Mitophagy modulation for the treatment of cardiovascular diseases.

BACKGROUND: Defects of mitophagy, the selective form of autophagy for mitochondria, are commonly observed in several cardiovascular diseases and represent the main cause of mitochondrial dysfunction. For this reason, mitophagy has emerged as a novel and potential therapeutic target. METHODS: In this review, we discuss current evidence about the biological significance of mitophagy in relevant preclinical models of cardiac and vascular diseases, such as heart failure, ischemia/reperfusion injury, metabolic cardiomyopathy and atherosclerosis. RESULTS: Multiple studies have shown that cardiac and vascular mitophagy is an adaptive mechanism in response to stress, contributing to cardiovascular homeostasis. Mitophagy defects lead to cell death, ultimately impairing cardiac and vascular function, whereas restoration of mitophagy by specific compounds delays disease progression. CONCLUSIONS: Despite previous efforts, the molecular mechanisms underlying mitophagy activation in response to stress are not fully characterized. A comprehensive understanding of different forms of mitophagy active in the cardiovascular system is extremely important for the development of new drugs targeting this process. Human studies evaluating mitophagy abnormalities in patients at high cardiovascular risk also represent a future challenge.

Molecular mechanisms underlying the beneficial effects of exercise and dietary interventions in the prevention of cardiometabolic diseases.

Cardiometabolic diseases still represent a major cause of mortality worldwide. In addition to pharmacological approaches, lifestyle interventions can also be adopted for the prevention of these morbid conditions. Lifestyle changes include exercise and dietary restriction protocols, such as calorie restriction and intermittent fasting, which were shown to delay cardiovascular ageing and elicit health-promoting effects in preclinical models of cardiometabolic diseases. Beneficial effects are mediated by the restoration of multiple molecular mechanisms in heart and vessels that are compromised by metabolic stress. Exercise and dietary restriction rescue mitochondrial dysfunction, oxidative stress and inflammation. They also improve autophagy. The result of these effects is a marked improvement of vascular and heart function. In this review, we provide a comprehensive overview of the molecular mechanisms involved in the beneficial effects of exercise and dietary restriction in models of diabetes and obesity. We also discuss clinical studies and gap in animal-to-human translation.

Long COVID and the cardiovascular system-elucidating causes and cellular mechanisms in order to develop targeted diagnostic and therapeutic strategies: a joint Scientific Statement of the ESC Working Groups on Cellular Biology of the Heart and Myocardial and Pericardial Diseases.

Long COVID has become a world-wide, non-communicable epidemic, caused by long-lasting multiorgan symptoms that endure for weeks or months after SARS-CoV-2 infection has already subsided. This scientific document aims to provide insight into the possible causes and therapeutic options available for the cardiovascular manifestations of long COVID. In addition to chronic fatigue, which is a common symptom of long COVID, patients may present with chest pain, ECG abnormalities, postural orthostatic tachycardia, or newly developed supraventricular or ventricular arrhythmias. Imaging of the heart and vessels has provided evidence of chronic, post-infectious perimyocarditis with consequent left or right ventricular failure, arterial wall inflammation, or microthrombosis in certain patient populations. Better understanding of the underlying cellular and molecular mechanisms of long COVID will aid in the development of effective treatment strategies for its cardiovascular manifestations. A number of mechanisms have been proposed, including those involving direct effects on the myocardium, microthrombotic damage to vessels or endothelium, or persistent inflammation. Unfortunately, existing circulating biomarkers, coagulation, and inflammatory markers, are not highly predictive for either the presence or outcome of long COVID when measured 3 months after SARS-CoV-2 infection. Further studies are needed to understand underlying mechanisms, identify specific biomarkers, and guide future preventive strategies or treatments to address long COVID and its cardiovascular sequelae.

Mitochondrial a Kinase Anchor Proteins in Cardiovascular Health and Disease: A Review Article on Behalf of the Working Group on Cellular and Molecular Biology of the Heart of the Italian Society of Cardiology.

Second messenger cyclic adenosine monophosphate (cAMP) has been found to regulate multiple mitochondrial functions, including respiration, dynamics, reactive oxygen species production, cell survival and death through the activation of cAMP-dependent protein kinase A (PKA) and other effectors. Several members of the large family of A kinase anchor proteins (AKAPs) have been previously shown to locally amplify cAMP/PKA signaling to mitochondria, promoting the assembly of signalosomes, regulating multiple cardiac functions under both physiological and pathological conditions. In this review, we will discuss roles and regulation of major mitochondria-targeted AKAPs, along with opportunities and challenges to modulate their functions for translational purposes in the cardiovascular system.

