Hypertension is a key risk factor for heart failure, with the latter characterized by diaphragm muscle weakness that is mediated in part by increased oxidative stress. In the present study, we used a ...deoxycorticosterone acetate (DOCA)-salt mouse model to determine whether hypertension could independently induce diaphragm dysfunction and further investigated the effects of high-intensity interval training (HIIT). Sham-treated (n = 11), DOCA-salt-treated (n = 11), and DOCA-salt+HIIT-treated (n = 15) mice were studied over 4 wk. Diaphragm contractile function, protein expression, enzyme activity, and fiber cross-sectional area and type were subsequently determined. Elevated blood pressure confirmed hypertension in DOCA-salt mice independent of HIIT (P < 0.05). Diaphragm forces were impaired by ∼15-20% in DOCA-salt vs. sham-treated mice (P < 0.05), but this effect was prevented after HIIT. Myosin heavy chain (MyHC) protein expression tended to decrease (∼30%; P = 0.06) in DOCA-salt vs. sham- and DOCA-salt+HIIT mice, whereas oxidative stress increased (P < 0.05). Enzyme activity of NADPH oxidase was higher, but superoxide dismutase was lower, with MyHC oxidation elevated by ∼50%. HIIT further prevented direct oxidant-mediated diaphragm contractile dysfunction (P < 0.05) after a 30 min exposure to H
O-
(1 mM). Our data suggest that hypertension induces diaphragm contractile dysfunction via an oxidant-mediated mechanism that is prevented by HIIT.-Bowen, T. S., Eisenkolb, S., Drobner, J., Fischer, T., Werner, S., Linke, A., Mangner, N., Schuler, G., Adams, V. High-intensity interval training prevents oxidant-mediated diaphragm muscle weakness in hypertensive mice.
PURPOSEThis study aimed to investigate baseline, exercise testing, and exercise training–mediated predictors of change in peak oxygen uptake (V˙O2peak) from baseline to 12-wk follow-up (ΔV˙O2peak) in ...a post hoc analysis from the SMARTEX Heart Failure trial.
METHODSWe studied 215 patients with heart failure with left ventricular ejection fraction (LVEF) ≤35%, and New York Heart Association (NYHA) classes II–III who were randomized to either supervised high-intensity interval training with exercise target intensity of 90%–95% of peak heart rate (HRpeak) or supervised moderate continuous training (MCT) with target intensity of 60%–70% of HRpeak, or who received a recommendation of regular exercise on their own. Predictors of ΔV˙O2peak were assessed in two modelsa logistic regression model comparing highest and lowest tertiles (baseline parameters) and a multivariate linear regression model (test/training/clinical parameters).
RESULTSThe change in V˙O2peak in response to the interventions (ΔV˙O2peak) varied substantially, from −8.50 to +11.30 mL·kg·min. Baseline NYHA (class II gave higher odds vs III; odds ratio (OR), 7.1 (2.0–24.9); P = 0.002), LVEF (OR per percent, 1.1 (1.0–1.2); P = 0.005), and age (OR per 10 yr, 0.5 (0.3–0.8); P = 0.003) were associated with ΔV˙O2peak.In the multivariate linear regression, 34% of the variability in ΔV˙O2peak was explained by the increase in exercise training workload, ΔHRpeak between baseline and 12-wk posttesting, age, and ever having smoked.
CONCLUSIONExercise training response (ΔV˙O2peak) correlated negatively with age, LVEF, and NYHA class. The ability to increase workload during the training period and increased ΔHRpeak between baseline and the 12-wk test were associated with a positive outcome.
Aims
In late-stage chronic heart failure (CHF), elevated cytokines and cachexia are often observed. Several studies have shown that exercise training exerts beneficial effects on skeletal muscle in ...this setting. Furthermore, it has been shown that the expression of myostatin, a key regulator of skeletal muscle mass, is increased in a variety of cachectic states. This study aimed to investigate the expression of myostatin in CHF, the influence of exercise training on myostatin levels, and regulation of myostatin by tumour necrosis factor-α (TNF-α).
Methods and results
In an animal model of CHF (LAD-ligation model), protein expression of myostatin was elevated 2.4-fold in the skeletal muscle and more than four-times in the myocardium, compared with control (Co). Exercise training on a treadmill over 4 weeks led to a significant reduction in myostatin protein expression in the skeletal muscle and the myocardium of CHF animals, with values returning to baseline levels. In differentiated C2C12 cells, TNF-α induced the expression of myostatin through a p38MAPK-dependent pathway involving nuclear factor kappa-B (NF-κB). The increased TNF-α mRNA levels in the skeletal muscle of CHF animals correlated significantly with myostatin expression.
