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Contains fulltext : 283453.pdf (Publisher’s version ) (Closed access) Cardiovascular (CV) disease (CVD) remains the leading cause of major morbidity and CVD- and all-cause mortality in most of the world. It is now clear that regular physical activity (PA) and exercise training (ET) induces a wide range of direct and indirect physiologic adaptations and pleiotropic benefits for human general and CV health. Generally, higher levels of PA, ET, and cardiorespiratory fitness (CRF) are correlated with reduced risk of CVD, including myocardial infarction, CVD-related death, and all-cause mortality. Although exact details regarding the ideal doses of ET, including resistance and, especially, aerobic ET, as well as the potential adverse effects of extreme levels of ET, continue to be investigated, there is no question that most of the world's population have insufficient levels of PA/ET, and many also have lower than ideal levels of CRF. Therefore, assessment and promotion of PA, ET, and efforts to improve levels of CRF should be integrated into all health professionals' practices worldwide. In this state-of-the-art review, we discuss the exercise effects on many areas related to CVD, from basic aspects to clinical practice.

Coronavirus disease 2019 (COVID-19), caused by severe acute respiratory syndrome coronavirus 2, is being defined as the worst pandemic disease of modern times. Several professional health organizations have published position papers stating that there is no evidence to change the use of angiotensin-converting enzyme inhibitors (ACEIs) or angiotensin receptor blockers (ARBs) in the management of elevated blood pressure in the context of avoiding or treating COVID-19 infection. In this article, we review the evidence on the relationship between the renin-angiotensin-aldosterone system and COVID-19 infection. In agreement with current guidelines, patients with hypertension should continue taking antihypertensive medications as prescribed without interruption. Because ACEIs and ARBs are also used to retard the progression of chronic kidney disease, we suggest that these recommendations also apply to the use of these agents in chronic kidney disease. No differences generally exist between ARBs and ACEIs in terms of efficacy in decreasing blood pressure and improving other outcomes, such as all-cause mortality, cardiovascular mortality, myocardial infarction, heart failure, stroke, and end-stage renal disease. The ACEIs are associated with cough secondary to accumulation of bradykinin and angioedema, and withdrawal rates due to adverse events are lower with ARBs. Given their equal efficacy but fewer adverse events, ARBs could potentially be a more favorable treatment option in patients with COVID-19 at higher risk for severe forms of disease.

UEM1901 5.864 JCR (2019) Q1, 18/138 Cardiac & Cardiovascular Systems 1.459 SJR (2019) Q1, 58/362 Cardiology and Cardiovascular Medicine; Q2, 36/104 Epidemiology No data IDR 2019 UEM

Angiotensin-converting enzyme inhibitors (ACEi), angiotensin II receptor blockers (ARBs), and HMG-CoA reductase inhibitors ("statins") have been hypothesized to affect COVID-19 severity. However, up to now, no studies investigating this association have been conducted in the most vulnerable and affected population groups (ie, older adults residing in nursing homes). The objective of this study was to explore the association of ACEi/ARB and/or statins with clinical manifestations in COVID-19-infected older adults residing in nursing homes.We undertook a retrospective multicenter cohort study to analyze the association between ACEi/ARB and/or statin use with clinical outcome of COVID-19. The outcomes were (1) serious COVID-19 defined as long-stay hospital admission or death within 14 days of disease onset, and (2) asymptomatic (ie, no disease symptoms in the whole study period while still being diagnosed by polymerase chain reaction).A total of 154 COVID-19-positive subjects were identified, residing in 1 of 2 Belgian nursing homes that experienced similar COVID-19 outbreaks.Logistic regression models were applied with age, sex, functional status, diabetes, and hypertension as covariates.We found a statistically significant association between statin intake and the absence of symptoms during COVID-19 (odds ratio [OR] 2.91; confidence interval [CI] 1.27-6.71), which remained statistically significant after adjusting for covariates (OR 2.65; CI 1.13-6.68). Although the effects of statin intake on serious clinical outcome were in the same beneficial direction, these were not statistically significant (OR 0.75; CI 0.24-1.87). There was also no statistically significant association between ACEi/ARB and asymptomatic status (OR 2.72; CI 0.59-25.1) or serious clinical outcome (OR 0.48; CI 0.10-1.97).Our data indicate that statin intake in older, frail adults could be associated with a considerable beneficial effect on COVID-19 clinical symptoms. The role of statins and renin-angiotensin system drugs needs to be further explored in larger observational studies as well as randomized clinical trials.

