Skeletal muscle derived Musclin protects the heart during pathological overload.

Cachexia is associated with poor prognosis in chronic heart failure patients, but the underlying mechanisms of cachexia triggered disease progression remain poorly understood. Here, we investigate whether the dysregulation of myokine expression from wasting skeletal muscle exaggerates heart failure. RNA sequencing from wasting skeletal muscles of mice with heart failure reveals a reduced expression of Ostn, which encodes the secreted myokine Musclin, previously implicated in the enhancement of natriuretic peptide signaling. By generating skeletal muscle specific Ostn knock-out and overexpressing mice, we demonstrate that reduced skeletal muscle Musclin levels exaggerate, while its overexpression in muscle attenuates cardiac dysfunction and myocardial fibrosis during pressure overload. Mechanistically, Musclin enhances the abundance of C-type natriuretic peptide (CNP), thereby promoting cardiomyocyte contractility through protein kinase A and inhibiting fibroblast activation through protein kinase G signaling. Because we also find reduced OSTN expression in skeletal muscle of heart failure patients, augmentation of Musclin might serve as therapeutic strategy.

Improving exercise capacity and quality of life using non-invasive heart failure treatments: evidence from clinical trials.

Endpoints of large-scale trials in chronic heart failure have mostly been defined to evaluate treatments with regard to hospitalizations and mortality. However, patients with heart failure are also affected by very severe reductions in exercise capacity and quality of life. We aimed to evaluate the effects of heart failure treatments on these endpoints using available evidence from randomized trials. Interventions with evidence for improvements in exercise capacity include physical exercise, intravenous iron supplementation in patients with iron deficiency, and - with less certainty - testosterone in highly selected patients. Erythropoiesis-stimulating agents have been reported to improve exercise capacity in anaemic patients with heart failure. Sinus rhythm may have some advantage when compared with atrial fibrillation, particularly in patients undergoing pulmonary vein isolation. Studies assessing treatments for heart failure co-morbidities such as sleep-disordered breathing, diabetes mellitus, chronic kidney disease and depression have reported improvements of exercise capacity and quality of life; however, the available data are limited and not always consistent. The available evidence for positive effects of pharmacologic interventions using angiotensin-converting enzyme inhibitors, angiotensin receptor blockers, beta-blockers, and mineralocorticoid receptor antagonists on exercise capacity and quality of life is limited. Studies with ivabradine and with sacubitril/valsartan suggest beneficial effects at improving quality of life; however, the evidence base is limited in particular for exercise capacity. The data for heart failure with preserved ejection fraction are even less positive, only sacubitril/valsartan and spironolactone have shown some effectiveness at improving quality of life. In conclusion, the evidence for state-of-the-art heart failure treatments with regard to exercise capacity and quality of life is limited and appears not robust enough to permit recommendations for heart failure. The treatment of co-morbidities may be important for these patient-related outcomes. Additional studies on functional capacity and quality of life in heart failure are required.

Cardiotoxicity and Cardiovascular Biomarkers in Patients With Breast Cancer: Data From the GeparOcto-GBG 84 Trial.

