Background
The exercise intolerance in chronic heart failure with reduced ejection fraction (HFrEF) is mostly attributed to alterations in skeletal muscle. However, the mechanisms underlying the ...skeletal myopathy in patients with HFrEF are not completely understood. We hypothesized that (i) aerobic exercise training (AET) and inspiratory muscle training (IMT) would change skeletal muscle microRNA‐1 expression and downstream‐associated pathways in patients with HFrEF and (ii) AET and IMT would increase leg blood flow (LBF), functional capacity, and quality of life in these patients.
Methods
Patients age 35 to 70 years, left ventricular ejection fraction (LVEF) ≤40%, New York Heart Association functional classes II–III, were randomized into control, IMT, and AET groups. Skeletal muscle changes were examined by vastus lateralis biopsy. LBF was measured by venous occlusion plethysmography, functional capacity by cardiopulmonary exercise test, and quality of life by Minnesota Living with Heart Failure Questionnaire. All patients were evaluated at baseline and after 4 months.
Results
Thirty‐three patients finished the study protocol: control (n = 10; LVEF = 25 ± 1%; six males), IMT (n = 11; LVEF = 31 ± 2%; three males), and AET (n = 12; LVEF = 26 ± 2%; seven males). AET, but not IMT, increased the expression of microRNA‐1 (P = 0.02; percent changes = 53 ± 17%), decreased the expression of PTEN (P = 0.003; percent changes = −15 ± 0.03%), and tended to increase the p‐AKTser473/AKT ratio (P = 0.06). In addition, AET decreased HDAC4 expression (P = 0.03; percent changes = −40 ± 19%) and upregulated follistatin (P = 0.01; percent changes = 174 ± 58%), MEF2C (P = 0.05; percent changes = 34 ± 15%), and MyoD expression (P = 0.05; percent changes = 47 ± 18%). AET also increased muscle cross‐sectional area (P = 0.01). AET and IMT increased LBF, functional capacity, and quality of life. Further analyses showed a significant correlation between percent changes in microRNA‐1 and percent changes in follistatin mRNA (P = 0.001, rho = 0.58) and between percent changes in follistatin mRNA and percent changes in peak VO2 (P = 0.004, rho = 0.51).
Conclusions
AET upregulates microRNA‐1 levels and decreases the protein expression of PTEN, which reduces the inhibitory action on the PI3K‐AKT pathway that regulates the skeletal muscle tropism. The increased levels of microRNA‐1 also decreased HDAC4 and increased MEF2c, MyoD, and follistatin expression, improving skeletal muscle regeneration. These changes associated with the increase in muscle cross‐sectional area and LBF contribute to the attenuation in skeletal myopathy, and the improvement in functional capacity and quality of life in patients with HFrEF. IMT caused no changes in microRNA‐1 and in the downstream‐associated pathway. The increased functional capacity provoked by IMT seems to be associated with amelioration in the respiratory function instead of changes in skeletal muscle.
ClinicalTrials.gov (Identifier: NCT01747395)
Previous studies have demonstrated that muscle mechanoreflex and metaboreflex controls are altered in heart failure (HF), which seems to be due to changes in cyclooxygenase (COX) pathway and changes ...in receptors on afferent neurons, including transient receptor potential vanilloid type-1 (TRPV1) and cannabinoid receptor type-1 (CB1). The purpose of the present study was to test the hypotheses: 1) exercise training (ET) alters the muscle metaboreflex and mechanoreflex control of muscle sympathetic nerve activity (MSNA) in HF patients. 2) The alteration in metaboreflex control is accompanied by increased expression of TRPV1 and CB1 receptors in skeletal muscle. 3) The alteration in mechanoreflex control is accompanied by COX-2 pathway in skeletal muscle. Thirty-four consecutive HF patients with ejection fractions <40% were randomized to untrained (n = 17; 54 ± 2 yr) or exercise-trained (n = 17; 56 ± 2 yr) groups. MSNA was recorded by microneurography. Mechanoreceptors were activated by passive exercise and metaboreceptors by postexercise circulatory arrest (PECA). COX-2 pathway, TRPV1, and CB1 receptors were measured in muscle biopsies. Following ET, resting MSNA was decreased compared with untrained group. During PECA (metaboreflex), MSNA responses were increased, which was accompanied by the expression of TRPV1 and CB1 receptors. During passive exercise (mechanoreflex), MSNA responses were decreased, which was accompanied by decreased expression of COX-2, prostaglandin-E2 receptor-4, and thromboxane-A2 receptor and by decreased in muscle inflammation, as indicated by increased miRNA-146 levels and the stable NF-κB/IκB-α ratio. In conclusion, ET alters muscle metaboreflex and mechanoreflex control of MSNA in HF patients. This alteration with ET is accompanied by alteration in TRPV1 and CB1 expression and COX-2 pathway and inflammation in skeletal muscle.
