Aging whole blood transcriptome reveals candidate genes for SARS-CoV-2-related vascular and immune alterations.

The risk of severe COVID-19 increases with age as older patients are at highest risk. Thus, there is an urgent need to identify how severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) interacts with blood components during aging. We investigated the whole blood transcriptome from the Genotype-Tissue Expression (GTEx) database to explore differentially expressed genes (DEGs) translated into proteins interacting with viral proteins during aging. From 22 DEGs in aged blood, FASLG, CTSW, CTSE, VCAM1, and BAG3 were associated with immune response, inflammation, cell component and adhesion, and platelet activation/aggregation. Males and females older than 50 years old overexpress FASLG, possibly inducing a hyperinflammatory cascade. The expression of cathepsins (CTSW and CTSE) and the anti-apoptotic co-chaperone molecule BAG3 also increased throughout aging in both genders. By exploring single-cell RNA-sequencing data from peripheral blood of SARS-CoV-2-infected patients, we found FASLG and CTSW expressed in natural killer cells and CD8 + T lymphocytes, whereas BAG3 was expressed mainly in CD4 + T cells, naive T cells, and CD14 + monocytes. In addition, T cell exhaustion was associated with increased expression of CCL4L2 and DUSP4 over blood aging. LAG3, PDCD1, TIGIT, VCAM1, HLA-DRA, and TOX also increased in individuals aged 60-69 years old; conversely, the RGS2 gene decreased with aging. We further identified a distinct gene expression profile associated with type I interferon signaling following blood aging. These results revealed changes in blood molecules potentially related to SARS-CoV-2 infection throughout aging, emphasizing them as therapeutic candidates for aggressive clinical manifestation of COVID-19. KEY MESSAGES: • Prediction of host-viral interactions in the whole blood transcriptome during aging. • Expression levels of FASLG, CTSW, CTSE, VCAM1, and BAG3 increase in aged blood. • Blood interactome reveals targets involved with immune response, inflammation, and blood clots. • SARS-CoV-2-infected patients with high viral load showed FASLG overexpression. • Gene expression profile associated with T cell exhaustion and type I interferon signaling were affected with blood aging.

Plasma indoxyl sulfate levels predict cardiovascular events in patients with mild chronic heart failure.

Indoxyl sulfate (IS) is associated with either chronic kidney disease or renal failure, which may predict cardiovascular events via cardiorenal syndrome. The present study aimed to elucidate whether the plasma levels of IS can predict the occurrence of cardiovascular events in patients with chronic heart failure (CHF) and investigate which causes of CHF leading to cardiovascular events are highly influenced by plasma IS levels. We measured the plasma IS levels in 165 patients with CHF [valvular disease: 78, dilated cardiomyopathy: 29, hypertrophic cardiomyopathy (HCM): 25 and others: 33] admitted to our hospital in 2012, and we followed up these patients for more than 5 years (the median follow-up period: 5.3 years). We measured the plasma IS level in 165 patients with CHF, and Kaplan-Meier analyses showed that high plasma IS levels (≥ 0.79 µg/mL, the median value) could predict the occurrence of cardiovascular events, i.e., cardiovascular death or rehospitalization due to the worsening of CHF. The sub-analyses showed that the high IS level could predict cardiovascular events in patients with CHF due to HCM and that the plasma IS levels were closely associated with left ventricular (LV) dimension, LV systolic dysfunction, and plasma B-type natriuretic peptide levels, rather than LV diastolic dysfunction. Plasma IS level predicts cardiovascular events in patients with CHF, especially those with HCM along with cardiac dysfunction. Besides, IS may become a proper biomarker to predict cardiovascular events in patients with CHF.

Loss of Caveolin-1 and caveolae leads to increased cardiac cell stiffness and functional decline of the adult zebrafish heart.

Caveolin-1 is the main structural protein of caveolae, small membrane invaginations involved in signal transduction and mechanoprotection. Here, we generated cav1-KO zebrafish lacking Cav1 and caveolae, and investigated the impact of this loss on adult heart function and response to cryoinjury. We found that cardiac function was impaired in adult cav1-KO fish, which showed a significantly decreased ejection fraction and heart rate. Using atomic force microscopy, we detected an increase in the stiffness of epicardial cells and cells of the cortical zone lacking Cav1/caveolae. This loss of cardiac elasticity might explain the decreased cardiac contraction and function. Surprisingly, cav1-KO mutants were able to regenerate their heart after a cryoinjury but showed a transient decrease in cardiomyocyte proliferation.