Animal models and animal-free innovations for cardiovascular research: current status and routes to be explored. Consensus document of the ESC Working Group on Myocardial Function and the ESC Working Group on Cellular Biology of the Heart.

Cardiovascular diseases represent a major cause of morbidity and mortality, necessitating research to improve diagnostics, and to discover and test novel preventive and curative therapies, all of which warrant experimental models that recapitulate human disease. The translation of basic science results to clinical practice is a challenging task, in particular for complex conditions such as cardiovascular diseases, which often result from multiple risk factors and comorbidities. This difficulty might lead some individuals to question the value of animal research, citing the translational 'valley of death', which largely reflects the fact that studies in rodents are difficult to translate to humans. This is also influenced by the fact that new, human-derived in vitro models can recapitulate aspects of disease processes. However, it would be a mistake to think that animal models do not represent a vital step in the translational pathway as they do provide important pathophysiological insights into disease mechanisms particularly on an organ and systemic level. While stem cell-derived human models have the potential to become key in testing toxicity and effectiveness of new drugs, we need to be realistic, and carefully validate all new human-like disease models. In this position paper, we highlight recent advances in trying to reduce the number of animals for cardiovascular research ranging from stem cell-derived models to in situ modelling of heart properties, bioinformatic models based on large datasets, and state-of-the-art animal models, which show clinically relevant characteristics observed in patients with a cardiovascular disease. We aim to provide a guide to help researchers in their experimental design to translate bench findings to clinical routine taking the replacement, reduction, and refinement (3R) as a guiding concept.

Circadian rhythms in ischaemic heart disease: key aspects for preclinical and translational research: position paper of the ESC working group on cellular biology of the heart.

Circadian rhythms are internal regulatory processes controlled by molecular clocks present in essentially every mammalian organ that temporally regulate major physiological functions. In the cardiovascular system, the circadian clock governs heart rate, blood pressure, cardiac metabolism, contractility, and coagulation. Recent experimental and clinical studies highlight the possible importance of circadian rhythms in the pathophysiology, outcome, or treatment success of cardiovascular disease, including ischaemic heart disease. Disturbances in circadian rhythms are associated with increased cardiovascular risk and worsen outcome. Therefore, it is important to consider circadian rhythms as a key research parameter to better understand cardiac physiology/pathology, and to improve the chances of translation and efficacy of cardiac therapies, including those for ischaemic heart disease. The aim of this Position Paper by the European Society of Cardiology Working Group Cellular Biology of the Heart is to highlight key aspects of circadian rhythms to consider for improvement of preclinical and translational studies related to ischaemic heart disease and cardioprotection. Applying these considerations to future studies may increase the potential for better translation of new treatments into successful clinical outcomes.

Aortic thrombosis: the forgotten source of ischemic stroke. A case report and systematic review of the literature.

Ischemic stroke represents one of the most important health problems in industrialized countries, both for epidemiological and socio-economic impact. The presence of thrombi in the aorta is rare and its treatment has not been uniquely defined. Here we report the case of an 82-years-old man with aortic thrombosis and acute ischemic stroke.

COVID-19-related cardiac complications from clinical evidences to basic mechanisms: opinion paper of the ESC Working Group on Cellular Biology of the Heart.

The pandemic of coronavirus disease (COVID)-19 is a global threat, causing high mortality, especially in the elderly. The main symptoms and the primary cause of death are related to interstitial pneumonia. Viral entry also into myocardial cells mainly via the angiotensin converting enzyme type 2 (ACE2) receptor and excessive production of pro-inflammatory cytokines, however, also make the heart susceptible to injury. In addition to the immediate damage caused by the acute inflammatory response, the heart may also suffer from long-term consequences of COVID-19, potentially causing a post-pandemic increase in cardiac complications. Although the main cause of cardiac damage in COVID-19 remains coagulopathy with micro- (and to a lesser extent macro-) vascular occlusion, open questions remain about other possible modalities of cardiac dysfunction, such as direct infection of myocardial cells, effects of cytokines storm, and mechanisms related to enhanced coagulopathy. In this opinion paper, we focus on these lesser appreciated possibilities and propose experimental approaches that could provide a more comprehensive understanding of the cellular and molecular bases of cardiac injury in COVID-19 patients. We first discuss approaches to characterize cardiac damage caused by possible direct viral infection of cardiac cells, followed by formulating hypotheses on how to reproduce and investigate the hyperinflammatory and pro-thrombotic conditions observed in the heart of COVID-19 patients using experimental in vitro systems. Finally, we elaborate on strategies to discover novel pathology biomarkers using omics platforms.

