Capacity In Heart Failure Research Articles

Left atrial compliance index predicts exercise capacity in patients with heart failure and preserved ejection fraction irrespective of right ventricular dysfunction.

Predictors of exercise capacity in heart failure (HF) with preserved ejection fraction (HFpEF) remain of difficult determination. The aim of this study was to identify predictors of exercise capacity in a group of patients with HFpEF and right ventricle (RV) dysfunction METHODS: In 143 consecutive patients with HFpEF (age 62±9years, LV EF ≥45) and 41 controls, a complete echocardiographic study was performed. In addition to conventional measurements, LA compliance was calculated using the formula: [LAV max-LAV min/LAV min×100]. Exercise capacity was assessed using the six-minute walking test (6-MWT). Tricuspid annular plane systolic excursion (TAPSE)<1.7cm was utilized to categorize patients with RV dysfunction (n=40) from those with maintained RV function (n=103). Patients with RV dysfunction were older (P=0.002), had higher NYHA class (P=0.001), higher LV mass index (P=0.01), reduced septal and lateral MAPSE (all P<0.001), enlarged LA (P=0.001) impaired LA compliance index (P<0.001) and exhibited a more compromised 6-MWT (P=0.001). LA compliance index correlated more closely with 6-MWT (r=0.51, P<0.001) compared with the other LA indices (AP diameter, transverse diameter and volume indexed; r=-0.30, r=-0.35 and r=-0.38, respectively). In multivariate analysis, LA compliance index <60% was 88% sensitive and 61% specific (AUC 0.80, CI=0.67-0.92 P=0.001) in predicting exercise capacity. An impairment in LA compliance was profound in patients with HFpEF and RV dysfunction and seems to be most powerful independent predictor of limited exercise capacity.

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.

High‐Sensitivity Troponin I in Hospitalized and Ambulatory Patients With Heart Failure With Preserved Ejection Fraction: Insights From the Heart Failure Clinical Research Network

BackgroundWe sought to study the prevalence of high‐sensitivity troponin and its association with cardiac structure and outcomes in ambulatory and hospitalized patients with heart failure with a preserved ejection fraction (HFpEF).Methods and ResultsA post hoc analysis utilized data from HFpEF patients: DOSE (Diuretic Optimization Strategies Evaluation) and CARRESS‐HF (Cardiorenal Rescue Study in Acute Decompensated Heart Failure) enrolled patients hospitalized with acute HFpEF, and RELAX (Phosphodiesterase‐5 Inhibition to Improve Clinical Status and Exercise Capacity in Heart Failure With Preserved Ejection Fraction) enrolled ambulatory patients with HFpEF. High‐sensitivity troponin I (hs‐TnI) was measured in hospitalized patients at baseline, at 72 to 96 hours, on day 7, and on day 60. In ambulatory patients hs‐TnI was measured at baseline and at week 24. In the ambulatory cohort, correlations between hs‐TnI and cardiac structure and function were assessed. The association between hs‐TnI and a 60‐day composite of emergency room visits, readmissions, and death was assessed for hospitalized patients using multivariable Cox proportional hazard models. The study population included 139 hospitalized and 212 ambulatory patients with HFpEF and hs‐TnI measured at baseline. The median (25th, 75th percentiles) baseline troponin was 17.6 (11.1, 41.0) ng/L in hospitalized patients and 9.5 (5.3, 19.7) ng/L in ambulatory patients (P<0.001). The prevalence of elevated hs‐TnI (>99% percentile upper reference limit was 86% in hospitalized patients and 53% among ambulatory patients, with stable elevation in ambulatory patients during follow‐up. HFpEF patients with a hs‐TnI above the median were older with worse left ventricular hypertrophy and diastolic dysfunction. Continuously valued hs‐TnI (per doubling) was associated with increased risk of composite end point (adjusted hazard ratio 1.20, 95% confidence interval 1.00‐1.43; P=0.042).ConclusionsHs‐TnI is commonly elevated among both hospitalized and ambulatory patients with HFpEF. Increased hs‐TnI levels are associated with worse cardiac structure and increased risk of adverse events.

Curcumin improves exercise performance of mice with coronary artery ligation-induced HFrEF: Nrf2 and antioxidant mechanisms in skeletal muscle.

