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GLP-1 and insulin regulation of skeletal and cardiac muscle microvascular perfusion in type 2 diabetes.
Love, KM, Liu, J, Regensteiner, JG, Reusch, JEB, Liu, Z
Journal of diabetes. 2020;(7):488-498
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Abstract
Muscle microvasculature critically regulates skeletal and cardiac muscle health and function. It provides endothelial surface area for substrate exchange between the plasma compartment and the muscle interstitium. Insulin fine-tunes muscle microvascular perfusion to regulate its own action in muscle and oxygen and nutrient supplies to muscle. Specifically, insulin increases muscle microvascular perfusion, which results in increased delivery of insulin to the capillaries that bathe the muscle cells and then facilitate its own transendothelial transport to reach the muscle interstitium. In type 2 diabetes, muscle microvascular responses to insulin are blunted and there is capillary rarefaction. Both loss of capillary density and decreased insulin-mediated capillary recruitment contribute to a decreased endothelial surface area available for substrate exchange. Vasculature expresses abundant glucagon-like peptide 1 (GLP-1) receptors. GLP-1, in addition to its well-characterized glycemic actions, improves endothelial function, increases muscle microvascular perfusion, and stimulates angiogenesis. Importantly, these actions are preserved in the insulin resistant states. Thus, treatment of insulin resistant patients with GLP-1 receptor agonists may improve skeletal and cardiac muscle microvascular perfusion and increase muscle capillarization, leading to improved delivery of oxygen, nutrients, and hormones such as insulin to the myocytes. These actions of GLP-1 impact skeletal and cardiac muscle function and systems biology such as functional exercise capacity. Preclinical studies and clinical trials involving the use of GLP-1 receptor agonists have shown salutary cardiovascular effects and improved cardiovascular outcomes in type 2 diabetes mellitus. Future studies should further examine the different roles of GLP-1 in cardiac as well as skeletal muscle function.
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Impact of Nutrition on Cardiovascular Function.
Bianchi, VE
Current problems in cardiology. 2020;(1):100391
Abstract
The metabolic sources of energy for myocardial contractility include mainly free fatty acids (FFA) for 95%, and in lesser amounts for 5% from glucose and minimal contributions from other substrates such lactate, ketones, and amino acids. However, myocardial efficiency is influenced by metabolic condition, overload, and ischemia. During cardiac stress, cardiomyocytes increase glucose oxidation and reduce FFA oxidation. In patients with ischemic coronary disease and heart failure, the low oxygen availability limits myocardial reliance on FFA and glucose utilization must increase. Although glucose uptake is fundamental to cardiomyocyte function, an excessive intracellular glucose level is detrimental. Insulin plays a fundamental role in maintaining myocardial efficiency and in reducing glycemia and inflammation; this is particularly evident in obese and type-2 diabetic patients. An excess of F availability increase fat deposition within cardiomyocytes and reduces glucose oxidation. In patients with high body mass index, a restricted diet or starvation have positive effects on cardiac metabolism and function while, in patients with low body mass index, restrictive diets, or starvation have a deleterious effect. Thus, weight loss in obese patients has positive impacts on ventricular mass and function, whereas, in underweight heart failure patients, such weight reduction adds to the risk of heart damage, predisposing to cachexia. Nutrition plays an essential role in the evolution of cardiovascular disease and should be taken into account. An energy-restricted diet improves myocardial efficiency but can represent a potential risk of heart damage, particularly in patients affected by cardiovascular disease. Micronutrient integration has a marginal effect on cardiovascular efficiency.
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Ketogenesis in arrhythmogenic cardiomyopathy.
Huynh, K
Nature reviews. Cardiology. 2020;(5):266
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B-type natriuretic peptide and its role in altering Ca2+-regulatory proteins in heart failure-mechanistic insights.
Zhao, J, Xu, T, Zhou, Y, Zhou, Y, Xia, Y, Li, D
Heart failure reviews. 2020;(5):861-871
Abstract
Heart failure (HF) is a worldwide disease with high levels of morbidity and mortality. The pathogenesis of HF is complicated and involves imbalances in hormone and electrolyte. B-type natriuretic peptide (BNP) has served as a biomarker of HF severity, and in recent years, it has been used to treat the disease, thanks to its cardio-protective effects, such as diuresis, natriuresis, and vasodilatation. In stage C/D HF, symptoms are severe despite elevated BNP. Disturbances in Ca2+ homeostasis are often a dominating feature of the disease, causing Ca2+-regulatory protein dysfunction, including reduced expression and activity of sarcoplasmic reticulum Ca2+-ATPase2a (SERCA2a), impaired ryanodine receptors (RYRs) function, intensive Na+-Ca2+ exchanger (NCX), and downregulation of S100A1. The relationship between natriuretic peptides (NPs) and Ca2+-regulatory proteins has been widely studied and represents important mechanisms in the etiology of HF. In this review, we present evidence that BNP may regulate Ca2+-regulatory proteins, in particular, suppressing SERCA2a and S100A1 expression. However, relationships between BNP and other Ca2+-regulatory proteins remain vague.