Prognostically relevant periprocedural myocardial injury and infarction associated with percutaneous coronary interventions: a Consensus Document of the ESC Working Group on Cellular Biology of the Heart and European Association of Percutaneous Cardiovascular Interventions (EAPCI).

A substantial number of chronic coronary syndrome (CCS) patients undergoing percutaneous coronary intervention (PCI) experience periprocedural myocardial injury or infarction. Accurate diagnosis of these PCI-related complications is required to guide further management given that their occurrence may be associated with increased risk of major adverse cardiac events (MACE). Due to lack of scientific data, the cut-off thresholds of post-PCI cardiac troponin (cTn) elevation used for defining periprocedural myocardial injury and infarction, have been selected based on expert consensus opinions, and their prognostic relevance remains unclear. In this Consensus Document from the ESC Working Group on Cellular Biology of the Heart and European Association of Percutaneous Cardiovascular Interventions (EAPCI), we recommend, whenever possible, the measurement of baseline (pre-PCI) cTn and post-PCI cTn values in all CCS patients undergoing PCI. We confirm the prognostic relevance of the post-PCI cTn elevation >5× 99th percentile URL threshold used to define type 4a myocardial infarction (MI). In the absence of periprocedural angiographic flow-limiting complications or electrocardiogram (ECG) and imaging evidence of new myocardial ischaemia, we propose the same post-PCI cTn cut-off threshold (>5× 99th percentile URL) be used to define prognostically relevant 'major' periprocedural myocardial injury. As both type 4a MI and major periprocedural myocardial injury are strong independent predictors of all-cause mortality at 1 year post-PCI, they may be used as quality metrics and surrogate endpoints for clinical trials. Further research is needed to evaluate treatment strategies for reducing the risk of major periprocedural myocardial injury, type 4a MI, and MACE in CCS patients undergoing PCI.

Transverse aortic constriction induces gut barrier alterations, microbiota remodeling and systemic inflammation.

Accumulating evidence suggests that modifications of gut function and microbiota composition might play a pivotal role in the pathophysiology of several cardiovascular diseases, including heart failure (HF). In this study we systematically analysed gut microbiota composition, intestinal barrier integrity, intestinal and serum cytokines and serum endotoxin levels in C57BL/6 mice undergoing pressure overload by transverse aortic constriction (TAC) for 1 and 4 weeks. Compared to sham-operated animals, TAC induced prompt and strong weakening of intestinal barrier integrity, long-lasting decrease of colon anti-inflammatory cytokine levels, significant increases of serum levels of bacterial lipopolysaccharide and proinflammatory cytokines. TAC also exerted effects on microbiota composition, inducing significant differences in bacterial genera inside Actinobacteria, Firmicutes, Proteobacteria and TM7 phyla as shown by 16S rDNA sequencing of fecal samples from TAC or sham mice. These results suggest that gut modifications represent an important element to be considered in the development and progression of cardiac dysfunction in response to TAC and support this animal model as a valuable tool to establish the role and mechanisms of gut-heart crosstalk in HF. Evidence arising in this field might identify new treatment options targeting gut integrity and microbiota components to face adverse cardiac events.

Improving translational research in sex-specific effects of comorbidities and risk factors in ischaemic heart disease and cardioprotection: position paper and recommendations of the ESC Working Group on Cellular Biology of the Heart.