Although statins remain the cornerstone of lipid-lowering therapy for reducing the burden of atherosclerotic vascular disease, their administration has been associated with muscle-related adverse effects, including myalgia and rhabdomyolysis. Such adverse events are probably due to reduced antioxidant defenses associated with fewer intermediate metabolites in the cholesterol synthesis pathway. We hypothesize that the concomitant inhibition of xanthine oxidase via coadministration of allopurinol with statins could diminish reactive oxygen species (ROS)-related muscle damage, which would have in turn have positive effects on both the incidence of muscle-related adverse events and cardiovascular outcomes. Accordingly, inhibition of xanthine oxidase has been previously shown to be effective for reducing biomarkers of muscle damage following exercise in professional athletes. Because of the widespread statin utilization and increasing trends in their therapeutic use in atherosclerotic vascular diseases, the proposed strategy could have important clinical implications for reducing statin-induced myalgia and rhabdomyolysis. (C) 2014 Elsevier Ireland Ltd. All rights reserved.

• Moderate-intensity exercise improved peak oxygen consumption in hypertrophic cardiomyopathy.

It was initially assumed that heart rate and arterial blood pressure were modulated by normal respiration and muscle contraction. The arterial baroreflex, an inverse relationship between blood pressure and heart rate, was later reported. Nonetheless, it was then assumed that those responses involved vagal modulation. We summarize available evidence on the modulation of heart rate by acute or chronic aerobic exercise as well as its potential implications on blood pressure (BP) control. Numerous studies have tried to clarify whether aerobic exercise modifies neurally-mediated vasoconstriction, but they report contradictory results. In view of these incongruities, the aim of this narrative review is to summarize available evidence on the modulation of heart rate by acute or chronic aerobic exercise as well as its potential implications on BP control. We mainly focus on the effects of aerobic exercise in both heart rate and blood pressure. Heart rate and heart rate variability have been indistinctly considered similar metrics, but they have completely different meanings when properly used. Both are risk markers in cardiac disease, whereas heart rate variability is also an index of sympathovagal modulation of heart rate. On the other hand, heart rate recovery has been also used as an index for mirroring both cardiovascular fitness and autonomic function, and can be used as a measure of vagal reactivation. Importantly, it is now wellknown that a reduced rate of heart rate recovery represents a powerful predictor of overall mortality. In this review, due to its complexity, we have included studies in which any of these three parameters have been analyzed.

Aims: Here we report that chromatin, the complex and dynamic eukaryotic DNA packaging structure, is able to sense cellular redox changes. Histone H3, the only nucleosomal protein that possesses cysteine(s), can be modified by glutathione (GSH). Results: Using Biotin labeled glutathione ethyl ester (BioGEE) treatment of nucleosomes in vitro, we show that GSH, the most abundant antioxidant in mammals, binds to histone H3. BioGEE treatment of NIH3T3 cells indicates that glutathionylation of H3 is maximal in fast proliferating cells, correlating well with enhanced levels of H3 glutathionylation in different tumor cell lines. Furthermore, glutathionylation of H3 in vivo decreases in livers from aged SAMP8 and C57BL/6J mice. We demonstrate biochemically and by mass spectrometry that histone variants H3.2/H3.3 are glutathionylated on their cysteine residue 110. Furthermore, circular dichroism, thermal denaturation of reconstituted nucleosomes, and molecular modeling indicate that glutathionylation of histone H3 produces structural changes affecting nucleosomal stability. Innovation: We characterize the implications of histone H3 glutathionylation in cell physiology and the modulation of core histone proteins structure affected by this modification. Conclusion: Histone H3 senses cellular redox changes through glutathionylation of Cys, which increases during cell proliferation and decreases during aging. Glutathionylation of histone H3 affects nucleosome stability structure leading to a more open chromatin structure. Antioxid. Redox Signal. 19, 1305–1320.