A hallmark of chronic heart failure (HF) with low ejection fraction (HFrEF) is exercise intolerance. We hypothesized that reduced expression of nuclear factor E2-related factor 2 (Nrf2) in skeletal muscle contributes to impaired exercise performance. We further hypothesized that curcumin, a Nrf2 activator, would preserve or increase exercise capacity in HF. Experiments were carried out in mice with coronary artery ligation-induced HFrEF. Curcumin was deliveried by a subcutaneous osmotic minipump at a dose of 50 mg·kg-1·day-1 for 8 weeks. In vivo, in situ, and in vitro experiments were employed to evaluate exercise capacity, muscle function, and molecular mechanisms. We found that: 1) the maximal speed, running distance to exhaustion, and limb grip force were significantly lower in HFrEF mice compared with sham. Curcumin-treated HF mice displayed enhanced exercise performance compared with vehicle-treated HF mice; 2) both soleus (Sol) and extensor digitorum longus (EDL) muscles of HFrEF mice exhibited reduced force and rapid fatigue, which were ameliorated by curcumin; and 3) protein expression of Nrf2, hemeoxygenase-1, SOD2, myogenin, and MyoD were significantly lower, but total ubiquitinated proteins, MURF1, and atrogen-1 were higher in Sol and EDL of HFrEF compared with sham mice, whereas these alterations in Nrf2 signaling and antioxidant defenses in HFrEF were attenuated by curcumin, which had no effect on cardiac function per se in mice with severe HFrEF. These data suggest that impaired Nrf2 signaling intrinsic to skeletal muscle contributes to exercise intolerance in HFrEF. Skeletal muscle Nrf2 should be considered as a novel therapeutic target in severe HF. NEW & NOTEWORTHY These studies suggest that impaired nuclear factor E2-related factor 2 (Nrf2) signaling is a critical mechanism underlying the enhanced oxidative stress in skeletal muscle in heart failure with low ejection fraction (HFrEF). Curcumin prevents the decline in running performance in HFrEF mice by upregulating antioxidant defenses in skeletal muscle, likely mediated by activating Nrf2 signaling. These findings suggest a novel therapeutic target for the improvement of exercise capacity and quality of life in HFrEF patients.

Pulmonary hypertension-targeted therapies in heart failure: A systematic review and meta-analysis.

BackgroundPulmonary hypertension (PH) due to left heart failure (HF) is the most common form of PH. However, treatment is unclear because there are conflicting results about safety and efficacy of PH-targeted therapies.ObjectivesTo assess the effects of PH-targeted therapy on exercise capacity in HF patients.MethodsMEDLINE, EMBASE and the Cochrane Library were searched from January 1990 to July 2017 for randomized controlled trials comparing PH-targeted therapies to conventional therapy in HF. The primary outcome was to assess the effects on exercise capacity. Secondary outcomes included mortality, hospitalisation, NT-proBNP levels, echocardiographic and hemodynamics parameters and discontinuation rate.Results22 studies were included (n = 5448), including 3, 8 and 11 studies with low, high and unknown risk of bias, respectively. PH-targeted therapies were associated with an improvement of exercise capacity (standardized mean difference 0.29;95%CI:0.08–0.50, p = 0.006). Pre-specified subgroup analyses found that this improvement was predominantly observed in studies evaluating phosphodiesterase-5 inhibitors and prostanoids and in patients with reduced ejection fraction. Moreover, systolic pulmonary artery pressure measured by echocardiography was improved (mean difference: -7.5mmHg; [95%CI]: -14.9,-0.1, p = 0.05), which was also entirely driven by studies evaluating phosphodiesterase-5 inhibitors. However, PH-targeted therapies were associated with an increased treatment discontinuation rates and a potential increase in mortality compared to standard treatment.ConclusionsIn conclusion, PH-targeted therapies and especially phosphodiesterase-5 inhibitors may improve exercise capacity in patients with HF. However, an increase in adverse outcomes was likely. Moreover, most studies were at high or unknown risk of bias, precluding confident conclusions about the effects of PH-targeted therapies.

Protein acetylation in skeletal muscle mitochondria is involved in impaired fatty acid oxidation and exercise intolerance in heart failure.