Ischaemic heart disease (IHD) is a complex disorder and a leading cause of death and morbidity in both men and women. Sex, however, affects several aspects of IHD, including pathophysiology, incidence, clinical presentation, diagnosis as well as treatment and outcome. Several diseases or risk factors frequently associated with IHD can modify cellular signalling cascades, thus affecting ischaemia/reperfusion injury as well as responses to cardioprotective interventions. Importantly, the prevalence and impact of risk factors and several comorbidities differ between males and females, and their effects on IHD development and prognosis might differ according to sex. The cellular and molecular mechanisms underlying these differences are still poorly understood, and their identification might have important translational implications in the prediction or prevention of risk of IHD in men and women. Despite this, most experimental studies on IHD are still undertaken in animal models in the absence of risk factors and comorbidities, and assessment of potential sex-specific differences are largely missing. This ESC WG Position Paper will discuss: (i) the importance of sex as a biological variable in cardiovascular research, (ii) major biological mechanisms underlying sex-related differences relevant to IHD risk factors and comorbidities, (iii) prospects and pitfalls of preclinical models to investigate these associations, and finally (iv) will provide recommendations to guide future research. Although gender differences also affect IHD risk in the clinical setting, they will not be discussed in detail here.

The role of mitochondrial dynamics in cardiovascular diseases.

The process of mitochondrial dynamics is emerging as a core player in cardiovascular homeostasis. This process refers to the co-ordinated cycles of biogenesis, fusion, fission and degradation to which mitochondria constantly undergo to maintain their integrity, distribution and size. These mechanisms represent an early response to mitochondrial stress, confining organelle portions that are irreversibly damaged and preserving mitochondrial function. Accumulating evidence demonstrates that impairment in mitochondrial dynamics leads to myocardial damage and cardiac disease progression in a variety of disease models, including pressure overload, ischaemia/reperfusion and metabolic disturbance. These findings suggest that modulation of mitochondrial dynamics may be considered as a valid therapeutic strategy in cardiovascular diseases. In this review, we discuss the current evidence about the role of mitochondrial dynamics in cardiac pathophysiology, with a particular focus on the mechanisms underlying the development of cardiac hypertrophy and heart failure, metabolic and genetic cardiomyopathies, ischaemia/reperfusion injury, atherosclerosis and ischaemic stroke. LINKED ARTICLES: This article is part of a themed issue on Cellular metabolism and diseases. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v178.10/issuetoc.

Contribution of Primary Biological Aerosol Particles to airborne particulate matter in indoor and outdoor environments.

The atmospheric concentration of bioparticles was determined in some outdoor and indoor sites by using a commercial low-volume sampler and a detection method based on particle collection on polycarbonate filters, propidium iodide staining, observation by fluorescence microscopy and image analysis. Outdoor sampling was continuously carried out from May 2015 to October 2016 by cumulating monthly samples over individual filters. PBAPs contribution to PM10 concentration was in the range 0.7-13%. Seasonal differences were found in PBAPs concentration, shape and mass distribution. Higher concentrations were recorded during the warm period, when the bioparticles were more numerous, larger and more elongated. Simultaneous indoor and outdoor daily samples were collected during the spring of 2014 and 2017 in domestic environments. In indoor sites PBAPs were much higher in concentration than outdoors and showed a different visual appearance, with very wide polyhedral-shaped particles identifiable as skin flakes. Indoor/outdoor ratio (I/O) of PBAPs was in the range 6-16. Indoors, PBAPs contributed 21-77% to organic matter and 16-68% to PM10. When sampling into a sealed room, I/O was only 0.01 for individual bioparticles heavier than100 ng, while it was in the range 0.24-0.43 for PBAPs below 20 ng. This suggests that the infiltration factor of wide bioparticles was very low and that their concentration increase in indoor environments was due to indoor sources, namely the presence of human beings. Samplings carried out in different rooms of an apartment showed that most of the PBAPs mass was due to particles heavier than 100 ng, particularly in the bedroom.

Impact of chronic kidney disease on platelet aggregation in patients with acute coronary syndrome.