Conclusion
These alterations in myostatin expression in the skeletal and heart muscle following exercise training could help to explain the beneficial anti-catabolic effects of exercise training in CHF.
Background
Extensive evidence relating to transcatheter aortic valve replacement (TAVR) has accumulated in recent years, but mid-term outcomes are less reported. We investigated 996 patients after ...implantation of the CoreValve prosthesis for severe aortic stenosis in a real-world setting.
Objective
To report clinical and echocardiographic 3-year results from the ADVANCE study.
Methods
ADVANCE is a prospective, multicenter, fully monitored, nonrandomized clinical study. This analysis assessed valve-related events, predictors of early and mid-term mortality after TAVR, and systolic and diastolic prosthesis performance over 3 years.
Results
Three years after TAVR, the rate of major adverse cardiac/cerebrovascular events was 38.5%. All-cause mortality was 33.7%; cardiovascular mortality, 22.3%; VARC-1 stroke, 6.5%; and New York Heart Association class III/IV, 19.5%. Mean effective orifice area was consistently 1.7 cm
2
from discharge to 3 years, and average mean aortic valve gradient remained ≤10 mmHg. At 3 years, 12.6% of patients had moderate and none had severe paravalvular regurgitation. Multivariable analysis identified Society of Thoracic Surgeons (STS) score, device migration, prior atrial fibrillation, and major vascular complication as predictors of early mortality. Predictors of mid-term mortality included male gender, STS score, history of chronic obstructive pulmonary disease, history of cancer, stroke, life-threatening/disabling or major bleeding, and valve deterioration.
Conclusions
Our 3-year data demonstrate significant hemodynamic benefits and durable symptom relief after CoreValve prosthesis implantation. Postprocedural patient management should be carefully considered, since postprocedural valve-related events were identified as independent predictors of mid-term mortality.
Trial registration
ClinicalTrials.gov, NCT01074658.
Background As transcatheter aortic valve replacement expands to younger and/or lower risk patients, the long-term consequences of permanent pacemaker implantation are a concern. Pacemaker dependency ...and impact have not been methodically assessed in transcatheter aortic valve replacement trials. We report the incidence and predictors of pacemaker implantation and pacemaker dependency after transcatheter aortic valve replacement with the Lotus valve. Methods and Results A total of 912 patients with high/extreme surgical risk and symptomatic aortic stenosis were randomized 2:1 (Lotus:CoreValve) in REPRISE III (The Repositionable Percutaneous Replacement of Stenotic Aortic Valve through Implantation of Lotus Valve System-Randomized Clinical Evaluation) trial. Systematic assessment of pacemaker dependency was pre-specified in the trial design. Pacemaker implantation within 30 days was more frequent with Lotus than CoreValve. By multivariable analysis, predictors of pacemaker implantation included baseline right bundle branch block and depth of implantation; diabetes mellitus was also a predictor with Lotus. No association between new pacemaker implantation and clinical outcomes was found. Pacemaker dependency was dynamic (30 days: 43%; 1 year: 50%) and not consistent for individual patients over time. Predictors of pacemaker dependency at 30 days included baseline right bundle branch block, female sex, and depth of implantation. No differences in mortality or stroke were found between patients who were pacemaker dependent or not at 30 days. Rehospitalization was higher in patients who were not pacemaker dependent versus patients without a pacemaker or those who were dependent. Conclusions Pacemaker implantation was not associated with adverse clinical outcomes. Most patients with a new pacemaker at 30 days were not dependent at 1 year. Mortality and stroke were similar between patients with or without pacemaker dependency and patients without a pacemaker. Clinical Trial Registration URL: https://www.clinicaltrials.gov/. Unique identifier NCT02202434.
Pulmonary hypertension leads to right ventricular heart failure and ultimately to cardiac cachexia. Cardiac cachexia induces skeletal muscles atrophy and contractile dysfunction. MAFbx and MuRF1 are ...two key proteins that have been implicated in chronic muscle atrophy of several wasting states.
Monocrotaline (MCT) was injected over eight weeks into mice to establish pulmonary hypertension as a murine model for cardiac cachexia. The effects on skeletal muscle atrophy, myofiber force, and selected muscle proteins were evaluated in wild-type (WT), MuRF1, and MuRF2-KO mice by determining muscle weights, in vitro muscle force and enzyme activities in soleus and tibialis anterior (TA) muscle.
In WT, MCT treatment induced wasting of soleus and TA mass, loss of myofiber force, and depletion of citrate synthase (CS), creatine kinase (CK), and malate dehydrogenase (MDH) (all key metabolic enzymes). This suggests that the murine MCT model is useful to mimic peripheral myopathies as found in human cardiac cachexia. In MuRF1 and MuRF2-KO mice, soleus and TA muscles were protected from atrophy, contractile dysfunction, while metabolic enzymes were not lowered in MuRF1 or MuRF2-KO mice. Furthermore, MuRF2 expression was lower in MuRF1KO mice when compared to C57BL/6 mice.
