Understanding Myocardial Recovery in Diabetes and Heart Failure

了解糖尿病和心力衰竭的心肌恢复

• 批准号: 10426081
• 负责人: Stavros George Drakos
• 金额: --
• 依托单位: VA SALT LAKE CITY HEALTHCARE SYSTEM
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-10-01 至 2024-09-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10426081
• 关键词: Animal Model; Blood Circulation; Carbon; Cardiac; Cardiovascular system; Cause of Death; Cessation of life; Citric Acid Cycle; Clinical; Clinical Trials; Congestive Heart Failure; Data; Diabetes Mellitus; Disease; Epidemic; Event; Functional disorder; Gene Expression; General Population; Glucose; Heart; Heart failure; Heart-Assist Devices; Homeostasis; Hospitalization; Human; Impairment; Infusion procedures; Intervention; Investigation; Ketones; Label; Left Ventricular Ejection Fraction; Link; Lipolysis; Liver; Metabolic; Metabolism; Methods; Molecular; Mus; Myocardial; Myocardial tissue; Myocardium; NADP; Outcome; Oxidation-Reduction; Pathway interactions; Patients; Pentosephosphates; Pharmaceutical Preparations; Plasma; Population; Prevalence; Production; Prognosis; Pyruvate; Recovery; Reporting; Risk; Role; Sampling; Serum; Sodium; Source; Stable Isotope Labeling; Structure; Testing; Therapeutic Intervention; Tissues; Tracer; Up-Regulation; Veterans; beta-Hydroxybutyrate; cardiogenesis; complex chronic conditions; diabetic; fatty acid oxidation; flexibility; functional improvement; glucose uptake; heart function; heart metabolism; human model; implantation; improved; improved outcome; in vivo; indexing; inhibitor; inorganic phosphate; insight; ketogenesis; left ventricular assist device; new therapeutic target; non-diabetic; novel; novel strategies; oxidation; prospective; protein expression; restoration; uptake

Diabetes Mellitus (DM) is a global epidemic and its prevalence among US veterans is higher than the civilian population. Heart failure (HF) is the leading cause of death in diabetics. The coexistence of HF and DM poses clinical challenges and results in much poorer prognosis. Cardiac metabolism is central in the pathophysiology of both DM and HF but our understanding of the metabolic adaptations when they coexist is very limited. Co- existence of HF and DM in humans is a complex chronic condition that is difficult to recapitulate in an animal model. Hence, HF patients with DM undergoing therapy with left ventricular assist devices (LVAD) present a unique opportunity, as human cardiac tissue and serum become available, both before and after intervention. These samples become extremely more informative when we prospectively associate cardiac recovery with molecular and metabolic changes while on LVAD support. The infusion of non-radioactive 13C tracers in DM HF patients can further interrogate the dynamic metabolism. Our recent studies demonstrated that impairment of glucose oxidation in mice and humans is directly linked to development of HF. We also found that diabetic HF patients have significantly lower cardiac recovery rate following LVAD unloading compared to non-diabetics. Interestingly, well-controlled DM patients showed improvement of cardiac structure and function following LVAD support compared to poorly controlled. We hypothesize that well-controlled glycemia may enhance myocardial recovery through improved glucose uptake and oxidation (Aim 1a). We will compare changes of glucose uptake rate between pre- and post-LVAD implantation for each group. In addition, we will compare the relative flux from pyruvate to lactate, and from pyruvate to tricarboxylic acid (TCA) cycle between well-controlled and poorly controlled DM patients using 13C glucose. We will examine whether relative changes in flux of these pathways correlate with relative changes in cardiac function and structure between the two groups. Since our study of pentose phosphate (PPP) and one carbon metabolism (OCM) pathways indicated that upregulation of PPP and OCM correlate with restoration of redox homeostasis (NADP+/NADPH) and recovery, we hypothesize that redox homeostasis may be restored in diabetic HF patients with well-controlled glycemia through increased flux of PPP and OCM pathways (Aim 1b). Therefore, the group of well-controlled glycemia is likely to show significant improvement in relative LVEF and LVEDD change compared to the poorly controlled. Studies of HF in humans provided evidence that ß-hydroxybutyrate (ßOHB) utilization may be upregulated in hypertrophic and failing hearts. However, it is unknown whether this change is adaptive or maladaptive for myocardial recovery in HF with DM. Our studies showed that monocarboxylate transporter (MCT) 1 and 4 (involved in ßOHB transport) and ßOHB levels, are significantly higher in cardiac tissues of diabetic HF patients, compared to non-failing hearts. We hypothesize that increase flux of ßOHB oxidation in cardiac tissues of diabetic HF patients may correlate with the relative improvement in cardiac function and structure following LVAD unloading (Aim 2a). Furthermore, the advent of sodium-glucose cotransporter 2 inhibitors (SGLT2i), a new class of glucose-lowering drugs, has been shown to significantly reduce cardiovascular events, HF hospitalizations, and cardiovascular death in multiple clinical trials. Enhanced glucosuria as a result of SGLT2 inhibition has been shown to promote fatty acid oxidation and ketogenesis in the liver and increase plasma level of ßOHB. We hypothesize that high plasma ßOHB as a result of SGLT2 inhibition promotes its uptake and terminal oxidation in cardiac tissue of diabetic HF and improves cardiac function of the failing heart (Aim 2b). Our LVAD platform provides a novel approach to investigate this hypothesis and the mechanisms of SGLT2i beneficial cardiac effect on diabetic HF patients.