Higher Anxiety Is Associated with Lower Cardiovascular Autonomic Function in Female Twins.

Anxiety symptoms co-occur with cardiovascular health problems, with increasing evidence suggesting the role of autonomic dysfunction. Yet, there is limited behavior genetic research on underlying mechanisms. In this twin study, we investigated the phenotypic, genetic and environmental associations between a latent anxiety factor and three cardiovascular autonomic function factors: interbeat interval (IBI, time between heart beats), heart rate variability (HRV, overall fluctuation of heart-beat intervals) and baroreflex sensitivity (BRS, efficiency in regulating blood pressure [BP]). Multivariate twin models were fit using data of female twins (N = 250) of the Twin Interdisciplinary Neuroticism Study (TWINS). A significant negative association was identified between latent anxiety and BRS factors (r = -.24, 95% CI [-.40, -.07]). Findings suggest that this relationship was mostly explained by correlated shared environmental influences, and there was no evidence for pleiotropic genetic or unique environmental effects. We also identified negative relationships between anxiety symptoms and HRV (r = -.17, 95% CI [-.34, .00]) and IBI factors (r = -.13, 95% CI [-.29, .04]), though these associations did not reach statistical significance. Findings implicate that higher anxiety scores are associated with decreased efficiency in short-term BP regulation, providing support for autonomic dysfunction with anxiety symptomatology. The baroreflex system may be a key mechanism underlying the anxiety-cardiovascular health relationship.

Phylogenic Determinants of Cardiovascular Frailty, Focus on Hemodynamics and Arterial Smooth Muscle Cells.

The evolution of the circulatory system from invertebrates to mammals has involved the passage from an open system to a closed in-parallel system via a closed in-series system, accompanying the increasing complexity and efficiency of life's biological functions. The archaic heart enables pulsatile motion waves of hemolymph in invertebrates, and the in-series circulation in fish occurs with only an endothelium, whereas mural smooth muscle cells appear later. The present review focuses on evolution of the circulatory system. In particular, we address how and why this evolution took place from a closed, flowing, longitudinal conductance at low pressure to a flowing, highly pressurized and bifurcating arterial compartment. However, although arterial pressure was the latest acquired hemodynamic variable, the general teleonomy of the evolution of species is the differentiation of individual organ function, supported by specific fueling allowing and favoring partial metabolic autonomy. This was achieved via the establishment of an active contractile tone in resistance arteries, which permitted the regulation of blood supply to specific organ activities via its localized function-dependent inhibition (active vasodilation). The global resistance to viscous blood flow is the peripheral increase in frictional forces caused by the tonic change in arterial and arteriolar radius, which backscatter as systemic arterial blood pressure. Consequently, the arterial pressure gradient from circulating blood to the adventitial interstitium generates the unidirectional outward radial advective conductance of plasma solutes across the wall of conductance arteries. This hemodynamic evolution was accompanied by important changes in arterial wall structure, supported by smooth muscle cell functional plasticity, including contractility, matrix synthesis and proliferation, endocytosis and phagocytosis, etc. These adaptive phenotypic shifts are due to epigenetic regulation, mainly related to mechanotransduction. These paradigms actively participate in cardio-arterial pathologies such as atheroma, valve disease, heart failure, aneurysms, hypertension, and physiological aging.

Physiological and genomic evidence that selection on the transcription factor Epas1 has altered cardiovascular function in high-altitude deer mice.

Evolutionary adaptation to extreme environments often requires coordinated changes in multiple intersecting physiological pathways, but how such multi-trait adaptation occurs remains unresolved. Transcription factors, which regulate the expression of many genes and can simultaneously alter multiple phenotypes, may be common targets of selection if the benefits of induced changes outweigh the costs of negative pleiotropic effects. We combined complimentary population genetic analyses and physiological experiments in North American deer mice (Peromyscus maniculatus) to examine links between genetic variation in transcription factors that coordinate physiological responses to hypoxia (hypoxia-inducible factors, HIFs) and multiple physiological traits that potentially contribute to high-altitude adaptation. First, we sequenced the exomes of 100 mice sampled from different elevations and discovered that several SNPs in the gene Epas1, which encodes the oxygen sensitive subunit of HIF-2α, exhibited extreme allele frequency differences between highland and lowland populations. Broader geographic sampling confirmed that Epas1 genotype varied predictably with altitude throughout the western US. We then discovered that Epas1 genotype influences heart rate in hypoxia, and the transcriptomic responses to hypoxia (including HIF targets and genes involved in catecholamine signaling) in the heart and adrenal gland. Finally, we used a demographically-informed selection scan to show that Epas1 variants have experienced a history of spatially varying selection, suggesting that differences in cardiovascular function and gene regulation contribute to high-altitude adaptation. Our results suggest a mechanism by which Epas1 may aid long-term survival of high-altitude deer mice and provide general insights into the role that highly pleiotropic transcription factors may play in the process of environmental adaptation.