This study aimed to evaluate the effects of zolpidem CR (controlled release) on sleep and nocturnal ventilation in patients with congestive heart failure, a population at risk for insomnia and poor ...sleep quality.
Fifteen patients with heart failure (ischemic cardiomyopathy) and ejection fraction ≤ 45% in NYHA functional class I or II were evaluated with full polysomnography in a placebo-controlled, double-blind, randomized trial. Patients underwent three tests: (1) baseline polysomnography and, after randomization, (2) a new test with zolpidem CR 12.5 mg or placebo, and after 1 week, (3) a new polysomnography, crossing the "medication" used.
A 16% increase in total sleep time was found with the use of zolpidem CR and an increase in stage 3 NREM sleep (slow wave sleep). The apnea hypopnea index (AHI) did not change with zolpidem CR even after controlling for supine position; however, a slight but significant decrease was observed in lowest oxygen saturation compared with baseline and placebo conditions (83.60 ± 5.51; 84.43 ± 3.80; 80.71 ± 5.18, P = 0.002).
Zolpidem CR improved sleep structure in patients with heart failure, did not change apnea hypopnea index, but slightly decreased lowest oxygen saturation.
Abstract Background: Due to its poor prognosis and mortality rates, heart failure (HF) has been recognized as a malignant condition, comparable to some cancers in developed countries. Objectives: To ...compare mortality from HF and prevalent cancers using data from a nationwide database in Brazil. Methods: This was a descriptive, cross-sectional study using secondary data obtained from Brazilian administrative databases of death records and hospitalization claims maintained by the Ministry of Health. Data were analyzed according to main diagnosis, year of occurrence (2005-2015), sex and age group. Descriptive analyses of absolute number of events, hospitalization rate, mortality rate, and in-hospital mortality rate were performed. Results: The selected cancers accounted for higher mortality, lower hospitalization and higher in-hospital mortality rates than HF. In a group analysis, HF showed mortality rates of 100-150 per 100,000 inhabitants over the period, lower than the selected cancers. However, HF had a higher mortality rate than each type of cancer, even when compared to the most prevalent and deadly ones. Regarding hospitalization rates, HF was associated with a higher risk of hospitalization when compared to cancer-related conditions as a group. Conclusions: Our findings indicate that HF has an important impact on mortality, hospitalization and in-hospital mortality, comparable to or even worse than some types of cancer, representing a potential burden to the healthcare system.