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Pitfalls and Misinterpretations of Cardiac Findings on PET/CT Imaging: A Careful Look at the Heart in Oncology Patients.
Betancourt Cuellar, SL, Palacio, D, Benveniste, MF, Carter, BW, Gladish, G
Current problems in diagnostic radiology. 2019;(2):172-183
Abstract
Positron emission tomography (PET) computed tomography (CT) with 2-[fluorine-18] fluoro-2-deoxy-d-glucose (FDG) has been established as an effective modality for evaluation of cancer. Interpretations of patterns of physiologic 18F-FDG uptake by the heart is particularly difficult given the wide normal variations of 18F-FDG metabolic activity observed. Atypical patterns of focal or diffuse physiologic cardiac 18F-FDG uptake and post-therapeutic effects after radiation therapy, systemic diseases, or cardiomyopathy may also be confused with malignant disease on 18F-FDG PET/CT. In this article, we review the variations of normal cardiac 18F-FDG uptake observed in oncology patients and the appearances of other patterns of pathologic metabolic activity, related or not related to the malignancy being investigated, that may lead to false-negative and false-positive results.
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Potential Mechanisms of Sodium-Glucose Co-Transporter 2 Inhibitor-Related Cardiovascular Benefits.
Verma, S
The American journal of cardiology. 2019;:S36-S44
Abstract
The findings of recent clinical trials have shown that sodium-glucose co-transporter 2 (SGLT2) inhibitors produce effects beyond glucose lowering and have demonstrated beneficial cardiovascular effects that have been observed across a broad range of patients with type 2 diabetes mellitus. In particular, the cardiovascular benefit results largely from substantial and early effects of SGLT2 inhibition on cardiovascular death and hospitalization for heart failure. Recent cardiovascular outcomes trials (CVOTs) have also shown that relative risk reductions in cardiovascular outcomes were observed with SGLT2 inhibition both in patients with current and prior heart failure. Since the observed reductions of cardiovascular outcomes with SGLT2 inhibitor therapy were observed much earlier than would be expected by an anti-atherosclerotic effect, these results have led to speculation about the potential underlying pathways. Suggested mechanisms include natriuresis and osmotic diuresis; reductions in inflammation, oxidative stress, and arterial stiffness; reductions in blood pressure and body weight; and possible renoprotective effects. These effects could produce cardiovascular benefits through a range of cardiac effects, including reduction in left ventricular load, attenuation of cardiac fibrosis and inflammation, and improved myocardial energy production. Other possible mechanisms include inhibition of sodium-hydrogen exchange, increases in erythropoietin levels, and reduction in myocardial ischemia or reperfusion injury. It is likely that a range of mechanisms underlie the observed cardiovascular benefits of SGLT2 inhibitors; further elucidation of these mechanisms will be answered by ongoing research.
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Role of mitochondrial Ca2+ homeostasis in cardiac muscles.
Cao, JL, Adaniya, SM, Cypress, MW, Suzuki, Y, Kusakari, Y, Jhun, BS, O-Uchi, J
Archives of biochemistry and biophysics. 2019;:276-287
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Abstract
Recent discoveries of the molecular identity of mitochondrial Ca2+ influx/efflux mechanisms have placed mitochondrial Ca2+ transport at center stage in views of cellular regulation in various cell-types/tissues. Indeed, mitochondria in cardiac muscles also possess the molecular components for efficient uptake and extraction of Ca2+. Over the last several years, multiple groups have taken advantage of newly available molecular information about these proteins and applied genetic tools to delineate the precise mechanisms for mitochondrial Ca2+ handling in cardiomyocytes and its contribution to excitation-contraction/metabolism coupling in the heart. Though mitochondrial Ca2+ has been proposed as one of the most crucial secondary messengers in controlling a cardiomyocyte's life and death, the detailed mechanisms of how mitochondrial Ca2+ regulates physiological mitochondrial and cellular functions in cardiac muscles, and how disorders of this mechanism lead to cardiac diseases remain unclear. In this review, we summarize the current controversies and discrepancies regarding cardiac mitochondrial Ca2+ signaling that remain in the field to provide a platform for future discussions and experiments to help close this gap.