BackgroundExercise intolerance is a common clinical feature and is linked to poor prognosis in patients with heart failure (HF). Skeletal muscle dysfunction, including impaired energy metabolism in the skeletal muscle, is suspected to play a central role in this intolerance, but the underlying mechanisms remain elusive. Lysine acetylation, a recently identified post‐translational modification, has emerged as a major contributor to the derangement of mitochondrial metabolism. We thus investigated whether mitochondrial protein acetylation is associated with impaired skeletal muscle metabolism and lowered exercise capacity in both basic and clinical settings of HF.MethodsWe first conducted a global metabolomic analysis to determine whether plasma acetyl‐lysine is a determinant factor for peak oxygen uptake (peak VO2) in HF patients. We then created a murine model of HF (n = 11) or sham‐operated (n = 11) mice with or without limited exercise capacity by ligating a coronary artery, and we tested the gastrocnemius tissues by using mass spectrometry‐based acetylomics. A causative relationship between acetylation and the activity of a metabolic enzyme was confirmed in in vitro studies.ResultsThe metabolomic analysis verified that acetyl‐lysine was the most relevant metabolite that was negatively correlated with peak VO2 (r = −0.81, P < 0.01). At 4 weeks post‐myocardial infarction HF, a treadmill test showed lowered work (distance × body weight) and peak VO2 in the HF mice compared with the sham‐operated mice (11 ± 1 vs. 23 ± 1 J, P < 0.01; 143 ± 5 vs. 159 ± 3 mL/kg/min, P = 0.01; respectively). As noted, the protein acetylation of gastrocnemius mitochondria was 48% greater in the HF mice than the sham‐operated mice (P = 0.047). Acetylproteomics identified the mitochondrial enzymes involved in fatty acid β‐oxidation (FAO), the tricarboxylic acid cycle, and the electron transport chain as targets of acetylation. In parallel, the FAO enzyme (β‐hydroxyacyl CoA dehydrogenase) activity and fatty acid‐driven mitochondrial respiration were reduced in the HF mice. This alteration was associated with a decreased expression of mitochondrial deacetylase, Sirtuin 3, because silencing of Sirtuin 3 in cultured skeletal muscle cells resulted in increased mitochondrial acetylation and reduced β‐hydroxyacyl CoA dehydrogenase activity.ConclusionsEnhanced mitochondrial protein acetylation is associated with impaired FAO in skeletal muscle and reduced exercise capacity in HF. Our results indicate that lysine acetylation is a crucial mechanism underlying deranged skeletal muscle metabolism, suggesting that its modulation is a potential approach for exercise intolerance in HF.

Vitamin D Status and Exercise Capacity in Older Patients with Heart Failure with Preserved Ejection Fraction

Background: Older patients with heart failure with preserved ejection fraction have severe exercise intolerance. Vitamin D may play a role in cardiovascular and skeletal muscle function, and may therefore be implicated in exercise intolerance in heart failure with preserved ejection fraction. However, there are few data on vitamin D status and its relationship to exercise capacity in heart failure with preserved ejection fraction patients.Methods: Plasma 25-hydroxyvitamin D (25[OH]D) and exercise capacity (peak oxygen consumption, [VO2], 6-minute walk distance) were measured in 112 older heart failure with preserved ejection fraction patients (mean ± SD age = 70 ± 8 years) and 37 healthy age-matched controls. General linear models were used to compare 25(OH)D between heart failure with preserved ejection fraction patients and healthy controls, and to determine the cross-sectional association between 25(OH)D and exercise capacity. The association between 25(OH)D and left ventricular function was evaluated secondarily in heart failure with preserved ejection fraction patients.Results: 25(OH)D concentrations were significantly lower in heart failure with preserved ejection fraction vs healthy controls (11.4 ± 0.6 ng/mL vs 19.1 ± 2.1 ng/mL; P = .001, adjusted for age, race, sex, body mass index, season). More than 90% of heart failure with preserved ejection fraction patients had 25(OH)D insufficiency (<20 ng/mL) and 30% had frank 25(OH)D deficiency (<10 ng/mL). In heart failure with preserved ejection fraction patients, but not healthy controls, 25(OH)D was significantly correlated with peak VO2 (r = 0.26; P = 0.007) and 6-minute walk distance (r = 0.34; P < .001).Conclusions: More than 90% of heart failure with preserved ejection fraction patients had 25(OH)D insufficiency, and 30% were frankly deficient. Lower 25(OH)D was associated with lower peak VO2 and 6-minute walk distance in heart failure with preserved ejection fraction, suggesting that 25(OH)D insufficiency could contribute to exercise intolerance in this patient population. These findings provide the data and rationale for a future randomized trial designed to test the potential for vitamin D supplementation to improve exercise intolerance in heart failure with preserved ejection fraction.