We have recently described a new syndrome: strenuous endurance exercise-related atrial fibrillation (AF) under the acronym of ‘paroxysmal AF in young and middle-aged athletes’ (‘PAFIYAMA’). Provided that other risk factors for AF and underlying conditions have been excluded (1), the diagnostic criteria for this syndrome entail a number of conditions, classified as major and minor. An enhanced risk of AF has been clearly documented in endurance athletes (top-class, elite and recreational) (2-5), and such risk typically ranges between 1.2- to 15-fold compared to the general, sedentary population (the better cardiovascular fitness, the higher incidence of AF) (6-11). Anecdotally, the last author of this manuscript (F Sanchis-Gomar), a physician himself, was a competitive endurance cyclist for 10 years and a paradigm of PAFIYAMA syndrome. Briefly, he has suffered from left atrial enlargement and a first episode of paroxysmal AF early in life, at the age of 26 years. After 5 years of recurrent episodes, pulmonary vein isolation by trans-venous cryoablation seemed to be the only successful treatment. Although he has suffered no more AF episodes since then, high-intensity exercise would be no longer advisable.

Atrial fibrillation (AF) is the most common heart arrhythmia, the risk of which typically increases with age. This condition is commonly associated with major cardiovascular diseases and structural heart damage, while it is rarely observed in healthy young people. However, increasing evidence indicates that paroxysmal AF can also onset in young or middle-aged and otherwise healthy endurance athletes (e.g., cyclists, runners and cross-country skiers). Here we review the topic of AF associated with strenuous endurance exercise (SEE), for example cycling, running and cross-country skiing, especially at a competitive level, and we propose the definition of a new syndrome based on the accumulating data in the literature: SEE-related AF under the acronym of ‘PAFIYAMA’ (‘paroxysmal AF in young and middle-aged athletes’). Special emphasis is given to the proper differentiation of PAFIYAMA from ‘classical AF’ regarding pathophysiology, diagnosis and medical management. Sin financiación 4.034 JCR (2017) Q2, 41/128 Cardiac and Cardiovascular Systems 1.200 SJR (2017) Q1, 78/369 Cardiology and Cardiovascular Medicine No data IDR 2017 UEM

Myocardial infarction (MI), a major cause of death worldwide, further impairs the inherently low regenerative capacity of cardiomyocytes, with barely 1% of cardiomyocytes per year undergoing cell division [1]. While this low division rate increases in response to MI, it does not compensate for the loss of cardiomyocytes; thus, the area of scarred (fibrotic) tissue expands and such unfavorable tissue remodeling further deteriorates cardiac contractile capacity, ultimately leading to heart failure (HF).

The aim of this review is to summarize the incidence, prevalence, trend in mortality, and general prognosis of coronary heart disease (CHD) and a related condition, acute coronary syndrome (ACS). Although CHD mortality has gradually declined over the last decades in western countries, this condition still causes about one-third of all deaths in people older than 35 years. This evidence, along with the fact that mortality from CHD is expected to continue increasing in developing countries, illustrates the need for implementing effective primary prevention approaches worldwide and identifying risk groups and areas for possible improvement. FIS PI12/00914 Fondos FEDER No data JCR 2016 0.889 SJR (2016) Q1, 698/2886 Medicine (miscellaneous) No data IDR 2016 UEM

Atrial fibrillation (AF) is an important cardiovascular disease in theelderly [1]. Noticeably, it has been increasingly demonstrated thatserum uric acid (UA) is associated with AF [2–9]. In a recent meta-analysis performed by Tamariz and coworkers, the authors concludedthat high levels of UA and AF are clearly associated [10]. Interestingly,serum UA has been linked to AF in obstructive sleep apnea patients[11], whereas it has been also associated with thromboembolic risk inpatients with nonvalvular AF [12].The treatment of gout, a metabolic disorder caused by chronic hyper-uricemia, is based on administration of colchicine, xanthine oxidase (XO)competitive inhibitors such as allopurinol, and most recently, fubuxostat[13].IntheColchicineforPreventionofthePostpericardiotomySyndromeand Postoperative Atrial Fibrillation (COPPS) randomized clinical trial,Imazio et al. reported that colchicine prevents both postpericardiotomysyndromeandpostoperativeAFwhencolchicinewasgiven48to72hbe-fore cardiac surgery [14]. Singhal et al. also reported that colchicine mayreverse atrial remodeling and suppress AF in failing heart [15]. Interest-ingly,allopurinolhasrecentlybeenassociatedwithareducedriskofmyo-cardialinfarction(MI),whilenodecreasedriskofMIhasbeenfoundwithcolchicine administration [16].Although increasing evidence suggests that purine metabolism isimplicated in the pathophysiology of AF, mechanistic explanationshavenotbeendescribedsofar.Theexactmechanismofactionofcolchi-cine is not completely understood, even for the treatment of gout,whereas the high rate of adverse effects is regarded as an importanthurdle foritsprescription.Onthe other hand, higherUAreflectsupreg-ulatedXOactivity,animportantsourceofreactiveoxygenspecies(ROS)which may trigger cardiac tissue injury. It is well-known that allopuri-nol improves endothelial function, reduces blood pressure in essentialhypertensionandalsoexertssignificantanti-ischemiceffectsinpatientswith stable angina. These effects are probably attributable to decreasesROS levels. Finally, there are no data on the cardiovascular effects ofthe newly released non-purine XO inhibitor febuxostat.It is likely that the metabolism of purines is involved in the patho-physiologyofAF,andtherefore,anti-gouttherapyrepresentsapotentialstrategytopreventthistypeofarrhythmia.Atthispointintime,howev-er, the lack of knowledge about precise molecular mechanisms bywhich it operates greatly limits its applicability in the cardiologyarena. Further studies that clarify these mechanisms are needed toallow further progresses in this field.Conflicts of interestsThe authors declare that no conflict of interest exists.References