Differential MicroRNA expression following head-down tilt bed rest: implications for cardiovascular responses to microgravity.

Head-down tilt bedrest (HDBR), an analog of spaceflight, elicits changes in cardiovascular function that adversely affect astronaut performance. It is therefore fundamental to elucidate the molecular regulators of these changes. Study aim was to determine if cardiovascular-related circulating microRNA (miRNA) are altered following HDBR and if they relate to changes in cardiac function and peak aerobic capacity. Eleven participants completed 30-days HDBR at an ambient CO2 of 0.5% (replicate the in-flight CO2 levels). Blood samples were obtained 3 days (BDC-3) prior to and immediately (R + 0) following HDBR. 44-targeted circulating miRNAs (c-miRNA) identified from published roles in cardiovascular structure/function were analyzed via RT-qPCR. Resting stroke volume was evaluated via ultrasonography. Peak oxygen uptake ( V˙O2peak ) was determined using a graded exercise test on an electronically braked cycle ergometer. Ten cardiovascular-related miRNA were significantly increased following HDBR. The differentially expressed c-miRNA were grouped into clusters according to their expression profile. Cluster A included c-miRNA that have been identified as regulators of cardiac function and hypertrophy (c-miRNA-133), atrial fibrillation and mitochondrial function (c-miRNA-1), skeletal muscle atrophy (c-miRNA-1), and vascular control (c-miRNA-155). Cluster B contained c-miRNA identified as regulators of cardiac hypertrophy (c-miRNA-30, -15), fibrosis (c-miRNA-22, -18), mitochondrial function (miRNA-181), and aerobic capacity (c-miRNA-20a). Following HDBR resting stroke volume was decreased and correlated with changes in c-miRNA-378a and -18a. V˙O2peak was decreased and correlated with changes c-miRNA-133. In conclusion, we found that HDBR induced a distinct and specific cardiovascular-related miRNA response, which were associated with changes in cardiac function and peak aerobic capacity.

The Effects of Regular Exercise on Circulating Cardiovascular-related MicroRNAs.

The purpose of the present study was to examine the effects of regular exercise on the abundance of targeted circulating microRNAs (miRNAs). The present analysis examined 20 previously sedentary adults from the HERITAGE Family Study who completed 20 weeks of endurance exercise training. The expression of 53 miRNAs related to cardiovascular disease were measured in serum collected at baseline and post-training by performing RT-qPCR on the Human Cardiovascular Disease miRNA array (Qiagen, Germany). The effect of regular exercise on circulating miRNAs was assessed using paired t-tests of baseline and post-training expression levels. A false discovery rate threshold of 5% was used to determine significance. Regular exercise resulted in significantly decreased mean serum expression of nine miRNAs (miR-486-5p, let-7b-5p, miR-29c-3p, let-7e-5p, miR-93-5p, miR-7-5p, miR-25-3p, miR-92a-3p, and miR-29b-3p; fold change range: 0.64-83, p = 0.0002-0.01) and increased mean expression of five miRNAs (miR-142-3p, miR-221-3p, miR-126-3p, miR-146a-5p, and miR-27b-3p; fold change range: 1.41-3.60, p = 0.001-0.006). Enrichment analysis found that these 14 miRNAs target genes related to over 345 different biological pathways. These results provide further evidence of the effects of regular exercise on the circulating miRNA profile.

miRNA-378a as a key regulator of cardiovascular health following engineered nanomaterial inhalation exposure.

