PDF(Pubmed)
Abstract：
BACKGROUND: Type 2 diabetes (T2D) is a frequent comorbidity encountered in patients with severe aortic stenosis (AS), leading to an adverse left ventricular (LV) remodeling and dysfunction. Metabolic alterations have been suggested as contributors of the deleterious effect of T2D on LV remodeling and function in patients with severe AS, but so far, the underlying mechanisms remain unclear. Mitochondria play a central role in the regulation of cardiac energy metabolism.
OBJECTIVE: We aimed to explore the mitochondrial alterations associated with the deleterious effect of T2D on LV remodeling and function in patients with AS, preserved ejection fraction, and no additional heart disease.
METHODS: We combined an in-depth clinical, biological and echocardiography phenotype of patients with severe AS, with (n = 34) or without (n = 50) T2D, referred for a valve replacement, with transcriptomic and histological analyses of an intra-operative myocardial LV biopsy.
RESULTS: T2D patients had similar AS severity but displayed worse cardiac remodeling, systolic and diastolic function than non-diabetics. RNAseq analysis identified 1029 significantly differentially expressed genes. Functional enrichment analysis revealed several T2D-specific upregulated pathways despite comorbidity adjustment, gathering regulation of inflammation, extracellular matrix organization, endothelial function/angiogenesis, and adaptation to cardiac hypertrophy. Downregulated gene sets independently associated with T2D were related to mitochondrial respiratory chain organization/function and mitochondrial organization. Generation of causal networks suggested a reduced Ca2+ signaling up to the mitochondria, with the measured gene remodeling of the mitochondrial Ca2+ uniporter in favor of enhanced uptake. Histological analyses supported a greater cardiomyocyte hypertrophy and a decreased proximity between the mitochondrial VDAC porin and the reticular IP3-receptor in T2D.
CONCLUSIONS: Our data support a crucial role for mitochondrial Ca2+ signaling in T2D-induced cardiac dysfunction in severe AS patients, from a structural reticulum-mitochondria Ca2+ uncoupling to a mitochondrial gene remodeling. Thus, our findings open a new therapeutic avenue to be tested in animal models and further human cardiac biopsies in order to propose new treatments for T2D patients suffering from AS.
BACKGROUND: URL: https://www.
RESULTS: gov ; Unique Identifier: NCT01862237.
OBJECTIVE: We aimed to explore the mitochondrial alterations associated with the deleterious effect of T2D on LV remodeling and function in patients with AS, preserved ejection fraction, and no additional heart disease.
METHODS: We combined an in-depth clinical, biological and echocardiography phenotype of patients with severe AS, with (n = 34) or without (n = 50) T2D, referred for a valve replacement, with transcriptomic and histological analyses of an intra-operative myocardial LV biopsy.
RESULTS: T2D patients had similar AS severity but displayed worse cardiac remodeling, systolic and diastolic function than non-diabetics. RNAseq analysis identified 1029 significantly differentially expressed genes. Functional enrichment analysis revealed several T2D-specific upregulated pathways despite comorbidity adjustment, gathering regulation of inflammation, extracellular matrix organization, endothelial function/angiogenesis, and adaptation to cardiac hypertrophy. Downregulated gene sets independently associated with T2D were related to mitochondrial respiratory chain organization/function and mitochondrial organization. Generation of causal networks suggested a reduced Ca2+ signaling up to the mitochondria, with the measured gene remodeling of the mitochondrial Ca2+ uniporter in favor of enhanced uptake. Histological analyses supported a greater cardiomyocyte hypertrophy and a decreased proximity between the mitochondrial VDAC porin and the reticular IP3-receptor in T2D.
CONCLUSIONS: Our data support a crucial role for mitochondrial Ca2+ signaling in T2D-induced cardiac dysfunction in severe AS patients, from a structural reticulum-mitochondria Ca2+ uncoupling to a mitochondrial gene remodeling. Thus, our findings open a new therapeutic avenue to be tested in animal models and further human cardiac biopsies in order to propose new treatments for T2D patients suffering from AS.
BACKGROUND: URL: https://www.
RESULTS: gov ; Unique Identifier: NCT01862237.
摘要：
背景：2型糖尿病（T2D）是严重主动脉瓣狭窄（AS）患者常见的合并症，导致不良的左心室（LV）重塑和功能障碍。代谢改变已被认为是T2D对严重AS患者的LV重塑和功能的有害影响的贡献者。但到目前为止,潜在机制尚不清楚.线粒体在心脏能量代谢的调节中起着核心作用。
目的：我们旨在探讨与T2D对AS患者左心室重塑和功能的有害影响相关的线粒体改变，保留的射血分数，没有额外的心脏病。
方法：我们结合了深入的临床，重度AS患者的生物学和超声心动图表型，有(n=34)或没有(n=50)T2D，转介瓣膜置换,与术中心肌LV活检的转录组学和组织学分析。
结果：T2D患者的AS严重程度相似，但心脏重塑更差，收缩和舒张功能比非糖尿病患者。RNAseq分析鉴定出1029个显著差异表达的基因。功能富集分析揭示了几个T2D特异性上调途径，尽管合并症调整，聚集调节炎症，细胞外基质组织，内皮功能/血管生成，和适应心脏肥大。与T2D独立相关的下调基因集与线粒体呼吸链组织/功能和线粒体组织有关。因果网络的产生表明线粒体的Ca2+信号传导减少，与测量的线粒体Ca2+单转运蛋白的基因重塑有利于增强的摄取。组织学分析支持T2D中心肌细胞肥大更大，线粒体VDAC孔蛋白与网状IP3受体之间的接近度降低。
结论：我们的数据支持线粒体Ca2+信号在T2D诱导的严重AS患者心功能不全中的关键作用，从结构网状-线粒体Ca2解偶联到线粒体基因重塑。因此，我们的研究结果为在动物模型和进一步的人类心脏活检中进行测试开辟了一条新的治疗途径,以便为患有AS的T2D患者提出新的治疗方法.
背景：URL：https://www。
结果：gov；唯一标识符：NCT01862237。
目的：我们旨在探讨与T2D对AS患者左心室重塑和功能的有害影响相关的线粒体改变，保留的射血分数，没有额外的心脏病。
方法：我们结合了深入的临床，重度AS患者的生物学和超声心动图表型，有(n=34)或没有(n=50)T2D，转介瓣膜置换,与术中心肌LV活检的转录组学和组织学分析。
结果：T2D患者的AS严重程度相似，但心脏重塑更差，收缩和舒张功能比非糖尿病患者。RNAseq分析鉴定出1029个显著差异表达的基因。功能富集分析揭示了几个T2D特异性上调途径，尽管合并症调整，聚集调节炎症，细胞外基质组织，内皮功能/血管生成，和适应心脏肥大。与T2D独立相关的下调基因集与线粒体呼吸链组织/功能和线粒体组织有关。因果网络的产生表明线粒体的Ca2+信号传导减少，与测量的线粒体Ca2+单转运蛋白的基因重塑有利于增强的摄取。组织学分析支持T2D中心肌细胞肥大更大，线粒体VDAC孔蛋白与网状IP3受体之间的接近度降低。
结论：我们的数据支持线粒体Ca2+信号在T2D诱导的严重AS患者心功能不全中的关键作用，从结构网状-线粒体Ca2解偶联到线粒体基因重塑。因此，我们的研究结果为在动物模型和进一步的人类心脏活检中进行测试开辟了一条新的治疗途径,以便为患有AS的T2D患者提出新的治疗方法.
背景：URL：https://www。
结果：gov；唯一标识符：NCT01862237。