P3725Effects of mineralocorticoid receptor antagonists on diastolic function and exercise capacity in heart failure with preserved ejection fraction: a meta-analysis of randomized controlled trials

P3725Effects of mineralocorticoid receptor antagonists on diastolic function and exercise capacity in heart failure with preserved ejection fraction: a meta-analysis of randomized controlled trials

Determinants of the beneficial effect of mineralocorticoid receptor antagonism on exercise capacity in heart failure with reduced ejection fraction.

The determinants of the impact of mineralocorticoid receptor antagonism (MRA) on exercise tolerance in heart failure with reduced ejection fraction (HFrEF) have not been sufficiently characterised. We sought to investigate the factors associated with improvement in exercise capacity following the introduction of spironolactone to therapy in HFrEF patients, as well as to assess the association between improvement in exercise capacity and changes in cardiac functional characteristics with treatment. In 120 patients (age 62 ± 11 years) with stable chronic HFrEF, remaining on optimal pharmacotherapy, spironolactone 25 mg/d was added to treatment. Echocardiographic assessment, including myocardial deformation, and treadmill exercise tests were performed at baseline and at six-month follow-up. According to the functional improvement at follow-up, patients were stratified into two groups: with increase in exercise capacity > 20% (IMPRpos, n = 68) and < 20% (IMPRneg, n = 52) of the baseline value. The IMPRpos subset demonstrated significantly larger improvement in left ventricular systolic and diastolic functions at follow-up, as assessed by global longitudinal deformation (GLS), ejection fraction, and tissue e' velocity. Functional improvement > 20% was independently predicted by diabetes (odds ratio [OR] 5.62, p = 0.011), estimated glomerular filtration rate (OR 0.95, p = 0.008), and B-type natriuretic peptide (BNP) at baseline (OR 0.54, p = 0.027), and associated with increase in GLS at follow-up (OR 1.40, p = 0.019). In patients with HFrEF, improvement in exercise capacity in response to the addition of spironolactone to treatment is more evident in the presence of diabetes, decreased renal function and lower BNP, and improvement in GLS is a contributor to this beneficial effect of MRA.

Relationship between exercise intervention and NO pathway in patients with heart failure with preserved ejection fraction

Objective: Elevated levels of arginine derivatives in the NO pathway, such as asymmetric dimethylarginine (ADMA), are related to disease severity and reduced exercise capacity in heart failure (HF). We investigated the influence of exercise intervention on these parameters and on L-arginine (L-Arg) and L-homoarginine (L-hArg) in HF with preserved ejection fraction (HFpEF) patients.Material and methods: Sixty-two patients (65 ± 6 years) were included in this analysis and randomized to supervised endurance/resistance training (ET) or to usual care (UC). EDTA-plasma was analysed for NO metabolites.Results: There were baseline associations for adjusted values of maximum workload with ADMA (r= −0.322, p = 0.028) and L-Arg/ADMA ratio (r = 0.331, p = 0.015), and for the 6-min walk test (6MWT) with ADMA (r= −0.314, p = 0.024) and L-Arg/ADMA ratio (r = 0.346, p = 0.015). No significant differences between UC and ET changes of NO parameters were observed at 3-month follow-up. Higher L-hArg levels were associated with a greater improvement in peak oxygen uptake (peak O2) at follow-up: 3.4 ± 2.8 vs. 1.1 ± 2.9 mL/min/kg (p = 0.005).Conclusions: Exercise intervention did not influence NO parameters in HFpEF patients, but L-hArg was related to change in peak O2.

Exercise on-transition uncoupling of ventilatory, gas exchange and cardiac hemodynamic kinetics accompany pulmonary oxygen stores depletion to impact exercise intolerance in human heart failure.