In addition to MuRF1, inactivation of MuRF2 also provides a potent protection from peripheral myopathy in cardiac cachexia. The protection of metabolic enzymes in both MuRF1KO and MuRF2KO mice as well as the dependence of MuRF2 expression on MuRF1 suggests intimate relationships between MuRF1 and MuRF2 during muscle atrophy signaling.
The degradation behavior and biocompatibility of pure molybdenum (Mo) were investigated. Dissolution of powder metallurgically manufactured and commercially available Mo was investigated by ion ...concentration measurement after immersion in modified Kokubo’s SBF (c-SBF-Ca) for 28 days at 37 °C and pH 7.4. Degradation layers and corrosion attack were examined with optical microscopy and REM/EDX analysis. Furthermore, potentiodynamic polarization measurements were conducted. Mo gradually dissolves in modified SBF releasing molybdate anions (MoO42−). The dissolution rate after 28 days is 10 µm/y for both materials and dissolution accelerates over time. A non-passivating, uniform and slowly soluble degradation product layer is observed. Additionally, apoptosis and necrosis assays with Mo ion extracts and colonization tests with human endothelial (HCAEC) and smooth muscle cell lines (HCASMC) on Mo substrates were performed. No adverse effects on cell viability were observed for concentrations expected from the dissolution of implants with typical geometries and substrates were densely colonized by both cell lines. Furthermore, Mo does not trigger thrombogenic or inflammatory responses. In combination with its favorable mechanical properties and the renal excretion of bio-available molybdate ions, Mo may be an alternative to established bioresorbable metals.
Heart failure (HF) is a chronic and progressive syndrome affecting worldwide billions of patients. Exercise intolerance and early fatigue are hallmarks of HF patients either with a reduced (HFrEF) or ...a preserved (HFpEF) ejection fraction. Alterations of the skeletal muscle contribute to exercise intolerance in HF. This review will provide a contemporary summary of the clinical and molecular alterations currently known to occur in the skeletal muscles of both HFrEF and HFpEF, and thereby differentiate the effects on locomotor and respiratory muscles, in particular the diaphragm. Moreover, current and future therapeutic options to address skeletal muscle weakness will be discussed focusing mainly on the effects of exercise training.
Background
Chronic heart failure (CHF) is commonly associated with muscle atrophy and increased inflammation. Irisin, a myokine proteolytically processed by the fibronectin type III domain containing ...5 (FNDC5) gene and suggested to be Peroxisome proliferator‐activated receptor gamma coactivator (PGC)‐1α activated, modulates the browning of adipocytes and is related to muscle mass. Therefore, we investigated whether skeletal muscle FNDC5 expression in CHF was reduced and if this was mediated by inflammatory cytokines and/or angiotensin II (Ang‐II).
Methods
Skeletal muscle FNDC5 mRNA/protein and PGC‐1α mRNA expression (arbitrary units) were analysed in: (i) rats with ischemic cardiomyopathy; (ii) mice injected with tumour necrosis factor‐α (TNF‐α) (24 h); (iii) mice infused with Ang‐II (4 weeks); and (iv) C2C12 myotubes exposed to recombinant cytokines or Ang‐II. Circulating TNF‐α, Ang‐II, and irisin was measured by ELISA.
Results
Ischemic cardiomyopathy reduced significantly FNDC5 protein (1.3 ± 0.2 vs. 0.5 ± 0.1) and PGC‐1α mRNA expression (8.2 ± 1.5 vs. 4.7 ± 0.7). In vivo TNF‐α and Ang‐II reduced FNDC5 protein expression by 28% and 45%, respectively. Incubation of myotubes with TNF‐α, interleukin‐1ß, or TNF‐α/interleukin‐1ß reduced FNDC5 protein expression by 47%, 37%, or 57%, respectively, whereas Ang‐II had no effect. PGC‐1α was linearly correlated to FNDC5 in all conditions. In CHF, animals circulating TNF‐α and Ang‐II were significantly increased, whereas irisin was significantly reduced. A negative correlation between circulating TNF‐α and irisin was evident.
Conclusion
A reduced expression of skeletal muscle FNDC5 in ischemic cardiomyopathy is likely modulated by inflammatory cytokines and/or Ang‐II via the down‐regulation of PGC‐1α. This may act as a protective mechanism either by slowing the browning of adipocytes and preserving energy homeostasis or by regulating muscle atrophy.
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