Nano-titanium dioxide (nano-TiO2), though one of the most utilized and produced engineered nanomaterials (ENMs), diminishes cardiovascular function through dysregulation of metabolism and mitochondrial bioenergetics following inhalation exposure. The molecular mechanisms governing this cardiac dysfunction remain largely unknown. The purpose of this study was to elucidate molecular mediators that connect nano-TiO2 exposure with impaired cardiac function. Specifically, we were interested in the role of microRNA (miRNA) expression in the resulting dysfunction. Not only are miRNA global regulators of gene expression, but also miRNA-based therapeutics provide a realistic treatment modality. Wild type and MiRNA-378a knockout mice were exposed to nano-TiO2 with an aerodynamic diameter of 182 ± 1.70 nm and a mass concentration of 11.09 mg/m3 for 4 h. Cardiac function, utilizing the Vevo 2100 Imaging System, electron transport chain complex activities, and mitochondrial respiration assessed cardiac and mitochondrial function. Immunoblotting and qPCR examined molecular targets of miRNA-378a. MiRNA-378a-3p expression was increased 48 h post inhalation exposure to nano-TiO2. Knockout of miRNA-378a preserved cardiac function following exposure as revealed by preserved E/A ratio and E/SR ratio. In knockout animals, complex I, III, and IV activities (∼2- to 6-fold) and fatty acid respiration (∼5-fold) were significantly increased. MiRNA-378a regulated proteins involved in mitochondrial fusion, transcription, and fatty acid metabolism. MiRNA-378a-3p acts as a negative regulator of mitochondrial metabolic and biogenesis pathways. MiRNA-378a knockout animals provide a protective effect against nano-TiO2 inhalation exposure by altering mitochondrial structure and function. This is the first study to manipulate a miRNA to attenuate the effects of ENM exposure.

Exploring the underlying biology of intrinsic cardiorespiratory fitness through integrative analysis of genomic variants and muscle gene expression profiling.

Intrinsic cardiorespiratory fitness (CRF) is defined as the level of CRF in the sedentary state. There are large individual differences in intrinsic CRF among sedentary adults. The physiology of variability in CRF has received much attention, but little is known about the genetic and molecular mechanisms that impact intrinsic CRF. These issues were explored in the present study by interrogating intrinsic CRF-associated DNA sequence variation and skeletal muscle gene expression data from the HERITAGE Family Study through an integrative bioinformatics guided approach. A combined analytic strategy involving genetic association, pathway enrichment, tissue-specific network structure, cis-regulatory genome effects, and expression quantitative trait loci was used to select and rank genes through a variation-adjusted weighted ranking scheme. Prioritized genes were further interrogated for corroborative evidence from knockout mouse phenotypes and relevant physiological traits from the HERITAGE cohort. The mean intrinsic V̇o2max was 33.1 ml O2·kg-1·min-1 (SD = 8.8) for the sample of 493 sedentary adults. Suggestive evidence was found for gene loci related to cardiovascular physiology (ATE1, CASQ2, NOTO, and SGCG), hematopoiesis (PICALM, SSB, CA9, and CASQ2), skeletal muscle phenotypes (SGCG, DMRT2, ADARB1, and CASQ2), and metabolism (ATE1, PICALM, RAB11FIP5, GBA2, SGCG, PRADC1, ARL6IP5, and CASQ2). Supportive evidence for a role of several of these loci was uncovered via association between DNA variants and muscle gene expression levels with exercise cardiovascular and muscle physiological traits. This initial effort to define the underlying molecular substrates of intrinsic CRF warrants further studies based on appropriate cohorts and study designs, complemented by functional investigations. NEW & NOTEWORTHY Intrinsic cardiorespiratory fitness (CRF) is measured in the sedentary state and is highly variable among sedentary adults. The physiology of variability in intrinsic cardiorespiratory fitness has received much attention, but little is known about the genetic and molecular mechanisms that impact intrinsic CRF. These issues were explored computationally in the present study, with further corroborative evidence obtained from analysis of phenotype data from knockout mouse models and human cardiovascular and skeletal muscle measurements.

Cardiovascular development and survival require Mef2c function in the myocardial but not the endothelial lineage.

MEF2C is a member of the highly conserved MEF2 family of transcription factors and is a key regulator of cardiovascular development. In mice, Mef2c is expressed in the developing heart and vasculature, including the endothelium. Loss of Mef2c function in germline knockout mice leads to early embryonic demise and profound developmental abnormalities in the cardiovascular system. Previous attempts to uncover the cause of embryonic lethality by specifically disrupting Mef2c function in the heart or vasculature failed to recapitulate the global Mef2c knockout phenotype and instead resulted in relatively minor defects that did not compromise viability or result in significant cardiovascular defects. However, previous studies examined the requirement of Mef2c in the myocardial and endothelial lineages using Cre lines that begin to be expressed after the expression of Mef2c has already commenced. Here, we tested the requirement of Mef2c in the myocardial and endothelial lineages using conditional knockout approaches in mice with Cre lines that deleted Mef2c prior to onset of its expression in embryonic development. We found that deletion of Mef2c in the early myocardial lineage using Nkx2-5Cre resulted in cardiac and vascular abnormalities that were indistinguishable from the defects in the global Mef2c knockout. In contrast, early deletion of Mef2c in the vascular endothelium using an Etv2::Cre line active prior to the onset of Mef2c expression resulted in viable offspring that were indistinguishable from wild type controls with no overt defects in vascular development, despite nearly complete early deletion of Mef2c in the vascular endothelium. Thus, these studies support the idea that the requirement of MEF2C for vascular development is secondary to its requirement in the heart and suggest that the observed failure in vascular remodeling in Mef2c knockout mice results from defective heart function.