Arterial baroreflex control of muscle sympathetic nerve activity (ABRMSNA) is impaired in chronic systolic heart failure (CHF). The purpose of the study was to test the hypothesis that exercise ...training would improve the gain and reduce the time delay of ABRMSNA in CHF patients. Twenty-six CHF patients, New York Heart Association Functional Class II-III, EF ≤ 40%, peak V̇o2 ≤ 20 ml·kg(-1)·min(-1) were divided into two groups: untrained (UT, n = 13, 57 ± 3 years) and exercise trained (ET, n = 13, 49 ± 3 years). Muscle sympathetic nerve activity (MSNA) was directly recorded by microneurography technique. Arterial pressure was measured on a beat-to-beat basis. Time series of MSNA and systolic arterial pressure were analyzed by autoregressive spectral analysis. The gain and time delay of ABRMSNA was obtained by bivariate autoregressive analysis. Exercise training was performed on a cycle ergometer at moderate intensity, three 60-min sessions per week for 16 wk. Baseline MSNA, gain and time delay of ABRMSNA, and low frequency of MSNA (LFMSNA) to high-frequency ratio (HFMSNA) (LFMSNA/HFMSNA) were similar between groups. ET significantly decreased MSNA. MSNA was unchanged in the UT patients. The gain and time delay of ABRMSNA were unchanged in the ET patients. In contrast, the gain of ABRMSNA was significantly reduced 3.5 ± 0.7 vs. 1.8 ± 0.2, arbitrary units (au)/mmHg, P = 0.04 and the time delay of ABRMSNA was significantly increased (4.6 ± 0.8 vs. 7.9 ± 1.0 s, P = 0.05) in the UT patients. LFMSNA-to-HFMSNA ratio tended to be lower in the ET patients (P < 0.08). Exercise training prevents the deterioration of ABRMSNA in CHF patients.
Aims
We tested the hypothesis that the effects of combined inspiratory muscle training and aerobic exercise training (IMT + AET) on muscle sympathetic nerve activity (MSNA) and forearm blood flow in ...patients with heart failure with reduced ejection fraction are more pronounced than the effects of AET alone.
Methods and results
Patients aged 30–70 years, New York Heart Association Functional Class II‐III, and left ventricular ejection fraction ≤40% were randomly assigned to four groups: IMT (n = 11), AET (n = 12), IMT + AET (n = 9), and non‐training (NT; n = 10). MSNA was recorded using microneurography. Forearm blood flow was measured by venous occlusion plethysmography and inspiratory muscle strength by maximal inspiratory pressure. IMT consisted of 30 min sessions, five times a week, for 4 months. Moderate AET consisted of 60 min sessions, three times a week for 4 months. AET (−10 ± 2 bursts/min, P = 0.03) and IMT + AET (−13 ± 4 bursts/min, P = 0.007) reduced MSNA. These responses in MSNA were not different between AET and IMT + AET groups. IMT (0.22 ± 0.08 mL/min/100 mL, P = 0.03), AET (0.27 ± 0.09 mL/min/100 mL, P = 0.01), and IMT + AET (0.35 ± 0.12 mL/min/100 mL, P = 0.008) increased forearm blood flow. No differences were found between groups. AET (3 ± 1 mL/kg/min, P = 0.006) and IMT + AET (4 ± 1 mL/kg/min, P = 0.001) increased peak oxygen consumption. These responses were similar between these groups. IMT (20 ± 3 cmH2O, P = 0.005) and IMT + AET (18 ± 3 cmH2O, P = 0.01) increased maximal inspiratory pressure. No significant changes were observed in the NT group.
Conclusions
IMT + AET causes no additive effects on neurovascular control in patients with heart failure with reduced ejection fraction compared with AET alone. These findings may be, in part, because few patients had inspiratory muscle weakness.
Purpose
Central and peripheral chemoreceptors are hypersensitized in patients with heart failure with reduced ejection fraction. Whether this autonomic alteration occurs in patients with heart ...failure with preserved ejection fraction (HFpEF) remains little known. We test the hypothesis that the central and peripheral chemoreflex control of muscle sympathetic nerve activity (MSNA) is altered in HFpEF.
