Patients with diabetes mellitus have >2× the risk for developing heart failure (HF; HF with reduced ejection fraction and HF with preserved ejection fraction). Cardiovascular outcomes, hospitalization, and prognosis are worse for patients with diabetes mellitus relative to those without. Beyond the structural and functional changes that characterize diabetic cardiomyopathy, a complex underlying, and interrelated pathophysiology exists. Despite the success of many commonly used antihyperglycemic therapies to lower hyperglycemia in type 2 diabetes mellitus the high prevalence of HF persists. This, therefore, raises the possibility that additional factors beyond glycemia might contribute to the increased HF risk in diabetes mellitus. This review summarizes the state of knowledge about the impact of existing antihyperglycemic therapies on HF and discusses potential mechanisms for beneficial or deleterious effects. Second, we review currently approved pharmacological therapies for HF and review evidence that addresses their efficacy in the context of diabetes mellitus. Dysregulation of many cellular mechanisms in multiple models of diabetic cardiomyopathy and in human hearts have been described. These include oxidative stress, inflammation, endoplasmic reticulum stress, aberrant insulin signaling, accumulation of advanced glycated end-products, altered autophagy, changes in myocardial substrate metabolism and mitochondrial bioenergetics, lipotoxicity, and altered signal transduction such as GRK (g-protein receptor kinase) signaling, renin angiotensin aldosterone signaling and β-2 adrenergic receptor signaling. These pathophysiological pathways might be amenable to pharmacological therapy to reduce the risk of HF in the context of type 2 diabetes mellitus. Successful targeting of these pathways could alter the prognosis and risk of HF beyond what is currently achieved using existing antihyperglycemic and HF therapeutics.

Heart Failure in Type 2 Diabetes Mellitus.

The endothelium, a cellular monolayer lining the blood vessel wall, plays a critical role in maintaining multiorgan health and homeostasis. Endothelial functions in health include dynamic maintenance of vascular tone, angiogenesis, hemostasis, and the provision of an antioxidant, anti-inflammatory, and antithrombotic interface. Dysfunction of the vascular endothelium presents with impaired endothelium-dependent vasodilation, heightened oxidative stress, chronic inflammation, leukocyte adhesion and hyperpermeability, and endothelial cell senescence. Recent studies have implicated altered endothelial cell metabolism and endothelial-to-mesenchymal transition as new features of endothelial dysfunction. Endothelial dysfunction is regarded as a hallmark of many diverse human panvascular diseases, including atherosclerosis, hypertension, and diabetes. Endothelial dysfunction has also been implicated in severe coronavirus disease 2019. Many clinically used pharmacotherapies, ranging from traditional lipid-lowering drugs, antihypertensive drugs, and antidiabetic drugs to proprotein convertase subtilisin/kexin type 9 inhibitors and interleukin 1β monoclonal antibodies, counter endothelial dysfunction as part of their clinical benefits. The regulation of endothelial dysfunction by noncoding RNAs has provided novel insights into these newly described regulators of endothelial dysfunction, thus yielding potential new therapeutic approaches. Altogether, a better understanding of the versatile (dys)functions of endothelial cells will not only deepen our comprehension of human diseases but also accelerate effective therapeutic drug discovery. In this review, we provide a timely overview of the multiple layers of endothelial function, describe the consequences and mechanisms of endothelial dysfunction, and identify pathways to effective targeted therapies. SIGNIFICANCE STATEMENT: The endothelium was initially considered to be a semipermeable biomechanical barrier and gatekeeper of vascular health. In recent decades, a deepened understanding of the biological functions of the endothelium has led to its recognition as a ubiquitous tissue regulating vascular tone, cell behavior, innate immunity, cell-cell interactions, and cell metabolism in the vessel wall. Endothelial dysfunction is the hallmark of cardiovascular, metabolic, and emerging infectious diseases. Pharmacotherapies targeting endothelial dysfunction have potential for treatment of cardiovascular and many other diseases.

Endothelial Dysfunction in Atherosclerotic Cardiovascular Diseases and Beyond: From Mechanism to Pharmacotherapies.

The increased risk of cardiovascular morbidity and mortality in rheumatoid arthritis and gout has been increasingly acknowledged in past decades, with accumulating evidence that gout, just as with rheumatoid arthritis, is an independent cardiovascular risk factor. Although both diseases have a completely different pathogenesis, the underlying pathophysiological mechanisms in systemic inflammation overlap to some extent. Following the recognition that systemic inflammation has an important causative role in cardiovascular disease, anti-inflammatory therapy in both conditions and urate-lowering therapies in gout are expected to lower the cardiovascular burden of patients. Unfortunately, much of the existing data showing that urate-lowering therapy has consistent beneficial effects on cardiovascular outcomes in patients with gout are of low quality and contradictory. We will discuss the latest evidence in this respect. Cardiovascular disease risk management for patients with rheumatoid arthritis and gout is essential. Clinical guidelines and implementation of cardiovascular risk management in daily clinical practice, as well as unmet needs and areas for further investigation, will be discussed.