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Hyperglycemia-induced cardiac contractile dysfunction in the diabetic heart.
Singh, RM, Waqar, T, Howarth, FC, Adeghate, E, Bidasee, K, Singh, J
Heart failure reviews. 2018;(1):37-54
Abstract
The development of a diabetic cardiomyopathy is a multifactorial process, and evidence is accumulating that defects in intracellular free calcium concentration [Ca2+]i or its homeostasis are related to impaired mechanical performance of the diabetic heart leading to a reduction in contractile dysfunction. Defects in ryanodine receptor, reduced activity of the sarcoplasmic reticulum calcium pump (SERCA) and, along with reduced activity of the sodium-calcium exchanger (NCX) and alterations in myofilament, collectively cause a calcium imbalance within the diabetic cardiomyocytes. This in turn is characterized by cytosolic calcium overloading or elevated diastolic calcium leading to heart failure. Numerous studies have been performed to identify the cellular, subcellular, and molecular derangements in diabetes-induced cardiomyopathy (DCM), but the precise mechanism(s) is still unknown. This review focuses on the mechanism behind DCM, the onset of contractile dysfunction, and the associated changes with special emphasis on hyperglycemia, mitochondrial dysfunction in the diabetic heart. Further, management strategies, including treatment and emerging therapeutic modalities, are discussed.
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Clinical Impact of Left Ventricular Diastolic Dysfunction in Chronic Kidney Disease.
Ogawa, T, Nitta, K
Contributions to nephrology. 2018;:81-91
Abstract
Left ventricular diastolic dysfunction (LVDD) frequently occurs in chronic kidney disease (CKD) and is associated with heart failure and higher mortality. LVDD is observed in patients with early stages of CKD and is associated with cardiovascular events, in patients undergoing incident hemodialysis in the absence of systolic function. The pathogenesis of CKD includes abnormal ventricular filling in diastole and a higher LV filling pressure (LVFP) because of LV hypertrophy (LVH), in addition to myocardial interstitial fibrosis. Therefore, LV dysfunction tends to cause pulmonary congestion. In patients with CKD, the mechanism of LVDD is complicated and mainly involves LVH, which is a physiological response to pressure and volume overload. Other factors related to CKD, including LVH, neurohumoral alterations, inflammation, anemia, and mineral disorders, might cause the development of LVDD. Echocardiography is frequently used for noninvasive evaluation of diastolic function and for estimating LVFP. Echocardiographic quantification of LVFP is based on the E/e' ratio, where E is the early mitral flow velocity on transmitral Doppler and e' is the early mitral annulus velocity obtained from tissue Doppler. An E/e' ratio <8 is considered to be normal, whereas a ratio >15 is considered to mirror the increase in LVFP. The main strategy for treating LVDD is to minimize the large volume shift to control blood pressure and prevent myocardial interstitial fibrosis.
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Distinct Myocardial Targets for Diabetes Therapy in Heart Failure With Preserved or Reduced Ejection Fraction.
Paulus, WJ, Dal Canto, E
JACC. Heart failure. 2018;(1):1-7
Abstract
Noncardiac comorbidities such as diabetes mellitus (DM) have different outcomes in heart failure with preserved ejection fraction (HFpEF) compared with heart failure with reduced ejection fraction (HFrEF). These different outcomes are the result of distinct myocardial effects of DM on HFpEF and HFrEF, which relate to different mechanisms driving myocardial remodeling in each heart failure phenotype. Myocardial remodeling is driven by microvascular endothelial inflammation in HFpEF and by cardiomyocyte cell death in HFrEF. Evidence consists of: different biomarker profiles, in which inflammatory markers are prominent in HFpEF and markers of myocardial injury or wall stress are prominent in HFrEF; reduced coronary flow reserve with microvascular rarefaction in HFpEF; and upregulation of free radical-producing enzymes in endothelial cells in HFpEF and in cardiomyocytes in HFrEF. As biopsies from patients with diabetic cardiomyopathy reveal, DM affects failing myocardium by phenotype-specific mechanisms. In HFpEF, DM mainly increases cardiomyocyte hypertrophy and stiffness, probably because of hyperinsulinemia and microvascular endothelial inflammation. In HFrEF, DM augments replacement fibrosis because of cardiomyocyte cell death induced by lipotoxicity or advanced glycation end products. Because DM exerts distinct effects on myocardial remodeling in HFpEF and HFrEF, the heart failure phenotype is important for DM therapy.