In contrast to knowledge that heart failure (HF) patients demonstrate peak exercise uncoupling across ventilation, gas exchange and cardiac haemodynamics, whether this dyssynchrony follows that at the exercise on-transition is unclear. This study tested whether exercise on-transition temporal lag for ventilation relative to gas exchange and oxygen pulse (O2 pulse) couples with effects from abnormal pulmonary gaseous oxygen store (O2store ) contributions to V˙O2 to interdependently precipitate persistently elevated ventilatory demand and low oxidative metabolic capacity in HF. Beat-to-beat HR and breath-to-breath ventilation and gas exchange were continuously acquired in HF (N = 9, ejection fraction = 30 ± 9%) and matched controls (N = 10) during square-wave ergometry at 60% V˙O2peak (46 ± 14 vs 125 ± 54-W, P < .001). Temporal responses across V˙E , V˙O2 and O2 pulse were assessed for the exercise on-transition using single exponential model Phase II on-kinetic time constants (τ = time to reach 63% steady-state rise). Breath-to-breath gas fractions and respiratory flows were used to determine O2stores . HF vs controls: τ for V˙E (137 ± 93 vs 74 ± 40-seconds, P = .03), V˙O2 (60 ± 40 vs 23 ± 5-seconds, P = .03) and O2 pulse (28 ± 18 vs 23 ± 15-seconds, P = .59). Within HF, τ for V˙E differed from O2 pulse (P < .02), but not V˙O2 . Exercise V˙E rise (workload indexed) differed in HF vs controls (545 ± 139 vs 309 ± 88-mL min-1 W-1 , P < .001). Exercise on-transition O2store depletion in HF exceeded controls, generally persisting to end-exercise. These data suggest HF demonstrated exercise on-transition O2store depletion (high O2store contribution to V˙O2 ) coupled with dyssynchronous V˙E , V˙O2 and O2 pulse kinetics-not attributable to prolonged cardiac haemodynamics. Persistent high ventilatory demand and low oxidative metabolic capacity in HF may be precipitated by physiological uncoupling occurring within the exercise on-transition.

Delayed Therapy with A Hydrogen Sulfide Donor, JK1, Protects against Pressure Overload ‐ Induced Heart Failure

Background and HypothesisHydrogen sulfide (H2S) protects against heart failure by ameliorating oxidative stress, improving mitochondrial function, increasing nitric oxide bioavailability, and attenuating apoptosis. However, at present there is insufficient evidence supporting the cardioprotective effects of H2S in delayed‐treatment settings which more closely mimics the heart failure in human. In current study, we tested the efficacy of delayed therapy with a novel H2S donor, JK1, in a murine model of transverse aortic constriction (TAC) induced heart failure (HF).MethodsMale C57/BL6J mice at 10 weeks (wks) of age were subjected to TAC for 18 weeks. JK1 (200 μg/kg/d, n=20) or the control compound that is devoid of H2S (200 μg/kg/d, n=18) was administered via i.p. injection twice per day starting at 3 wks post TAC. Echocardiography was performed at baseline and tri‐weekly for 18 weeks post TAC to assess LV structure and function. LV hemodynamics, cardiac fibrosis, vascular reactivity (isolated thoracic aorta), and exercise capacity were measured at the endpoint.ResultsDelayed treatment with JK1 preserved left ventricular (LV) ejection fraction (LVEF 54.6 ± 1.4% vs. 29.7 ± 2.9%, p &lt; 0.01), reduced LV dilation (p &lt; 0.01), and attenuated eccentric hypertrophy (p &lt; 0.01). JK1 treated mice displayed lower LV end‐diastolic pressure (LVEDP 11.4 ± 0.8 mmHg vs. 22.9 ± 1.2 mmHg, p &lt; 0.01) and improved relaxation time constant (Tau 7.2 ± 0.4 ms vs. 10.05 ± 0.6 ms, p &lt; 0.01). Global cardiac fibrosis was markedly reduced in mice received JK1 treatment (5.8 ± 1.5% vs. 17.1 ± 2.4%, p &lt; 0.01). In addition, acetylcholine‐mediated vasorelaxation was significantly improved in mice received JK1 treatment (Max. Relaxation, 66.1 ± 4.6% vs. 31.5 ± 3.6%, p &lt; 0.01; EC50, 605.3 ± 115.9 nM vs. 161.8 ± 31.5 nM, p &lt; 0.01). More importantly, mice received JK1 treatment had greater exercise capacity when compared to those received control (Distance, 0.520 ± 0.083 km vs. 0.089 ± 0.006 km, p &lt; 0.05).ConclusionThese results demonstrate that delayed administration of a novel H2S donor, JK1, significantly preserves systolic LV function, attenuates fibrotic remodeling, and improves LV hemodynamics. JK1 treatment provides benefits beyond the heart as it significantly ameliorates the damage to endothelium caused by HF. In addition, JK1 treatment markedly enhances the exercise capacity in HF. Studies are currently underway to define the molecular mechanisms involved in JK1‐induced cardiovascular protection.Support or Funding Information