Background Patients with breast cancer can be affected by cardiotoxic reactions through cancer therapies. Cardiac biomarkers, like NT-proBNP (N-terminal pro-B-type natriuretic peptide) and high-sensitivity cardiac troponin T, might have predictive value. Methods and Results Echocardiography, ECG, hemodynamic parameters, NT-proBNP and high-sensitivity cardiac troponin T were assessed in 853 patients with early-stage breast cancer randomized in the German Breast Group GeparOcto-GBG 84 phase III trial. Patients received neo-adjuvant dose-dense, dose-intensified epirubicin, paclitaxel, and cyclophosphamide (iddEPC group, n=424) or paclitaxel, non-pegylated doxorubicin, and in triple negative breast cancer, (paclitaxel, non-pegylated doxorubicin, carboplatin group, n=429) treatment for 18 weeks. Patients positive for human epidermal growth receptor 2 (n=354, 41.5%) received monoclonal antibodies on top of allocated therapy; 119 (12.9%) of all patients showed a cardiotoxic reaction during therapy (15 [1.8%] using a more strict definition). Presence of cardiotoxic reactions was irrespective of treatment allocation (P=0.31). Small but significant increases in NT-proBNP developed early in patients with a cardiotoxic reaction as compared with those without in whom NT-proBNP rose only towards the end of therapy (P=0.04). High-sensitivity cardiac troponin T rose early in both groups. Logistic regression showed that NT-proBNP (odds ratio [OR], 1.03; 95% CI, 1.008-1.055; P=0.01) and hemoglobin (OR, 1.31; 95% CI, 1.05-1.63; P=0.02) measured at 6 weeks after treatment initiation were significantly associated with cardiotoxic reactions. Conclusions NT-proBNP and hemoglobin are significantly associated with cardiotoxic reactions in patients with early-stage breast cancer undergoing dose-dense and dose-intensified chemotherapy, but high-sensitivity cardiac troponin T is not. Registration URL: http://www.clinicaltrials.gov; Unique identifier: NCT02125344.

Muscle mass, muscle strength, and functional capacity in patients with heart failure of Chagas disease and other aetiologies.

AIMS: Patients with Chagas disease and heart failure (HF) have a poor prognosis similar to that of patients with ischaemic or dilated cardiomyopathy. However, the impact of body composition and muscle strength changes in these aetiologies is still unknown. We aimed to evaluate these parameters across aetiologies in two distinct cohort studies [TESTOsterone-Heart Failure trial (TESTO-HF; Brazil) and Studies Investigating Co-morbidities Aggravating Heart Failure (SICA-HF; Germany)]. METHODS AND RESULTS: A total of 64 male patients with left ventricular ejection fraction ≤40% were matched for body mass index and New York Heart Association class, including 22 patients with Chagas disease (TESTO-HF; Brazil), and 20 patients with dilated cardiomyopathy and 22 patients with ischaemic heart disease (SICA-HF; Germany). Lean body mass (LBM), appendicular lean mass (ALM), and fat mass were assessed by dual energy X-ray absorptiometry. Sarcopenia was defined as ALM divided by height in metres squared <7.0 kg/m2 (ALM/height2 ) and handgrip strength cut-off for men according to the European Working Group on Sarcopenia in Older People. All patients performed maximal cardiopulmonary exercise testing. Forearm blood flow (FBF) was measured by venous occlusion plethysmography. Chagasic and ischaemic patients had lower total fat mass (16.3 ± 8.1 vs. 19.3 ± 8.0 vs. 27.6 ± 9.4 kg; P < 0.05) and reduced peak oxygen consumption (VO2 ) (1.17 ± 0.36 vs. 1.15 ± 0.36 vs. 1.50 ± 0.45 L/min; P < 0.05) than patients with dilated cardiomyopathy, respectively. Chagasic patients showed a trend towards decreased LBM when compared with ischaemic patients (48.3 ± 7.6 vs. 54.2 ± 6.3 kg; P = 0.09). Chagasic patients showed lower handgrip strength (27 ± 8 vs. 37 ± 11 vs. 36 ± 14 kg; P < 0.05) and FBF (1.84 ± 0.54 vs. 2.75 ± 0.76 vs. 3.42 ± 1.21 mL/min/100 mL; P < 0.01) than ischaemic and dilated cardiomyopathy patients, respectively. There was no statistical difference in the distribution of sarcopenia between groups (P = 0.87). In addition, FBF correlated positively with LBM (r = 0.31; P = 0.012), ALM (r = 0.25; P = 0.046), and handgrip strength (r = 0.36; P = 0.004). In a logistic regression model using peak VO2 as the dependent variable, haemoglobin (odds ratio, 1.506; 95% confidence interval, 1.043-2.177; P = 0.029) and ALM (odds ratio, 1.179; 95% confidence interval, 1.011-1.374; P = 0.035) were independent predictors for peak VO2 adjusted by age, left ventricular ejection fraction, New York Heart Association, creatinine, and FBF. CONCLUSIONS: Patients with Chagas disease and HF have decreased fat mass and exhibit reduced peripheral blood flow and impaired muscle strength compared with ischaemic HF patients. In addition, patients with Chagas disease and HF show a tendency to have greater reduction in total LBM, with ALM remaining an independent predictor of reduced functional capacity in these patients. The percentage of patients affected by sarcopenia was equal between groups.