AIMS: Chronic kidney disease (CKD) is associated with increased thrombotic events and seems to influence platelet reactivity. Conflicting results have been published on platelet response in CKD patients with stable coronary artery disease. The aim of our study was to investigate the impact of CKD on platelet aggregation in acute coronary syndrome (ACS) patients receiving dual antiplatelet therapy, included the more potent P2Y12 inhibitors. METHODS: We enrolled 206 patients with ACS, divided in two groups, according to the presence or the absence of moderate/severe CKD. Platelet aggregation was performed with light transmission aggregometry and results are expressed as percentage of maximum platelet aggregation. High residual platelet reactivity (HRPR) was defined as maximum platelet aggregation more than 59%. RESULTS: Patients with CKD [estimate glomerular filtration rate (eGFR) < 60 ml/min/1.73 m, n = 28] were prevalent older, diabetic, had previous coronary revascularization. In these patients, platelet aggregation was significantly higher than in those with eGFR ≥ 60 ml/min/1.73 m (ADP 10 µmol/l: 28.46 ±â€Š26.19 vs. 16.64 ±â€Š12.79, P < 0.001; ADP 20 µmol/l: 30.07 ±â€Š25.89 vs. 17.46 ±â€Š12.82, P < 0.001). HRPR was observed in 4.4% of patients, with higher prevalence in those with eGFR less than 60 ml/min/1.73 m [21.4 vs. 1.7%, P < 0.001, odds ratio (OR) [95% confidence interval (CI)] = 15.91 (3.71-68.17), P < 0.001]. At multivariate analysis, after correction for baseline confounders, eGFR [adjusted OR (95% CI) = 0.95 (0.91-0.98), P = 0.007], together with the use of clopidogrel [adjusted OR (95% CI) = 23.59 (4.01-138.82), P < 0.001], emerged as determinants of HRPR. CONCLUSION: In patients with ACS receiving dual antiplatelet therapy, CKD is associated with an increasing ADP-induced platelet aggregation and higher prevalence of HRPR, which is mainly correlated to clopidogrel use.

Cardiomyocyte ageing and cardioprotection: consensus document from the ESC working groups cell biology of the heart and myocardial function.

Advanced age is a major predisposing risk factor for the incidence of coronary syndromes and comorbid conditions which impact the heart response to cardioprotective interventions. Advanced age also significantly increases the risk of developing post-ischaemic adverse remodelling and heart failure after ischaemia/reperfusion (IR) injury. Some of the signalling pathways become defective or attenuated during ageing, whereas others with well-known detrimental consequences, such as glycoxidation or proinflammatory pathways, are exacerbated. The causative mechanisms responsible for all these changes are yet to be elucidated and are a matter of active research. Here, we review the current knowledge about the pathophysiology of cardiac ageing that eventually impacts on the increased susceptibility of cells to IR injury and can affect the efficiency of cardioprotective strategies.

Diastolic dysfunction in severe aortic stenosis: Old but still gold.

A simple, widely applicable and reproducible risk predictor may improve patient care, risk stratification, and clinical decision making for symptomatic severe aortic stenosis (sAS) patients undergoing transcatheter aortic valve implantation (TAVI). Baseline severe left ventricular diastolic dysfunction identified by E/A ratio in sAS patients undergoing TAVI is associated with increased post-procedural all-cause mortality or heart failure hospitalization but is not an independent predictor of outcome. Large studies employing multimodality imaging of cardiac function/structure and accounting for sex and comorbidities will be necessary to validate DD parameters (or their combination) in sAS patients undergoing TAVI.

Novel Basic Science Insights to Improve the Management of Heart Failure: Review of the Working Group on Cellular and Molecular Biology of the Heart of the Italian Society of Cardiology.

Despite important advances in diagnosis and treatment, heart failure (HF) remains a syndrome with substantial morbidity and dismal prognosis. Although implementation and optimization of existing technologies and drugs may lead to better management of HF, new or alternative strategies are desirable. In this regard, basic science is expected to give fundamental inputs, by expanding the knowledge of the pathways underlying HF development and progression, identifying approaches that may improve HF detection and prognostic stratification, and finding novel treatments. Here, we discuss recent basic science insights that encompass major areas of translational research in HF and have high potential clinical impact.

Ageing, sex, and cardioprotection.

Translation of cardioprotective interventions aimed at reducing myocardial injury during ischaemia-reperfusion from experimental studies to clinical practice is an important yet unmet need in cardiovascular medicine. One particular challenge facing translation is the existence of demographic and clinical factors that influence the pathophysiology of ischaemia-reperfusion injury of the heart and the effects of treatments aimed at preventing it. Among these factors, age and sex are prominent and have a recognised role in the susceptibility and outcome of ischaemic heart disease. Remarkably, some of the most powerful cardioprotective strategies proven to be effective in young animals become ineffective during ageing. This article reviews the mechanisms and implications of the modulatory effects of ageing and sex on myocardial ischaemia-reperfusion injury and their potential effects on cardioprotective interventions. LINKED ARTICLES: This article is part of a themed issue on Risk factors, comorbidities, and comedications in cardioprotection. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v177.23/issuetoc.