AXIAL SARCOPENIA, SUBCUTANEOUS, ABDOMINAL VISCERAL AND PERICARDIAL ADIPOSITY IN HEART FAILURE WITH PRESERVED AND REDUCED EJECTION FRACTION

Abnormalities in body composition (subcutaneous adiposity, visceral adiposity, sarcopenia) can influence metabolic dysfunction and exercise capacity in heart failure. However, a comprehensive assessment of subcutaneous, abdominal visceral and pericardial fat, as well as skeletal muscle mass in heart

Pharmacological Interventions Effective in Improving Exercise Capacity in Heart Failure.

Heart failure (HF) is characterised by exercise intolerance, which substantially impairs quality of life (QOL) and prognosis. The aim of this review is to summarise the state of the art on pharmacological interventions that are able to improve exercise capacity in HF. Ivabradine, trimetazidine and intravenous iron are the only drugs included in the European Society of Cardiology HF guidelines that have consistently been shown to positively affect functional capacity in HF. The beneficial effects on HF symptoms, physical performance and QOL using these pharmacological approaches are described.

Cardiac Rehabilitation in Patients With Left Ventricular Assist Device: A SYSTEMATIC REVIEW AND META-ANALYSIS.

Exercise-based cardiac rehabilitation (EBCR) has been demonstrated to improve functional capacity in heart failure (HF). However, there are limited data on the effect of EBCR in patients with advanced HF and left ventricular assist devices (LVADs). This meta-analysis sought to evaluate the effects of EBCR on functional capacity in patients with LVAD. PubMed, Web of Science, CINAHL, and Cochrane Library databases were searched for randomized studies assessing the impact of EBCR in patients following LVAD implantation compared with standard therapy (ST). Using pre-defined criteria, appropriate studies were identified and selected. Data from selected studies were extracted in a standardized fashion and a meta-analysis was performed using a random-effects model with DerSimonian Liard weighting. Analysis employed weighted mean difference (WMD) as the effect size and intention-to-treat (ITT) principle. Study quality, publication bias, and heterogeneity were assessed. Six trials with a total of 183 patients (EBCR: 125; ST: 58) were identified. Mean age was 51 years and 83% were males. The initiation of EBCR varied from LVAD implantation during the index hospitalization to 10 mo post-LVAD implantation. The median rehabilitation period ranged from 6 to 10 wk. Exercise-based cardiac rehabilitation was associated with improved peak oxygen uptake ((Equation is included in full-text article.)O2) in all trials. Quantitative analysis was performed on 3 randomized studies involving 61 patients (EBCR = 39, ST = 22). Exercise-based cardiac rehabilitation was associated with significantly greater peak (Equation is included in full-text article.)O2 (WMD: 3.00 mL/kg/min; 95% CI: 0.64-5.35, P = .001). Similarly, 6-minute walk distance (6MWD) showed significantly greater improvement in the EBCR group than in the ST group (WMD: 60.06 m; 95% CI, 22.61-97.50, P = .002). Heterogeneity was low among the included trials. Exclusion sensitivity and per-protocol analysis demonstrated results consistent with ITT analysis. None of the included studies reported serious adverse events related to EBCR, which supports the safety of EBCR after LVAD implantation. This systematic review and meta-analysis demonstrated that EBCR following LVAD implantation is associated with greater improvement in functional capacity compared with ST as reflected by improved peak (Equation is included in full-text article.)O2 and 6MWD. However, given the small number of patients, further research into the clinical impact of EBCR in LVAD patients is necessary.

Highlights From the Circulation Family of Journals.

Highlights From the Circulation Family of Journals.

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.

Progenitor Cells and Clinical Outcomes in Patients With Heart Failure.