https://www.thelancet.com/pdfs/journals/lanrhe/PIIS2665-9913(20)30221-6.pdf

Cardiovascular risk in inflammatory arthritis: rheumatoid arthritis and gout

Mitochondria are key regulators of cell fate through controlling ATP generation and releasing pro-apoptotic factors. Cardiac ischemia/reperfusion (I/R) injury to the coronary microcirculation has manifestations ranging in severity from reversible edema to interstitial hemorrhage. A number of mechanisms have been proposed to explain the cardiac microvascular I/R injury including edema, impaired vasomotion, coronary microembolization, and capillary destruction. In contrast to their role in cell types with higher energy demands, mitochondria in endothelial cells primarily function in signaling cellular responses to environmental cues. It is clear that abnormal mitochondrial signatures, including mitochondrial oxidative stress, mitochondrial fission, mitochondrial fusion, and mitophagy, play a substantial role in endothelial cell function. While the pathogenic role of each of these mitochondrial alterations in the endothelial cells I/R injury remains complex, profiling of mitochondrial oxidative stress and mitochondrial dynamics in endothelial cell dysfunction may offer promising potential targets in the search for novel diagnostics and therapeutics in cardiac microvascular I/R injury. The objective of this review is to discuss the role of mitochondrial oxidative stress on cardiac microvascular endothelial cells dysfunction. Mitochondrial dynamics, including mitochondrial fission and fusion, are critically discussed to understand their roles in endothelial cell survival. Finally, mitophagy, as a degradative mechanism for damaged mitochondria, is summarized to figure out its contribution to the progression of microvascular I/R injury.

https://www.mdpi.com/2218-273X/10/1/85/pdf

Pathological Roles of Mitochondrial Oxidative Stress and Mitochondrial Dynamics in Cardiac Microvascular Ischemia/Reperfusion Injury.

Germline mutations in cellular-energy associated genes have been shown to lead to various monogenic disorders. Notably, mitochondrial disorders often impact skeletal muscle, brain, liver, heart, and kidneys, which are the body's top energy-consuming organs. However, energy-related dysfunctions have not been widely seen as causes of common diseases, although evidence points to such a link for certain disorders. During acute energy consumption, like extreme exercise, cells increase the favorability of the adenylate kinase reaction 2-ADP -> ATP+AMP by AMP deaminase degrading AMP to IMP, which further degrades to inosine and then to purines hypoxanthine -> xanthine -> urate. Thus, increased blood urate levels may act as a barometer of extreme energy consumption. AMP deaminase deficient subjects experience some negative effects like decreased muscle power output, but also positive effects such as decreased diabetes and improved prognosis for chronic heart failure patients. That may reflect decreased energy consumption from maintaining the pool of IMP for salvage to AMP and then ATP, since de novo IMP synthesis requires burning seven ATPs. Similarly, beneficial effects have been seen in heart, skeletal muscle, or brain after treatment with allopurinol or febuxostat to inhibit xanthine oxidoreductase, which catalyzes hypoxanthine -> xanthine and xanthine -> urate reactions. Some disorders of those organs may reflect dysfunction in energy-consumption/production, and the observed beneficial effects related to reinforcement of ATP re-synthesis due to increased hypoxanthine levels in the blood and tissues. Recent clinical studies indicated that treatment with xanthine oxidoreductase inhibitors plus inosine had the strongest impact for increasing the pool of salvageable purines and leading to increased ATP levels in humans, thereby suggesting that this combination is more beneficial than a xanthine oxidoreductase inhibitor alone to treat disorders with ATP deficiency.

/pdf/shortage-of-cellular-atp-as-a-cause-of-diseases-and-3lrwn1q2rm.pdf

Shortage of Cellular ATP as a Cause of Diseases and Strategies to Enhance ATP

Xanthine oxidase inhibitors (XOI), classified as purine-like (allopurinol and oxypurinol) and non-purine (febuxostat and topiroxostat) XOI, present antioxidant properties by reducing the production of reactive oxygen species derived from purine metabolism Oxidative stress is an important factor related to endothelial dysfunction and ischemia-reperfusion injury, and may be implicated in the pathogenesis of heart failure, hypertension, and ischemic heart disease However, there is contradictory evidence regarding the possible cardiovascular (CV) protective effect exerted by XOI Our objective is to compare the incidence of major adverse cardiovascular events (MACE), mortality, total (TCE) and specific CV events in randomized controlled trials (RCTs) testing XOI against placebo or no treatment PubMed, EMBASE, Web of Science, Cochrane Central, Lilacs databases were searched from inception to Dec 30 2016, along with hand searching RCTs including exclusively adult individuals, lasting ≥ 4 weeks, with no language restriction, were eligible Independent paired researchers selected studies and extracted data Considering the expected rarity of events, Peto and DerSimonian/Laird odds ratios (OR), the latter in case of heterogeneity, were used for analysis Random-effects meta-regression was used to explore heterogeneity The analysis of MACE included 81 articles (10,684 patients, 6434 patient-years) XOI did not significantly reduce risk of MACE (ORP = 071, 95% CI 046–109) and death (089, 059–133), but reduced risk of TCE (060, 044–082; serious TCE: 064, 046 to 089), and hypertension (054, 037 to 080) There was protection for MACE in patients with previous ischemic events (042, 023–076) Allopurinol protected for myocardial infarction (038, 017–083), hypertension (032, 018–058), TCE (048, 031 to 075, I2 = 55%) and serious TCE (056, 036 to 086, I2 = 44%) Meta-regression associated increasing dose of allopurinol with higher risk of TCE and serious TCE (P   300 mg/day) may be associated with loss of CV protection

/pdf/xanthine-oxidase-inhibitors-for-prevention-of-cardiovascular-1kepoh7hw9.pdf

Fernando da Silva Stein

Papers

Xanthine oxidase inhibitors for prevention of cardiovascular events: a systematic review and meta-analysis of randomized controlled trials