Australian Regenerative Medicine Institute, Monash University, Australia; Department of Cardiology and Angiology, Experimental Cardiology, Hannover Medical School, Germany.
The Jackson Laboratory, USA.
Mol Metab. 2019 Feb;20:102-114. doi: 10.1016/j.molmet.2018.11.002. Epub 2018 Nov 15.
Congenital heart disease (CHD) is the most frequent birth defect worldwide. The number of adult patients with CHD, now referred to as ACHD, is increasing with improved surgical and treatment interventions. However the mechanisms whereby ACHD predisposes patients to heart dysfunction are still unclear. ACHD is strongly associated with metabolic syndrome, but how ACHD interacts with poor modern lifestyle choices and other comorbidities, such as hypertension, obesity, and diabetes, is mostly unknown.
We used a newly characterized mouse genetic model of ACHD to investigate the consequences and the mechanisms associated with combined obesity and ACHD predisposition. Metformin intervention was used to further evaluate potential therapeutic amelioration of cardiac dysfunction in this model.
ACHD mice placed under metabolic stress (high fat diet) displayed decreased left ventricular ejection fraction. Comprehensive physiological, biochemical, and molecular analysis showed that ACHD hearts exhibited early changes in energy metabolism with increased glucose dependence as main cardiac energy source. These changes preceded cardiac dysfunction mediated by exposure to high fat diet and were associated with increased disease severity. Restoration of metabolic balance by metformin administration prevented the development of heart dysfunction in ACHD predisposed mice.
This study reveals that early metabolic impairment reinforces heart dysfunction in ACHD predisposed individuals and diet or pharmacological interventions can be used to modulate heart function and attenuate heart failure. Our study suggests that interactions between genetic and metabolic disturbances ultimately lead to the clinical presentation of heart failure in patients with ACHD. Early manipulation of energy metabolism may be an important avenue for intervention in ACHD patients to prevent or delay onset of heart failure and secondary comorbidities. These interactions raise the prospect for a translational reassessment of ACHD presentation in the clinic.
先天性心脏病（CHD）是全球最常见的出生缺陷。随着外科手术和治疗干预的改进，现在被称为成人先天性心脏病（ACHD）的患者数量正在增加。然而，ACHD 使患者易患心脏功能障碍的机制仍不清楚。ACHD 与代谢综合征密切相关，但 ACHD 如何与不良的现代生活方式选择和其他合并症（如高血压、肥胖和糖尿病）相互作用，在很大程度上尚不清楚。
我们使用新建立的 ACHD 小鼠遗传模型来研究与肥胖和 ACHD 易感性相关的后果和机制。使用二甲双胍干预进一步评估该模型中心律失常治疗的潜在改善。
处于代谢应激（高脂肪饮食）下的 ACHD 小鼠表现出左心室射血分数降低。综合生理、生化和分子分析表明，ACHD 心脏表现出能量代谢的早期变化，以增加葡萄糖依赖性作为主要心脏能量来源。这些变化早于高脂肪饮食介导的心脏功能障碍，并与疾病严重程度增加相关。通过二甲双胍给药恢复代谢平衡可防止 ACHD 易感性小鼠发生心脏功能障碍。
这项研究揭示了早期代谢损伤会加重 ACHD 易感性个体的心脏功能障碍，饮食或药物干预可用于调节心脏功能并减轻心力衰竭。我们的研究表明，遗传和代谢紊乱之间的相互作用最终导致 ACHD 患者出现心力衰竭。早期对能量代谢的干预可能是预防或延迟 ACHD 患者心力衰竭和继发性合并症发生的重要途径。这些相互作用提出了在临床中重新评估 ACHD 表现的转化可能性。
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