Mitochondrial dysfunction in cardiovascular disease: Current status of translational research/clinical and therapeutic implications.

Mitochondria provide energy to the cell during aerobic respiration by supplying ~95% of the adenosine triphosphate (ATP) molecules via oxidative phosphorylation. These organelles have various other functions, all carried out by numerous proteins, with the majority of them being encoded by nuclear DNA (nDNA). Mitochondria occupy ~1/3 of the volume of myocardial cells in adults, and function at levels of high-efficiency to promptly meet the energy requirements of the myocardial contractile units. Mitochondria have their own DNA (mtDNA), which contains 37 genes and is maternally inherited. Over the last several years, a variety of functions of these organelles have been discovered and this has led to a growing interest in their involvement in various diseases, including cardiovascular (CV) diseases. Mitochondrial dysfunction relates to the status where mitochondria cannot meet the demands of a cell for ATP and there is an enhanced formation of reactive-oxygen species. This dysfunction may occur as a result of mtDNA and/or nDNA mutations, but also as a response to aging and various disease and environmental stresses, leading to the development of cardiomyopathies and other CV diseases. Designing mitochondria-targeted therapeutic strategies aiming to maintain or restore mitochondrial function has been a great challenge as a result of variable responses according to the etiology of the disorder. There have been several preclinical data on such therapies, but clinical studies are scarce. A major challenge relates to the techniques needed to eclectically deliver the therapeutic agents to cardiac tissues and to damaged mitochondria for successful clinical outcomes. All these issues and progress made over the last several years are herein reviewed.

COVID-19 infection and body weight: A deleterious liaison in a J-curve relationship.

During the course of the COVID-19 pandemic, obesity has been shown to be an independent risk factor for high morbidity and mortality. Obesity confers poor outcomes in younger (<60 years) patients, an age-group considered low-risk for complications, a privilege that is negated by obesity. Findings are consistent, the higher the body mass index (BMI) the worse the outcomes. Ectopic (visceral) obesity also promotes proinflammatory, prothrombotic, and vasoconstrictive states, thus enhancing the deleterious effects of COVID-19 disease. Less, albeit robust, evidence also exists for a higher risk of COVID-19 infection incurred with underweight. Thus, the relationship of COVID-19 and BMI has a J-curve pattern, where patients with both overweight/obesity and underweight are more susceptible to the ailments of COVID-19. The pathophysiology underlying this link is multifactorial, mostly relating to the inflammatory state characterizing obesity, the impaired immune response to infectious agents coupled with increased viral load, the overexpression in adipose tissue of the receptors and proteases for viral entry, an increased sympathetic activity, limited cardiorespiratory reserve, a prothrombotic milieu, and the associated comorbidities. All these issues are herein reviewed, the results of large studies and meta-analyses are tabulated and the pathogenetic mechanisms and the BMI relationship with COVID-19 are pictorially illustrated.

The role of the autonomic nervous system in cardiac arrhythmias: The neuro-cardiac axis, more foe than friend?

The autonomic nervous system (ANS) with its two limbs, the sympathetic (SNS) and parasympathetic nervous system (PSNS), plays a critical role in the modulation of cardiac arrhythmogenesis. It can be both pro- and/or anti-arrhythmic at both the atrial and ventricular level of the myocardium. Intricate mechanisms, different for specific cardiac arrhythmias, are involved in this modulatory process. More data are available for the arrhythmogenic effects of the SNS, which, when overactive, can trigger atrial and/or ventricular "adrenergic" arrhythmias in susceptible individuals (e.g. in patients with paroxysmal atrial fibrillation-PAF, ventricular pre-excitation, specific channelopathies, ischemic heart disease or cardiomyopathies), while it can also negate the protective anti-arrhythmic drug effects. However, there is also evidence that PSNS overactivity may be responsible for triggering "vagotonic" arrhythmias (e.g. PAF, Brugada syndrome, idiopathic ventricular fibrillation). Thus, a fine balance is necessary to attain in these two limbs of the ANS in order to maintain eurhythmia, which is a difficult task to accomplish. Over the years, in addition to classical drug therapies, where beta-blockers prevail, several ANS-modulating interventions have been developed aiming at prevention and management of arrhythmias. Among them, techniques of cardiac sympathetic denervation, renal denervation, vagal stimulation, ganglionated plexi ablation and the newer experimental method of optogenetics have been employed. However, in many arrhythmogenic diseases, ANS modulation is still an investigative tool. Initial data are encouraging; however, further studies are needed to explore the efficacy of such interventions. These issues are herein reviewed and old and recent literature data are discussed, tabulated and pictorially illustrated.

Osteological and Soft-Tissue Evidence for Pneumatization in the Cervical Column of the Ostrich (Struthio camelus) and Observations on the Vertebral Columns of Non-Volant, Semi-Volant and Semi-Aquatic Birds.

Postcranial skeletal pneumaticity (PSP) is a condition most notably found in birds, but that is also present in other saurischian dinosaurs and pterosaurs. In birds, skeletal pneumatization occurs where bones are penetrated by pneumatic diverticula, membranous extensions that originate from air sacs that serve in the ventilation of the lung. Key questions that remain to be addressed include further characterizing (1) the skeletal features that can be used to infer the presence/absence and extent of PSP in birds and non-avian dinosaurs, and (2) the association between vertebral laminae and specific components of the avian respiratory system. Previous work has used vertebral features such as pneumatic foramina, fossae, and laminae to identify/infer the presence of air sacs and diverticula, and to discuss the range of possible functions of such features. Here, we tabulate pneumatic features in the vertebral column of 11 avian taxa, including the flightless ratites and selected members of semi-volant and semi-aquatic Neornithes. We investigate the associations of these osteological features with each other and, in the case of Struthio camelus, with the specific presence of pneumatic diverticula. We find that the mere presence of vertebral laminae does not indicate the presence of skeletal pneumaticity, since laminae are not always associated with pneumatic foramina or fossae. Nevertheless, laminae are more strongly developed when adjacent to foramina or fossae. In addition, membranous air sac extensions and adjacent musculature share the same attachment points on the vertebrae, rendering the use of such features for reconstructing respiratory soft tissue features ambiguous. Finally, pneumatic diverticula attach to the margins of laminae, foramina, and/or fossae prior to their intraosseous course. Similarities in PSP distribution among the examined taxa are concordant with their phylogenetic interrelationships. The possible functions of PSP are discussed in brief, based upon variation in the extent of PSP between taxa with differing ecologies.