31 HFpEF, further divided according with the presence of at least moderate (&gt;2+/4+) Ex-MR. Results: Ex-MR rate was 58%, 41% and 42% in HFrEF, HFmrEF and HFpEF, respectively. Ex-MR was associated with echocardiographic signs of RV-PC uncoupling (TAPSE/PASP ratio), particularly enhanced by the exercise in HFpEF patients. HFpEF with Ex-MR showed a distinct phenotype with chronotropic competence and increased peripheral oxygen extraction, compared to Ex-MR - cohort, possible expression of a compensatory mechanism to significant reduction in contractile reverse. The Ex-MR was associated with lower peak VO2 and workload in HFrEF and HFmrEF, while there were no differences related to HFpEF. The presence of Ex-MR significantly compromised also ventilatory efficiency (VE/VCO2) in all HF classes. Conclusion: Ex-MR emerged as a new mechanism of functional limitation in HFpEF, sharing a common pathophysiological basis with other HF patients. The RV-PC uncoupling is the best haemodynamic correlate of Ex-MR.

Breathing With Heart Failure

The syndrome of heart failure (HF) is often accompanied by numerous derangements in ventilatory function. These pathophysiological changes in ventilatory function are believed to augment the mechanical work required to breathe during exercise (Wb). However, the precise contributions of resistive and elastic work to this overall higher Wb in HF remain unclear. PURPOSE: To quantify the resistive and elastic components of Wb during exercise in HF patients and age-matched, healthy controls at standardized levels of minute ventilation ( ). METHODS: The elastic and resistive Wb were assessed in 9 male HF patients (NYHA class I-III) and 9 age-matched, healthy male controls at minute ventilations of 20, 40, 60 and 80 L[BULLET OPERATOR]min-1 during graded exercise. The components of Wb were quantified using oesophageal manometry and modified Campbell diagrams. RESULTS: Dynamic lung compliance was lower across all minute ventilations in HF patients (P<0.05). Moreover, the inspiratory and expiratory resistive Wb was higher in HF patients compared with controls at any given (P<0.05). The inspiratory elastic Wb was higher at minute ventilations of 40-60 L[BULLET OPERATOR]min-1 during exercise in HF patients. (P<0.05). CONCLUSIONS: The findings of this study indicate that the overall higher Wb in HF patients may be more so related to greater amounts of resistive than elastic Wb during exercise.