The term sarcopenia was originally created to refer age-related loss of muscle mass with consequent loss of strength (Morley et al., 2001). There are now four international definitions of sarcopenia (Cruz-Jentoft et al., 2010; Muscaritoli et al., 2010; Morley et al., 2011). In essence they all agree, requiring a measure of walking capability [either low gait speed or a limited endurance (distance) in a 6-min walk], together with an appendicular lean mass of

The discovery of irisin as a novel and promising peptidic hormone for the treatment of obesity and diabetes has recently been reported. As a result, great hopes have been raised based on this finding, hypothesizing that irisin might provide additional benefits, not only for obesity and diabetes, but also for a wide range of pathological conditions requiring therapeutical and clinical attention. However, controversial results and conclusions on circulating irisin concentrations and correlations with other variables, including its role in metabolism, have recently been reported. Although laboratory assessment of irisin by ELISA is easily available and may provide interesting information for therapeutics and clinical practice, the heterogeneous and often discrepant results published so far, raise serious concerns about its measurement, indicating that it may still not be ready for use or whether irisin really exists. We highlight here some aspects on these discrepancies and contradictions, and put forward their implications.

This is an open-access article distributed under the terms of the Creative Commons Attribution License.-- et al., The predominant X-linked form of Dyskeratosis congenita results from mutations in DKC1, which encodes dyskerin, a protein required for ribosomal RNA modification that is also a component of the telomerase complex. We have previously found that expression of an internal fragment of dyskerin (GSE24.2) rescues telomerase activity in X-linked dyskeratosis congenita (X-DC) patient cells. Here we have found that an increased basal and induced DNA damage response occurred in X-DC cells in comparison with normal cells. DNA damage that is also localized in telomeres results in increased heterochromatin formation and senescence. Expression of a cDNA coding for GSE24.2 rescues both global and telomeric DNA damage. Furthermore, transfection of bacterial purified or a chemically synthesized GSE24.2 peptide is able to rescue basal DNA damage in X-DC cells. We have also observed an increase in oxidative stress in X-DC cells and expression of GSE24.2 was able to diminish it. Altogether our data indicated that supplying GSE24.2, either from a cDNA vector or as a peptide reduces the pathogenic effects of Dkc1 mutations and suggests a novel therapeutic approach., This work was supported by grants: PI11-0949 and PI12/02263 FIS, SAF2008-01338 from the Ministerio de Ciencia e Innovación. Grants, PROMETEO2010/074 from Generalitat Valenciana and Fundación Salud 2000 to FVP. CMG, JLGG and CPQ are supported by CIBER de Enfermedades Raras.

The discovery of irisin as a novel and promising peptidic hormone has raised hopes regarding the hypothesis that irisin may provide additional benefits, not only for obesity and diabetes, but also for a wide range of pathological conditions since this hormone may prove to be therapeutically and clinically beneficial. In addition, a new hormone, betatrophin, has recently been identified by Yi and coworkers. Both hormones are connected by a new pathway clearly involved in insulin resistance. We hypothesize here how these hormones may be linked and their possible implications in both aged-reduced restricted regenerative capacity and dedifferentiated β cells of diabetic patients.