糖尿病(DM)是一种全球性的流行病，美国退伍军人的患病率高于平民 人口。心力衰竭(HF)是糖尿病患者的主要死亡原因。HF和DM并存的姿势 临床挑战和结果是预后要差得多。心脏代谢在病理生理学中处于中心地位。 糖尿病和心力衰竭都存在，但我们对它们共存时的代谢适应的了解非常有限。共同-- 人类存在的心力衰竭和糖尿病是一种复杂的慢性疾病，在动物身上很难概括。 模特。因此，接受左心室辅助装置(LVAD)治疗的糖尿病心衰患者表现为 独一无二的机会，因为人类心脏组织和血清在干预前后都可以获得。 当我们前瞻性地将心脏恢复与心脏恢复联系在一起时，这些样本变得极其信息丰富 接受左心辅助治疗时的分子和代谢变化。非放射性~(13)C示踪剂在糖尿病中的应用 心衰患者可进一步了解动态代谢情况。 我们最近的研究表明，在小鼠和人类中葡萄糖氧化的损害是直接的 与心力衰竭的发展有关。我们还发现，糖尿病心衰患者的心脏复苏率显著降低。 与非糖尿病患者相比，左冠状动脉前降支后的心率。有趣的是，控制良好的糖尿病患者显示 与控制较差的患者相比，LVAD支持后心脏结构和功能的改善。我们 假设良好控制的血糖可以通过改善血糖促进心肌恢复 葡萄糖摄取和氧化(目标1a)。我们将比较治疗前后葡萄糖摄取率的变化。 每组均行左冠状动脉左前降支植入术后。此外，我们将比较丙酮酸到乳酸的相对通量， 控制良好和控制不良的糖尿病患者之间从丙酮酸到三羧酸(TCA)的循环 使用13C葡萄糖。我们将检验这些路径的流量的相对变化是否与相对的 两组间心脏功能和结构的变化。自从我们对磷酸戊糖的研究以来 (PPP)和一碳代谢(OCM)途径表明，PPP和OCM上调相关 随着氧化还原动态平衡的恢复(NADP+/NADPH)和恢复，我们假设氧化还原 血糖控制良好的糖尿病心衰患者可通过增加 PPP和OCM途径的流量(目标1b)。因此，血糖控制良好的人群很可能表现出 相对LVEF和LVEDD的变化与控制不良组相比有显著改善。 对人体中的HF的研究提供了证据，证明？羟丁酸酯(？OHB)的利用可能是 在肥大和衰竭的心脏中表达上调。然而，目前尚不清楚这种变化是适应性的还是 糖尿病合并心力衰竭患者的心肌恢复适应不良。我们的研究表明，单羧酸盐转运体 (MCT)1和4(参与OHB转运)和OHB水平在以下心脏组织中显著升高 糖尿病心衰患者与非心力衰竭患者相比。我们假设增加OHB氧化的通量 在糖尿病心衰患者心脏组织中的表达可能与心脏相对改善有关 LVAD卸载后的功能和结构(目标2a)。此外，葡萄糖钠的问世 辅转运蛋白2抑制剂(SGLT2i)是一类新型降糖药物，已被证明具有显著的降糖作用。 在多项临床试验中减少心血管事件、心力衰竭住院和心血管死亡。 抑制SGLT2导致的葡萄糖尿增加已被证明促进脂肪酸氧化和 肝脏中酮的生成和升高血浆OHB水平。我们假设高血浆≈OHb是一个 SGLT2抑制结果促进糖尿病心衰大鼠心肌组织摄取和终末氧化 并改善衰竭心脏的心功能(目标2b)。我们的LVAD平台提供了一种新的方法 探讨SGLT2i对糖尿病心衰患者心脏有益作用的假说及其机制。