Muscle wasting as an independent predictor of survival in patients with chronic heart failure.

BACKGROUND: Skeletal muscle wasting is an extremely common feature in patients with heart failure, affecting approximately 20% of ambulatory patients with even higher values during acute decompensation. Its occurrence is associated with reduced exercise capacity, muscle strength, and quality of life. We sought to investigate if the presence of muscle wasting carries prognostic information. METHODS: Two hundred sixty-eight ambulatory patients with heart failure (age 67.1 ± 10.9 years, New York Heart Association class 2.3 ± 0.6, left ventricular ejection fraction 39 ± 13.3%, and 21% female) were prospectively enrolled as part of the Studies Investigating Co-morbidities Aggravating Heart Failure. Muscle wasting as assessed using dual-energy X-ray absorptiometry was present in 47 patients (17.5%). RESULTS: During a mean follow-up of 67.2 ± 28.02 months, 95 patients (35.4%) died from any cause. After adjusting for age, New York Heart Association class, left ventricular ejection fraction, creatinine, N-terminal pro-B-type natriuretic peptide, and iron deficiency, muscle wasting remained an independent predictor of death (hazard ratio 1.80, 95% confidence interval 1.01-3.19, P = 0.04). This effect was more pronounced in patients with heart failure with reduced than in heart failure with preserved ejection fraction. CONCLUSIONS: Muscle wasting is an independent predictor of death in ambulatory patients with heart failure. Clinical trials are needed to identify treatment approaches to this co-morbidity.

Does CBT have lasting effects in the treatment of PTSD after one year of follow-up? A systematic review of randomized controlled trials.

INTRODUCTION: While several previous meta-analyses have documented the short-term efficacy of cognitive-behavioral therapy (CBT), its long-term efficacy remains unknown. Posttraumatic stress disorder (PTSD) is a serious, debilitating, often chronic and disabling disease. OBJECTIVE: To estimate the long-term efficacy of CBT in the treatment of PTSD by assessing the maintenance of the effect after one year of follow-up. METHOD: We performed a systematic review through electronic database searches including ISI Web of Science, PubMed, PsycInfo and Pilots. We included randomized studies in which CBT was compared with a control group (waiting list or usual care) in adults with PTSD that reported at least one year of CBT follow-up. RESULTS: Our search identified 2,324 studies and 8 were selected. CBT was shown to be effective in the treatment of PTSD in the post-treatment period. Improvement in PTSD symptoms was statistically significant in relation to the control group. The improvement observed in the treatment group or single group (formed by both treatment group and control group, which was submitted to the intervention after a few weeks on the waiting list) was maintained in the follow-up. CONCLUSION: Due to the lack of control groups in the follow-up period in six of the eight studies included in this review, there is still no proper methodological basis to assert that CBT has lasting effects in the treatment of PTSD. Our study found serious methodological shortcomings and the need to fill this gap in the literature through the development of studies with robust and sophisticated designs.

