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: 10595643
• 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/10595643
• 关键词: Animal Model; Carbon; Cardiac; Cardiovascular system; Cause of Death; Cessation of life; Circulation; Citric Acid Cycle; Clinical; Clinical Trials; Congestive Heart Failure; Data; Development; Diabetes Mellitus; Disease; Epidemic; Event; Functional disorder; Gene Expression; Gene Expression Profiling; General Population; Glucose; Heart; Heart failure; Heart-Assist Devices; Homeostasis; Hospitalization; Human; Impairment; Infusion procedures; Intervention; 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; 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; insight; ketogenesis; left ventricular assist device; new therapeutic target; non-diabetic; novel; novel strategies; oxidation; prospective; protein expression; restoration; symporter; 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（Diabetes Mellitus，DM）是一种全球性流行病，其在美国退伍军人中的患病率高于平民 人口心力衰竭（HF）是糖尿病患者死亡的主要原因。HF和DM的共存 临床挑战并导致更差的预后。心脏代谢在病理生理学中处于中心地位 但我们对DM和HF共存时的代谢适应性的理解非常有限。共 人类HF和DM的存在是一种复杂的慢性疾病，难以在动物中重现 模型因此，接受左心室辅助装置（LVAD）治疗的糖尿病心力衰竭患者， 这是一个独特的机会，因为在干预前后都可以获得人类心脏组织和血清。 当我们前瞻性地将心脏恢复与 分子和代谢变化。非放射性~（13）C示踪剂在糖尿病中的应用 HF患者可以进一步询问动态代谢。 我们最近的研究表明，小鼠和人类的葡萄糖氧化损伤直接影响着 与HF的发展有关。我们还发现，糖尿病HF患者的心脏恢复明显较低 与非糖尿病患者相比，LVAD卸载后的发生率。有趣的是，控制良好的糖尿病患者显示， 与控制不良相比，LVAD支持后心脏结构和功能改善。我们 假设良好控制灌注可以通过改善 葡萄糖摄取和氧化（目标1a）。我们将比较治疗前和治疗后葡萄糖摄取率的变化。 每组的LVAD植入后。此外，我们将比较从丙酮酸到乳酸的相对通量， 以及控制良好和控制不良的DM患者之间从丙酮酸到三羧酸（TCA）的循环 使用13C葡萄糖。我们将研究这些途径的相对变化是否与相对 两组心脏功能和结构的变化。自从我们对磷酸戊糖的研究 (PPP)和一碳代谢（OCM）途径表明PPP和OCM的上调相关 随着氧化还原稳态（NADP +/NADPH）的恢复和恢复，我们假设氧化还原 在血糖控制良好的糖尿病HF患者中， PPP和OCM途径的通量（目标1b）。因此，控制良好的群体很可能会表现出 与控制不良相比，LVEF和LVEDD的相对变化显著改善。 人体HF研究提供的证据表明，β-羟基丁酸（β OHB）的利用可能是 在肥大和衰竭的心脏中上调。然而，目前尚不清楚这种变化是否是适应性的， 不适应HF合并DM的心肌恢复。我们的研究表明单羧酸转运蛋白 (MCT)1和4（参与β OHB转运）和β OHB水平，在心脏组织中显著较高， 糖尿病心力衰竭患者与非心力衰竭患者相比。我们假设增加β OHB氧化通量 在糖尿病HF患者的心脏组织中， LVAD卸载后的功能和结构（目标2a）。此外，葡萄糖钠的出现 协同转运蛋白2抑制剂（SGLT 2i）是一类新型降糖药物， 在多项临床试验中减少心血管事件、HF住院和心血管死亡。 SGLT 2抑制导致的糖尿增强已显示可促进脂肪酸氧化， 肝脏中的酮生成并增加血浆β OHB水平。我们假设高血浆β OHB作为一种 SGLT 2抑制的结果促进其在糖尿病HF心脏组织中的摄取和终末氧化 并改善衰竭心脏的心脏功能（目标2b）。我们的LVAD平台提供了一种新颖的方法 探讨SGLT 2i对糖尿病心力衰竭患者心脏有益作用的机制。