At this time, news editorials were noting obesity as an underappreciated risk factor for COVID-19.4 This risk is particularly relevant in the USA because the prevalence of obesity is around 40%, ...versus a prevalence of 6·2% in China, 20% in Italy, and 24% in Spain.5 With use of least squares univariate and multivariate linear regression, we examined the correlation between body-mass index (BMI) and age in patients with COVID-19 admitted to ICU at university hospitals at Johns Hopkins, University of Cincinnati, New York University, University of Washington, Florida Health, and University of Pennsylvania (appendix). Obesity can restrict ventilation by impeding diaphragm excursion, impairs immune responses to viral infection,6 is pro-inflammatory, and induces diabetes and oxidant stress to adversely affect cardiovascular function.7 We conclude that in populations with a high prevalence of obesity, COVID-19 will affect younger populations more than previously reported. Public messaging to younger adults, reducing the threshold for virus testing in obese individuals, and maintaining greater vigilance for this at-risk population should reduce the prevalence of severe COVID-19 disease.
Heart failure with preserved ejection fraction (HFpEF) affects half of all patients with heart failure worldwide, is increasing in prevalence, confers substantial morbidity and mortality, and has ...very few effective treatments. HFpEF is arguably the greatest unmet medical need in cardiovascular disease. Although HFpEF was initially considered to be a haemodynamic disorder characterized by hypertension, cardiac hypertrophy and diastolic dysfunction, the pandemics of obesity and diabetes mellitus have modified the HFpEF syndrome, which is now recognized to be a multisystem disorder involving the heart, lungs, kidneys, skeletal muscle, adipose tissue, vascular system, and immune and inflammatory signalling. This multiorgan involvement makes HFpEF difficult to model in experimental animals because the condition is not simply cardiac hypertrophy and hypertension with abnormal myocardial relaxation. However, new animal models involving both haemodynamic and metabolic disease, and increasing efforts to examine human pathophysiology, are revealing new signalling pathways and potential therapeutic targets. In this Review, we discuss the cellular and molecular pathobiology of HFpEF, with the major focus being on mechanisms relevant to the heart, because most research has focused on this organ. We also highlight the involvement of other important organ systems, including the lungs, kidneys and skeletal muscle, efforts to characterize patients with the use of systemic biomarkers, and ongoing therapeutic efforts. Our objective is to provide a roadmap of the signalling pathways and mechanisms of HFpEF that are being characterized and which might lead to more patient-specific therapies and improved clinical outcomes.
The clinical syndrome comprising heart failure (HF) symptoms but with a left ventricular ejection fraction (EF) that is not diminished, eg, HF with preserved EF, is increasingly the predominant form ...of HF in the developed world, and soon to reach epidemic proportions. It remains among the most challenging of clinical syndromes for the practicing clinician and scientist alike, with a multitude of proposed mechanisms involving the heart and other organs and complex interplay with common comorbidities. Importantly, its morbidity and mortality are on par with HF with reduced EF, and as the list of failed treatments continues to grow, HF with preserved EF clearly represents a major unmet medical need. The field is greatly in need of a more unified approach to its definition and view of the syndrome that engages integrative and reserve pathophysiology beyond that related to the heart alone. We need to reflect on prior treatment failures and the message this is providing, and redirect our approaches likely with a paradigm shift in how the disease is viewed. Success will require interactions between clinicians, translational researchers, and basic physiologists. Here, we review recent translational and clinical research into HF with preserved EF and give perspectives on its evolving demographics and epidemiology, the role of multiorgan deficiencies, potential mechanisms that involve the heart and other organs, clinical trials, and future directions.
Cyclic nucleotide phosphodiesterases (PDEs) form an 11-member superfamily comprising 100 different isoforms that regulate the second messengers cyclic adenosine or guanosine 3′,5′-monophosphate (cAMP ...or cGMP). These PDE isoforms differ with respect to substrate selectivity and their localized control of cAMP and cGMP within nanodomains that target specific cellular pools and synthesis pathways for the cyclic nucleotides. Seven PDE family members are physiologically relevant to regulating cardiac function, disease remodeling of the heart, or both: PDE1 and PDE2, both dual-substrate (cAMP and cGMP) esterases; PDE3, PDE4, and PDE8, which principally hydrolyze cAMP; and PDE5A and PDE9A, which target cGMP. New insights regarding the different roles of PDEs in health and disease and their local signaling control are broadening the potential therapeutic utility for PDE-selective inhibitors. In this review, we discuss these PDEs, focusing on the different mechanisms by which they control cardiac function in health and disease by regulating intracellular nanodomains.
Arterial stiffness is a growing epidemic associated with increased risk of cardiovascular events, dementia, and death. Decreased compliance of the central vasculature alters arterial pressure and ...flow dynamics and impacts cardiac performance and coronary perfusion. This article reviews the structural, cellular, and genetic contributors to arterial stiffness, including the roles of the scaffolding proteins, extracellular matrix, inflammatory molecules, endothelial cell function, and reactive oxidant species. Additional influences of atherosclerosis, glucose regulation, chronic renal disease, salt, and changes in neurohormonal regulation are discussed. A review of the hemodynamic impact of arterial stiffness follows. A number of lifestyle changes and therapies that reduce arterial stiffness are presented, including weight loss, exercise, salt reduction, alcohol consumption, and neuroendocrine-directed therapies, such as those targeting the renin-angiotensin aldosterone system, natriuretic peptides, insulin modulators, as well as novel therapies that target advanced glycation end products.
Decades of progress in developmental cardiology has advanced our understanding of the early aspects of heart development, including cardiomyocyte (CM) differentiation. However, control of the CM ...maturation that is subsequently required to generate adult myocytes remains elusive. Here, we analyzed over 200 microarray datasets from early embryonic to adult hearts and identified a large number of genes whose expression shifts gradually and continuously during maturation. We generated an atlas of integrated gene expression, biological pathways, transcriptional regulators, and gene regulatory networks (GRNs), which show discrete sets of key transcriptional regulators and pathways activated or suppressed during CM maturation. We developed a GRN-based program named MatStatCM that indexes CM maturation status. MatStatCM reveals that pluripotent-stem-cell-derived CMs mature early in culture but are arrested at the late embryonic stage with aberrant regulation of key transcription factors. Our study provides a foundation for understanding CM maturation.
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•Transcriptional landscape during cardiomyocyte maturation•A GRN-based method to assess maturation status of cardiomyocytes is developed•PSC-CMs undergo maturation but are arrested at the late embryonic stage•Misregulated transcriptional factors may alter PSC-CM maturation in vitro
Based on maturation stage-specific gene regulatory networks, Uosaki et al. develop a method to assess the maturation status of cardiomyocytes and find that the maturation of PSC-CMs is arrested at a late embryonic stage with inactive PPARs and active CTNNB1.
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