Does CBT have lasting effects in the treatment of PTSD after one year of follow-up? A systematic review of randomized controlled trials / A TCC possui efeitos duradouros no tratamento do TEPT após um ano de seguimento? Revisão sistemática de ensaios clínicos randomizados

Abstract Introduction: While several previous meta-analyses have documented the short-term efficacy of cognitive-behavioral therapy (CBT), its long-term efficacy remains unknown. Posttraumatic stress disorder (PTSD) is a serious, debilitating, often chronic and disabling disease. Objective: To estimate the long-term efficacy of CBT in the treatment of PTSD by assessing the maintenance of the effect after one year of follow-up. Method: We performed a systematic review through electronic database searches including ISI Web of Science, PubMed, PsycInfo and Pilots. We included randomized studies in which CBT was compared with a control group (waiting list or usual care) in adults with PTSD that reported at least one year of CBT follow-up. Results: Our search identified 2,324 studies and 8 were selected. CBT was shown to be effective in the treatment of PTSD in the post-treatment period. Improvement in PTSD symptoms was statistically significant in relation to the control group. The improvement observed in the treatment group or single group (formed by both treatment group and control group, which was submitted to the intervention after a few weeks on the waiting list) was maintained in the follow-up. Conclusion: Due to the lack of control groups in the follow-up period in six of the eight studies included in this review, there is still no proper methodological basis to assert that CBT has lasting effects in the treatment of PTSD. Our study found serious methodological shortcomings and the need to fill this gap in the literature through the development of studies with robust and sophisticated designs.

Resumo Introdução: Várias meta-análises anteriores documentaram a eficácia a curto prazo da terapia cognitivo-comportamental (TCC). No entanto, sua eficácia a longo prazo permanece desconhecida. O transtorno de estresse pós-traumático (TEPT) é uma doença crônica grave, debilitante e incapacitante. Objetivo: Estimar a eficácia a longo prazo da TCC no tratamento do TEPT, avaliando a manutenção do efeito após um ano de seguimento. Métodos: Realizamos uma revisão sistemática através de pesquisas nas bases de dados eletrônicas ISI Web of Science, PubMed, PsycInfo e Pilots. Incluímos estudos randomizados nos quais a TCC foi comparada com um grupo controle (lista de espera ou tratamento usual) em adultos com TEPT que relataram pelo menos um ano de seguimento da TCC. Resultados: A pesquisa identificou 2.324 estudos e 8 foram selecionados. A TCC mostrou-se eficaz no tratamento do TEPT no período pós-tratamento. A melhora nos sintomas de TEPT foi estatisticamente significativa em relação ao grupo controle. A melhora observada no grupo de tratamento ou grupo único (formado por ambos os grupos de tratamento e controle, que foi submetido à intervenção após algumas semanas na lista de espera) foi mantida no seguimento. Conclusão: Devido à ausência de grupo controle no período de follow-up em 6 dos 8 estudos incluídos nesta revisão, ainda não há base metodológica adequada para afirmar que a TCC tem efeitos duradouros no tratamento do TEPT. Nosso estudo encontrou graves deficiências metodológicas e a necessidade de preencher essa lacuna na literatura através de estudos com delineamentos robustos e sofisticados.

Systematic review of the efficacy of cognitive-behavior therapy related treatments for victims of natural disasters: a worldwide problem.

Natural disasters can have devastating consequences. Each year, about 225 million people are victims of natural disasters worldwide, and up to 13,5 million of these people can develop post-traumatic stress disorder (PTSD) in the first or second year following the disaster. Cognitive-behavior therapy (CBT) is the first-choice treatment for this disorder. In order to evaluate the efficacy of psychotherapeutic treatment based on cognitive-behavior therapy for people who developed post traumatic stress disorder after natural disasters we conducted a systematic search of published studies. We used the terms reported below in the electronic databases ISI Web of Science, PsycINFO, PubMed, PILOTS and Scopus with no restrictions of language or publication date. Articles that described randomized controlled, non-randomized controlled and non controlled studies on the efficacy of cognitive-behavior therapy for individuals diagnosed with post-traumatic stress disorder after exposure to a natural disaster were eligible for inclusion. The studies were required to use a standardized measure of effectiveness before and after the intervention and have a group of patients who had used cognitive-behavior therapy as the only intervention. Our search identified 820 studies, and 11 were selected for this review. These 11 studies involved 742 subjects, 10 related to earthquakes and 1 to a hurricane. The cognitive-behavior therapy techniques used were various: 7 studies used exposure therapy, 2 studies used problem solving, and the only 2 studies with adolescents used techniques including reconstructions and reprocessing of the traumatic experience. As limitations, the search involved only five electronic databases, no experts in the field were consulted, and the heterogeneity of the findings made it impossible to perform a meta-analysis. The results suggest the efficacy of cognitive-behavior therapy, particularly exposure techniques, for the treatment of post-traumatic stress disorder after earthquakes. However, further studies with stronger methodologies, i.e. randomized-control trials and non-randomized controlled trials, are needed.

