Atrial fibrillation (AF) is the most common clinical tachyarrhythmia associated with significant morbidity and mortality and is expected to affect approximately 30 million North Americans and Europeans by 2050. AF is a persistent disease, caused by progressive, often age-related, derailment of proteostasis resulting in structural remodeling of the atrial cardiomyocytes. It has been widely acknowledged that the progressive nature of the disease hampers the effective functional conversion to sinus rhythm in patients and explains the limited effect of current drug therapies. Therefore, research is directed at preventing new-onset AF by limiting the development of substrates underlying AF promotion. Upstream therapy refers to the use of drugs that modify the atrial substrate- or target-specific mechanisms of AF, with the ultimate aim to prevent the occurrence (primary prevention) and recurrence of the arrhythmia following (spontaneous) conversion and to prevent the progression of AF (secondary prevention). Recently, we observed that heat shock protein (HSP)-inducing drugs, such as geranylgeranylacetone, prevent derailment of proteostasis and remodeling of cardiomyocytes and thereby attenuate the AF substrate in cellular, Drosophila melanogaster, and animal experimental models. Also, correlative data from human studies were consistent with a protective role of HSPs in preventing the progression from paroxysmal AF to permanent AF and in the recurrence of AF. In this review, we discuss novel HSP-inducing compounds as emerging therapeutics for the primary and secondary prevention of AF. © 2012 Elsevier Inc.
Skeletal muscle-related symptoms are common in both acute coronavirus disease (Covid)-19 and post-acute sequelae of Covid-19 (PASC). In this narrative review, we discuss cellular and molecular pathways that are affected and consider these in regard to skeletal muscle involvement in other conditions, such as acute respiratory distress syndrome, critical illness myopathy, and post-viral fatigue syndrome. Patients with severe Covid-19 and PASC suffer from skeletal muscle weakness and exercise intolerance. Histological sections present muscle fibre atrophy, metabolic alterations, and immune cell infiltration. Contributing factors to weakness and fatigue in patients with severe Covid-19 include systemic inflammation, disuse, hypoxaemia, and malnutrition. These factors also contribute to post-intensive care unit (ICU) syndrome and ICU-acquired weakness and likely explain a substantial part of Covid-19-acquired weakness. The skeletal muscle weakness and exercise intolerance associated with PASC are more obscure. Direct severe acute respiratory syndrome coronavirus (SARS-CoV)-2 viral infiltration into skeletal muscle or an aberrant immune system likely contribute. Similarities between skeletal muscle alterations in PASC and chronic fatigue syndrome deserve further study. Both SARS-CoV-2-specific factors and generic consequences of acute disease likely underlie the observed skeletal muscle alterations in both acute Covid-19 and PASC.
BackgroundPhysical exercise is an intervention that might protect against doxorubicin‐induced cardiotoxicity. In this meta‐analysis and systematic review, we aimed to estimate the effect of exercise on doxorubicin‐induced cardiotoxicity and to evaluate mechanisms underlying exercise‐mediated cardioprotection using (pre)clinical evidence.Methods and ResultsWe conducted a systematic search in PubMed, Embase, and Cochrane Central Register of Controlled Trials (CENTRAL) databases. Cochrane's and Systematic Review Centre for Laboratory Animal Experimentation (SYRCLE) risk‐of‐bias tools were used to assess the validity of human and animal studies, respectively. Cardiotoxicity outcomes reported by ≥3 studies were pooled and structured around the type of exercise intervention. Forty articles were included, of which 3 were clinical studies. Overall, in humans (sample sizes ranging from 24 to 61), results were indicative of exercise‐mediated cardioprotection, yet they were not sufficient to establish whether physical exercise protects against doxorubicin‐induced cardiotoxicity. In animal studies (n=37), a pooled analysis demonstrated that forced exercise interventions significantly mitigated in vivo and ex vivo doxorubicin‐induced cardiotoxicity compared with nonexercised controls. Similar yet slightly smaller effects were found for voluntary exercise interventions. We identified oxidative stress and related pathways, and less doxorubicin accumulation as mechanisms underlying exercise‐induced cardioprotection, of which the latter could act as an overarching mechanism.ConclusionsAnimal studies indicate that various exercise interventions can protect against doxorubicin‐induced cardiotoxicity in rodents. Less doxorubicin accumulation in cardiac tissue could be a key underlying mechanism. Given the preclinical evidence and limited availability of clinical data, larger and methodologically rigorous clinical studies are needed to clarify the role of physical exercise in preventing cardiotoxicity in patients with cancer.RegistrationURL: https://www.crd.york.ac.uk/prospero; Unique identifier: CRD42019118218.
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