Cardiac Response to Exercise in Normal Ageing: What Can We Learn from Masters Athletes?

BACKGROUND: Ageing is associated with an inexorable decline in cardiac and vascular function, resulting in an increased risk of Cardiovascular Disease (CVD). Lifestyle factors such as exercise have emerged as a primary therapeutic target in the prevention of CVD, yet older individuals are frequently reported as being the least active, with few meeting the recommended physical activity guidelines. In contrast, well trained older individuals (Masters athletes) have superior functional capacity than their sedentary peers and are often comparable with young non-athletes. Therefore, the 'masters' athlete may be viewed as a unique non-pharmacological model which may allow researchers to disentangle the inexorable from the preventable and the magnitude of the unavoidable 'true' reduction in cardiac function due to ageing. CONCLUSION: This review examines evidence from studies which have compared cardiac structure and function in well trained older athletes, with age-matched controls but otherwise healthy.

Connexins and Pannexins in Vascular Function and Disease.

Connexins (Cxs) and pannexins (Panxs) are ubiquitous membrane channel forming proteins that are critically involved in many aspects of vascular physiology and pathology. The permeation of ions and small metabolites through Panx channels, Cx hemichannels and gap junction channels confers a crucial role to these proteins in intercellular communication and in maintaining tissue homeostasis. This review provides an overview of current knowledge with respect to the pathophysiological role of these channels in large arteries, the microcirculation, veins, the lymphatic system and platelet function. The essential nature of these membrane proteins in vascular homeostasis is further emphasized by the pathologies that are linked to mutations and polymorphisms in Cx and Panx genes.

Regulators of G protein signaling in cardiovascular function during pregnancy.

G protein-coupled receptor signaling mechanisms are implicated in many aspects of cardiovascular control, and dysfunction of such signaling mechanisms is commonly associated with disease states. Investigators have identified a large number of regulator of G protein signaling (RGS) proteins that variously contribute to the modulation of intracellular second-messenger signaling kinetics. These many RGS proteins each interact with a specific set of second-messenger cascades and receptor types and exhibit tissue-specific expression patterns. Increasing evidence supports the contribution of RGS proteins, or their loss, in the pathogenesis of cardiovascular dysfunctions. This review summarizes the current understanding of the functional contributions of RGS proteins, particularly within the B/R4 family, in cardiovascular disorders of pregnancy including gestational hypertension, uterine artery dysfunction, and preeclampsia.

Minority stress and leukocyte gene expression in sexual minority men living with treated HIV infection.

Sexual minority (i.e., non-heterosexual) individuals experience poorer mental and physical health, accounted for in part by the additional burden of sexual minority stress occurring from being situated in a culture favoring heteronormativity. Informed by previous research, the purpose of this study was to identify the relationship between sexual minority stress and leukocyte gene expression related to inflammation, cancer, immune function, and cardiovascular function. Sexual minority men living with HIV who were on anti-retroviral medication, had viral load < 200 copies/mL, and had biologically confirmed, recent methamphetamine use completed minority stress measures and submitted blood samples for RNA sequencing on leukocytes. Differential gene expression and pathway analyses were conducted comparing those with clinically elevated minority stress (n = 18) and those who did not meet the clinical cutoff (n = 20), covarying reactive urine toxicology results for very recent stimulant use. In total, 90 differentially expressed genes and 138 gene set pathways evidencing 2-directional perturbation were observed at false discovery rate (FDR) < 0.10. Of these, 41 of the differentially expressed genes and 35 of the 2-directionally perturbed pathways were identified as functionally related to hypothesized mechanisms of inflammation, cancer, immune function, and cardiovascular function. The neuroactive-ligand receptor pathway (implicated in cancer development) was identified using signaling pathway impact analysis. Our results suggest several potential biological pathways for future work investigating the relationship between sexual minority stress and health.