Methods
Patients aged 55–80 years with symptoms of heart failure, body mass index ≤ 35 kg/m
2
, left ventricular ejection fraction > 50%, left atrial volume index > 34 mL/m
2
, left ventricular early diastolic filling velocity and early diastolic tissue velocity of mitral annulus ratio (E/e′ index) ≥ 13, and BNP levels > 35 pg/mL were included in the study (HFpEF,
n
= 9). Patients without heart failure with preserved ejection fraction (non-HFpEF,
n
= 9), aged-paired, were also included in the study. Peripheral chemoreceptors stimulation (10% O
2
and 90% N
2
, with CO
2
titrated) and central chemoreceptors stimulation (7% CO
2
and 93% O
2
) were conducted for 3 min. MSNA was evaluated by microneurography technique, and forearm blood flow (FBF) by venous occlusion plethysmography.
Results
During hypoxia, MSNA responses were greater (
p
< 0.001) and FBF responses were lower in patients with HFpEF (
p
= 0.006). Likewise, MSNA responses during hypercapnia were higher (
p
< 0.001) and forearm vascular conductance (FVC) levels were lower (
p
= 0.030) in patients with HFpEF.
Conclusions
Peripheral and central chemoreflex controls of MSNA are hypersensitized in patients with HFpEF, which seems to contribute to the increase in MSNA in these patients. In addition, peripheral and central chemoreceptors stimulation in patients with HFpEF causes muscle vasoconstriction.
1 Pulmonary Function and Clinical Exercise Physiology Unit (SEFICE), Division of Respiratory Diseases, Department of Medicine, Federal University of Sao Paulo (UNIFESP), São Paulo;
2 Division of ...Cardiology, Department of Medicine, Federal University of Sao Paulo (UNIFESP), São Paulo; and
3 Cardiopulmonary Laboratory, Nucleus of Research in Physical Exercise, Federal University of São Carlos (UFSCar), São Carlos, SP, Brazil
Submitted July 6, 2009
; accepted in final form September 4, 2009
Impaired muscle blood flow at the onset of heavy-intensity exercise may transiently reduce microvascular O 2 pressure and decrease the rate of O 2 transfer from capillary to mitochondria in chronic heart failure (CHF). However, advances in the pharmacological treatment of CHF (e.g., angiotensin-converting enzyme inhibitors and third-generation β-blockers) may have improved microvascular O 2 delivery to an extent that intramyocyte metabolic inertia might become the main locus of limitation of O 2 uptake ( O 2 ) kinetics. We assessed the rate of change of pulmonary O 2 ( O 2 p ), (estimated) fractional O 2 extraction in the vastus lateralis ( deoxy-Hb+Mb by near-infrared spectroscopy), and cardiac output ( T ) during high-intensity exercise performed to the limit of tolerance (Tlim) in 10 optimally treated sedentary patients (ejection fraction = 29 ± 8%) and 11 controls. Sluggish O 2 p and T kinetics in patients were significantly related to lower Tlim values ( P < 0.05). The dynamics of deoxy-Hb+Mb, however, were faster in patients than controls mean response time (MRT) = 15.9 ± 2.0 s vs. 19.0 ± 2.9 s; P < 0.05 with a subsequent response "overshoot" being found only in patients (7/10). Moreover, O 2 /MRT-deoxy-Hb+Mb ratio was greater in patients (4.69 ± 1.42 s vs. 2.25 ± 0.77 s; P < 0.05) and related to T kinetics and Tlim ( R = 0.89 and –0.78, respectively; P < 0.01). We conclude that despite the advances in the pharmacological treatment of CHF, disturbances in "central" and "peripheral" circulatory adjustments still play a prominent role in limiting O 2 p kinetics and tolerance to heavy-intensity exercise in nontrained patients.
blood flow; chronic heart failure; hemodynamics; near-infrared spectroscopy; oxygen consumption
Address for reprint requests and other correspondence: J. A. Neder, Pulmonary Function and Clinical Exercise Physiology Unit (SEFICE); Respiratory Division, Dept. of Medicine; Federal Univ. of São Paulo-Paulista School of Medicine (UNIFESP-EPM), Rua Professor Francisco de Castro 54, Vila Clementino, CEP 04020-050, São Paulo, Brazil (e-mail: albneder{at}pneumo.epm.br ).
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