Endogenous regenerative capacity, assessed as circulating progenitor cell (PC) numbers, is an independent predictor of adverse outcomes in patients with cardiovascular disease. However, their predictive role in heart failure (HF) remains controversial. We assessed the relationship between the number of circulating PCs and the pathogenesis and severity of HF and their impact on incident HF events. We recruited 2049 adults of which 651 had HF diagnosis. PCs were enumerated by flow cytometry as CD45med+ blood mononuclear cells expressing CD34, CD133, vascular endothelial growth factor receptor-2, and chemokine (C-X-C motif) receptor 4 epitopes. PC subsets were lower in number in HF and after adjustment for clinical characteristics in multivariable analyses, a low CD34+ and CD34+/CXCR+ cell count remained independently associated with a diagnosis of HF (P<0.01). PC levels were not significantly different in reduced versus preserved ejection fraction patients. In 514 subjects with HF, there were 98 (19.1%) all-cause deaths during a 2.2±1.5-year follow-up. In a Cox regression model adjusting for clinical variables, hematopoietic-enriched PCs (CD34+, CD34+/CD133+, and CD34+/CXCR4+) were independent predictors of all-cause death (hazard ratio 2.0, 1.6, 1.6-fold higher mortality, respectively; P<0.03) among HF patients. Endothelial-enriched PCs (CD34+/VEGF+) were independent predictors of mortality in patients with HF with preserved ejection fraction only (hazard ratio, 5.0; P=0.001). PC levels are lower in patients with HF, and lower PC counts are strongly and independently predictive of mortality. Strategies to increase PCs and exogenous stem cell therapies designed to improve regenerative capacity in HF, especially, in HF with preserved ejection fraction, need to be further explored.

Principles, insights, and potential pitfalls of the noninvasive determination of muscle oxidative capacity by near-infrared spectroscopy.

Skeletal muscle oxidative capacity is highly plastic, strongly associated with whole-body aerobic capacity (16, 18) and state of health. Loss of muscle oxidative capacity is associated with physical inactivity, aging and chronic disease (17), and has been implicated in the pathophysiology of obesity and diabetes (21). Evaluating these changes has traditionally been limited to invasive or costly assessments (biopsy or ³¹P MRS). To address this, Hamaoka and colleagues developed an innovative, non-invasive approach using near-infrared spectroscopy (NIRS) to quantitatively measure muscle oxygen consumption (mVO₂; 12) and use this to infer muscle oxidative capacity based on the mVO₂ recovery rate constant (k) (23; later modified 26). This technique has been subsequently used to interpret relative differences in oxidative capacity across a wide range of muscles, ages and disease states (Figure 1C). The purpose of this Viewpoint is to open a discussion on the principles, insights and potential pitfalls of using NIRS to measure k and infer muscle oxidative capacity.

ASC Methylation and Interleukin-1β Are Associated with Aerobic Capacity in Heart Failure.

Aerobic capacity, as measured by peak oxygen uptake (V˙O2), is one of the most powerful predictors of prognosis in heart failure (HF). Inflammation is a key factor contributing to alterations in aerobic capacity, and interleukin (IL)-1 cytokines are implicated in this process. The adaptor protein ASC is necessary for inflammasome activation of IL-1β and IL-18. ASC expression is controlled through epigenetic modification; lower ASC methylation is associated with worse outcomes in HF. The purpose of this study is to examine the relationships between ASC methylation, IL-1β, and IL-18 with V˙O2peak in persons with HF. This study examined the relationship between ASC methylation, IL-1β, and IL-18 with V˙O2peak in 54 stable outpatients with HF. All participants were NYHA class II or III, not engaged in an exercise program, and physically able to complete an exercise treadmill test. Mean V˙O2peak was 16.68 ± 4.7 mL·kg·min. V˙O2peak was positively associated with mean percent ASC methylation (r = 0.47, P = 0.001) and negatively associated with IL-1β (r = -0.38, P = 0.007). Multiple linear regression models demonstrated that V˙O2peak increased by 2.30 mL·kg·min for every 1% increase in ASC methylation and decreased by 1.91 mL·kg·min for every 1 pg·mL increase in plasma IL-1β. Mean percent ASC methylation and plasma IL-1β levels are associated with clinically meaningful differences in V˙O2peak in persons with HF. Inflammasome activation may play a mechanistic role in determining aerobic capacity. ASC methylation is a potentially modifiable mechanism for reducing the inflammatory response, thereby improving aerobic capacity in HF.