Building resilience for future adversity: a systematic review of interventions in non-clinical samples of adults.

BACKGROUND: Potentially traumatic events happen in people's lives, leading to the risk of the development of posttraumatic stress disorder, depression and even suicide. Resilience is an individual's ability to maintain or regain his/her mental health in the face of significant adversity or risk of death. The aim of this study was to conduct a systematic review of studies evaluating the effectiveness of resilience promotion interventions in adults. METHODS: Electronic searches were conducted in databases ISI, PsycINFO and PubMed, including every language and every year until January 20, 2013. We selected studies with nonclinical samples of adults that evaluated the effectiveness of the intervention through randomized and non-randomized controlled trials and open-ended studies. We also considered valid constructs directly related to resilience, such as hardiness. RESULTS: Among 2.337 studies, 13 were selected for the review, 5 through electronic databases and 8 through search in references or the "times cited list" (list of articles that cited the selected papers). Of these, 7 are randomized controlled trials, 5 non-randomized controlled trials, and one an open-ended trial. Most of the studies included reported some degree of improvement in resilience-like variables among those subjects exposed to resilience-promoting programs. Furthermore, positive findings were more consistent among randomized controlled trials--six out of the seven suggested efficacy. CONCLUSION: There is evidence pointing towards some degree of effectiveness of resilience promotion programs, despite the poor operationalization of the construct and great heterogeneity in the studies. Indeed, the analysis of the methodological quality of the selected studies was hampered by the poor quality of reporting. There were faults in reporting in most studies on almost all items (random sequence generation, allocation concealment, blinding of outcome assessment, incomplete outcome data, description of concurrent treatment and intent-to-treat analysis), except for the item "selective reporting". Additional efforts should be made to determine the actual effect size of the interventions, since this is crucial for calculating the cost-effectiveness of resilience promotion strategies.

CBT for pharmacotherapy non-remitters--a systematic review of a next-step strategy.

BACKGROUND: Non-remission rates to pharmacotherapy for anxiety disorders are related to higher relapse rates, decreased quality of life and greater functional impairment. Here we sought to investigate the efficacy of cognitive-behavior therapy (CBT) as a next-step strategy in the treatment of patients with anxiety disorders who did not remit after a pharmacological intervention. METHOD: We carried out a systematic review in the ISI, Pubmed and PsycINFO/PsychLit databases. Studies that did not use CBT and that did not focus on resistance to drug therapy were excluded. We considered resistant patients who failed to respond (did not fully remit) to an adequate trial of pharmacotherapy and still exhibited residual symptoms of anxiety disorder. RESULTS: We identified 603 references in our survey, of which 17 were included: eight were on OCD, five on panic disorder, and four on PTSD. No studies were found on social anxiety disorder and generalized anxiety disorder. We observed a lack of standardization of terminology and of definitions of resistance, which makes comparison of results difficult. Finally, all of the identified studies showed benefits from the addition of CBT as a next-step strategy. LIMITATIONS: A limited number of randomized controlled studies were found. CONCLUSIONS: CBT seems to be a promising next-step strategy for patients with anxiety disorders who did not remit with drug-based therapies. However, further clinical trials with strong methodological designs are needed to definitely establish its efficacy in this population.