Coordination of cardiac rhythmic output and circadian metabolic regulation in the heart.

Over the course of a 24-h day, demand on the heart rises and falls with the sleep/wake cycles of the organism. Cardiac metabolism oscillates appropriately, with the relative contributions of major energy sources changing in a circadian fashion. The cardiac peripheral clock is hypothesized to drive many of these changes, yet the precise mechanisms linking the cardiac clock to metabolism remain a source of intense investigation. Here we summarize the current understanding of circadian alterations in cardiac metabolism and physiology, with an emphasis on novel findings from unbiased transcriptomic studies. Additionally, we describe progress in elucidating the links between the cardiac peripheral clock outputs and cardiac metabolism, as well as their implications for cardiac physiology.

Exercise Training and Epigenetic Regulation: Multilevel Modification and Regulation of Gene Expression.

Exercise training elicits acute and adaptive long term changes in human physiology that mediate the improvement of performance and health state. The responses are integrative and orchestrated by several mechanisms, as gene expression. Gene expression is essential to construct the adaptation of the biological system to exercise training, since there are molecular processes mediating oxidative and non-oxidative metabolism, angiogenesis, cardiac and skeletal myofiber hypertrophy, and other processes that leads to a greater physiological status. Epigenetic is the field that studies about gene expression changes heritable by meiosis and mitosis, by changes in chromatin and DNA conformation, but not in DNA sequence, that studies the regulation on gene expression that is independent of genotype. The field approaches mechanisms of DNA and chromatin conformational changes that inhibit or increase gene expression and determine tissue specific pattern. The three major studied epigenetic mechanisms are DNA methylation, Histone modification, and regulation of noncoding RNA-associated genes. This review elucidates these mechanisms, focusing on the relationship between them and their relationship with exercise training, physical performance and the enhancement of health status. On this chapter, we clarified the relationship of epigenetic modulations and their intimal relationship with acute and chronic effect of exercise training, concentrating our effort on skeletal muscle, heart and vascular responses, that are the most responsive systems against to exercise training and play crucial role on physical performance and improvement of health state.

Genomic and non-genomic effects of androgens in the cardiovascular system: clinical implications.

The principle steroidal androgens are testosterone and its metabolite 5α-dihydrotestosterone (DHT), which is converted from testosterone by the enzyme 5α-reductase. Through the classic pathway with androgens crossing the plasma membrane and binding to the androgen receptor (AR) or via mechanisms independent of the ligand-dependent transactivation function of nuclear receptors, testosterone induces genomic and non-genomic effects respectively. AR is widely distributed in several tissues, including vascular endothelial and smooth muscle cells. Androgens are essential for many developmental and physiological processes, especially in male reproductive tissues. It is now clear that androgens have multiple actions besides sex differentiation and sexual maturation and that many physiological systems are influenced by androgens, including regulation of cardiovascular function [nitric oxide (NO) release, Ca2+ mobilization, vascular apoptosis, hypertrophy, calcification, senescence and reactive oxygen species (ROS) generation]. This review focuses on evidence indicating that interplay between genomic and non-genomic actions of testosterone may influence cardiovascular function.

Prioritizing Functional Capacity as a Principal End Point for Therapies Oriented to Older Adults With Cardiovascular Disease: A Scientific Statement for Healthcare Professionals From the American Heart Association.

Adults are living longer, and cardiovascular disease is endemic in the growing population of older adults who are surviving into old age. Functional capacity is a key metric in this population, both for the perspective it provides on aggregate health and as a vital goal of care. Whereas cardiorespiratory function has long been applied by cardiologists as a measure of function that depended primarily on cardiac physiology, multiple other factors also contribute, usually with increasing bearing as age advances. Comorbidity, inflammation, mitochondrial metabolism, cognition, balance, and sleep are among the constellation of factors that bear on cardiorespiratory function and that become intricately entwined with cardiovascular health in old age. This statement reviews the essential physiology underlying functional capacity on systemic, organ, and cellular levels, as well as critical clinical skills to measure multiple realms of function (eg, aerobic, strength, balance, and even cognition) that are particularly relevant for older patients. Clinical therapeutic perspectives and patient perspectives are enumerated to clarify challenges and opportunities across the caregiving spectrum, including patients who are hospitalized, those managed in routine office settings, and those in skilled nursing facilities. Overall, this scientific statement provides practical recommendations and vital conceptual insights.