The erythropoietin receptor (EpoR) was discovered and described in red blood cells (RBCs), stimulating its proliferation and survival. The target in humans for EpoR agonists drugs appears clear—to treat anemia. However, there is evidence of the pleitropic actions of erythropoietin (Epo). For that reason, rhEpo therapy was suggested as a reliable approach for treating a broad range of pathologies, including heart and cardiovascular diseases, neurodegenerative disorders (Parkinson’s and Alzheimer’s disease), spinal cord injury, stroke, diabetic retinopathy and rare diseases (Friedreich ataxia). Unfortunately, the side effects of rhEpo are also evident. A new generation of nonhematopoietic EpoR agonists drugs (asialoEpo, Cepo and ARA 290) have been investigated and further developed. These EpoR agonists, without the erythropoietic activity of Epo, while preserving its tissue-protective properties, will provide better outcomes in ongoing clinical trials. Nonhematopoietic EpoR agonists represent safer and more effective surrogates for the treatment of several diseases such as brain and peripheral nerve injury, diabetic complications, renal ischemia, rare diseases, myocardial infarction, chronic heart disease and others.

Physical exercise positively influences epigenetic mechanisms and improves health. Several issues remain unclear concerning the links between physical exercise and epigenetics. There is growing concern about the negative influence of excessive and persistent physical exercise on health. How an individual physically adapts to the prevailing environmental conditions might influence epigenetic mechanisms and modulate gene expression. In this article, we put forward the idea that physical exercise, especially long-term repetitive strenuous exercise, positively affects health, reduces the aging process, and decreases the incidence of cancer through induced stress and epigenetic mechanisms. We propose herein that stress may stimulate genetic adaptations through epigenetics that, in turn, modulate the link between the environment, human lifestyle factors, and genes.

Blood doping improves physical performance in sport. This is the reason why the antidop- ing authorities subject athletes to blood tests. Plasma volume expanders are prohibited agents used to reduce an artifi cial increase in hemato- logical values using diff erent illegal practices. The aim of our study was to test whether desmo- pressin (DDAVP)-induced hemodilution would alter the concentration of hematological param- eters used to detect blood doping in sports. This was an intra-subject crossover study. Venous blood samples were obtained from eight physi- cally active males on two occasions. On the fi rst o ccasion the subjects ingested 1.5 L of mineral water and 4.3 μ g / kg of DDAVP. On the second occasion the subjects ingested 1.5 L of mineral water. The samples were analyzed for hemato- crit, hemoglobin, reticulocytes, OFF Hr-Score, glucose, albumin, creatinine and total proteins. After treatment with DDAVP we found a signifi - cant decrease in the hematocrit, hemoglobin and in the OFF Hr-Score values. We also found a sig- nifi cant decrease in glucose, albumin, creatinine and total proteins concentration; however, in this case, all the values were signifi cantly below the physiological levels. Treatment with DDAVP has a very eff ective hemodilution eff ect. We con- sider that this substance should be included in the WADA ' s prohibited list.

We have recently purposed the definition of a new syndrome: strenuous endurance exercise-related atrial fibrillation (AF) under the acronym of ‘PAFIYAMA’ (‘paroxysmal AF in young and middle-aged athletes’). This syndrome may be the consequence, at least in part, of atrial fibrotic remodeling [increased left atrial (LA) size]. Although the management of this syndrome has deeply discussed, prevention is still in embryo. A number of circulation biomarkers, including proteins, cytokines and microRNA (miRNA) have been associated with cardiac adaptations to strenuous training and fibrosis. In particular, due to their involvement in a wide array of cardiac pathways under both physiological and pathological conditions, miRNA are deeply involved in cardiac biology, so that

Skeletal muscle can express and release substances such as cytokines or other peptides capable of modulating metabolic processes. These cytokines, named ‘myokines', function as hormones either locally within the muscle or by targeting distant organs. A novel peptidic myokine named ‘irisin' has been recently identified. It has been noted that circulating irisin levels are lower in type 2 diabetes (T2D) compared with nondiabetic controls as well as in patients with chronic kidney disease. In addition, a negative correlation between the hemoglobin A1c (HbA1c) and circulating levels of irisin has been also observed. Thus, the blood concentration of irisin may reflect the metabolic status of patients suffering from metabolism disorders. In addition to glycemia or HbA1c, ‘irisinemia' may also become a new promising concept employed to monitor metabolic disorders such as T2D or obesity, representing a novel and useful tool in the management of metabolic diseases in the near future.