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（DM）是一种全球流行病，美国退伍军人中的患病率高于平民 心力衰竭 (HF) 是糖尿病患者死亡的主要原因。 HF 和 DM 并存。 心脏代谢是病理生理学的核心。 DM 和 HF 都存在，但我们对它们共存时的代谢适应的了解非常有限。 人类存在的心力衰竭和糖尿病是一种复杂的慢性疾病，很难在动物身上重现 因此，接受左心室辅助装置 (LVAD) 治疗的 HF 合并 DM 患者呈现出一个模型。 独特的机会，因为在干预之前和之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 在 DM 中输注非放射性 13C 示踪剂时的分子和代谢变化。 心力衰竭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受损直接与 我们还发现，糖尿病性心力衰竭患者的心脏恢复速度明显较低。 与非糖尿病患者相比，LVAD 减负荷后的降压率有所下降，表明控制良好的 DM 患者。 与控制不佳相比，LVAD 支持后心脏结构和功能得到改善。 研究表明，良好控制的血糖可以通过改善血糖来促进心肌恢复 葡萄糖摄取和氧化（目标 1a）我们将比较前后葡萄糖摄取率的变化。 此外，每组的 LVAD 植入后，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糖尿病患者之间从丙酮酸到三羧酸 (TCA) 的循环 我们将使用 13C 葡萄糖来检查这些途径通量的相对变化是否与相对相关。 自从我们对磷酸戊糖进行研究以来，两组之间心脏功能和结构的变化。 (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，我们勇敢地面对氧化还原 血糖控制良好的糖尿病心力衰竭患者可以通过增加血糖来恢复稳态 PPP 和 OCM 途径的通量（目标 1b）因此，血糖控制良好的组很可能表现出。 与控制不佳的患者相比，相对 LVEF 和 LVEDD 变化显着改善。 对人类心力衰竭的研究提供的证据表明，β-羟基丁酸 (ßOHB) 的利用可能是 然而，尚不清楚这种变化是适应性的还是衰竭的。 我们的研究表明单羧酸转运蛋白对 HF 合并 DM 的心肌恢复不良。 (MCT) 1 和 4（参与 ßOHB 转运）和 ßOHB 水平在心脏组织中显着较高 与非衰竭心脏相比，糖尿病心力衰竭患者的 ßOHB 氧化通量有所增加。 糖尿病心力衰竭患者心脏组织中的变化可能与心脏功能的相对改善相关 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 (SGLT2i) 是一类新型降糖药物，已被证明可以显着 在多项临床试验中，可减少心血管事件、心力衰竭住院和心血管死亡。 SGLT2 抑制导致的糖尿增加已被证明可以促进脂肪酸氧化和 我们将高血浆 ßOHB 捕获为肝脏的生酮作用并增加血浆 ßOHB 水平。 SGLT2抑制促进其在糖尿病性心力衰竭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。 研究这一假设以及 SGLT2i 对糖尿病心力衰竭患者有益心脏作用的机制。