心脏代谢合并症作为心血管领域的多发病，其管理策略一直是医学研究的热点和难点。这类疾病涉及多个系统的病理生理变化，治疗难度极大。然而，正是这些挑战，促使我们不断探索和创新。2024年6月27日，WCC多发病率与代谢论坛于第十八届东方心脏病学会议（The 18th Oriental Congress of Cardiology，OCC 2024）与世界心脏病学大会（World Congress of Cardiology，WCC 2024）上顺利召开，与会专家们围绕心脏代谢合并症的发病机制、诊断技术、治疗策略以及未来发展方向展开深入研讨。
Cardiac metabolic comorbidities, as prevalent diseases in the cardiovascular field, have long been a focus and challenge in medical research. These diseases involve pathophysiological changes in multiple systems, making treatment extremely difficult. However, it is precisely these challenges that drive us to continuously explore and innovate. On June 27, 2024, the WCC Multimorbidity and Metabolism Forum was successfully held at the 18th Oriental Congress of Cardiology (OCC 2024) and the World Congress of Cardiology (WCC 2024). Experts engaged in in-depth discussions on the pathogenesis, diagnostic techniques, treatment strategies, and future directions of cardiac metabolic comorbidities.
参会嘉宾
Pablo Perel教授，伦敦卫生与热带医学学院
黄恺教授，华中科技大学同济医学院附属协和医院
Jay D Horton教授，美国德州大学西南医学中心
李华婷教授：上海交通大学附属第六人民医院
Attendees
Professor Pablo Perel, University of London, London School of Hygiene & Tropical Medicine;
Professor Huang Kai, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology;
Professor Jay D Horton, UT Southwestern Medical Center;
Professor Li Huating， Shanghai 6th People’s Hospital
李华婷：抗性淀粉重塑肠道菌群--肥胖治疗新途径
李华婷教授分享了其团队关于胰岛素抵抗与肥胖关系的最新研究成果。李教授指出，过度营养会导致脂肪组织、肝脏和骨骼肌的胰岛素抵抗，进而引发一系列代谢紊乱。而减重可以改善各器官的胰岛素敏感性，对代谢功能和肥胖相关并发症具有显著的治疗效果。
李教授介绍了评估胰岛素敏感性的多种方法，其中高胰岛素-正葡萄糖钳夹技术（HEC）被认为是金标准。并且详细阐述了扩展型HEC程序，该方法可同时测量葡萄糖代谢和脂质代谢等多个参数。李教授团队在研究中发现超重和肥胖人群的葡萄糖利用率显著低于正常体重者。同时，内脏型肥胖患者的葡萄糖氧化和非氧化率增幅均显著低于非内脏型肥胖患者，且游离脂肪酸水平更高。
李教授重点介绍了研究团队最新发表在Nature Metabolism杂志上的随机对照试验。该试验对37名超重或肥胖受试者进行了为期8周的抗性淀粉(RS)干预。结果显示，RS组平均减重2.8公斤，并改善了胰岛素敏感性、炎症反应和脂质代谢。研究进一步揭示，RS干预重塑了肠道菌群，特别是增加了青春双歧杆菌的丰度。通过粪便菌群移植和无菌小鼠实验，研究团队证实RS的减重效果依赖于肠道菌群，部分由青春双歧杆菌介导。
李教授解释道，青春双歧杆菌通过抑制脂质吸收、修复肠道屏障、降低系统性炎症和提高FGF21敏感性来缓解肥胖。这一发现为开发新型膳食干预策略提供了重要依据。
Professor Li Huating shared the latest findings on the relationship between insulin resistance and obesity. The study, published in Nature Metabolism, reveals the mechanism by which resistant starch (RS) improves obesity and metabolic disorders through modulation of gut microbiota.
The research first conducted a randomized controlled trial involving 37 overweight or obese subjects who underwent an 8-week intervention with RS or control starch (CS). Results showed that the RS group lost an average of 2.8 kg in weight, while also improving insulin sensitivity and reducing inflammatory response and lipid absorption.
Further research found that RS intervention reshaped the gut microbiota, significantly increasing the abundance of Bifidobacterium adolescentis, which was closely associated with improved metabolic parameters. When the fecal microbiota from RS and CS group subjects were transplanted into mice, those receiving the RS microbiota showed reduced body weight, fat content, and systemic inflammation.
To verify whether the weight loss effect of RS depends on gut microbiota, the research team conducted experiments in germ-free mice. Results showed that RS lost its weight loss effect in germ-free mice but regained it after supplementation with B. adolescentis. This confirms that the weight loss benefits of RS are partially mediated by B. adolescentis.
Mechanistic studies revealed that B. adolescentis alleviates obesity by inhibiting lipid absorption, repairing the intestinal barrier, reducing systemic inflammation, and improving FGF21 sensitivity in target tissues.
Professor Li stated that this study provides a practical lifestyle intervention method for treating obesity and related metabolic disorders. In an accompanying commentary published in Nature Metabolism, Professor Matthew M. Carter from Stanford University pointed out that this study demonstrates the clear utility of microbiota-targeted therapies for metabolic diseases and hints at the promise that optimized microbial therapeutics offer for the future.
This research not only deepens our understanding of the mechanisms of obesity but also opens up new avenues for developing novel dietary intervention strategies, potentially offering new solutions to the growing global obesity problem.
JAY D Horton:PCSK9从基因发现到降脂新疗法的跨越式发展
Jay D Horton教授分享了PCSK9从基因发现到治疗应用的研究历程。Horton教授介绍，PCSK9基因最初是在研究类固醇调节元件结合蛋白(SREBPs)时被发现的。随后的研究揭示，PCSK9蛋白可以促进低密度脂蛋白受体(LDLR)的降解，从而影响血液中胆固醇的水平。
Horton教授详细阐述了PCSK9的作用机制。研究发现，PCSK9通过与LDLR的表皮生长因子样结构域A(EGF-A)结合，促进LDLR的降解。这一发现为开发靶向PCSK9的治疗策略提供了重要依据。
值得注意的是，Horton教授强调，PCSK9的催化活性并不是其降解LDLR所必需的，这一发现为开发PCSK9抑制剂提供了新的思路。
在临床应用方面，Horton教授介绍了两种针对PCSK9的单克隆抗体药物：Alirocumab和Evolocumab。这两种药物在2015年获得FDA批准，用于治疗家族性高胆固醇血症和动脉粥样硬化性心脏病患者。临床试验结果显示，这些抗体药物可以显著降低患者的LDL胆固醇水平。PCSK9从基因发现到临床应用仅用了约12年时间，这在药物开发史上是相当快速的。这一成功案例不仅为高胆固醇血症患者带来了新的治疗选择，也为未来靶向治疗的开发提供了宝贵经验。
Professor Jay D Horton shared the research journey of PCSK9 from gene discovery to therapeutic application. Prof. Horton explained that the PCSK9 gene was initially discovered during studies on Sterol Regulatory Element Binding Proteins (SREBPs). Subsequent research revealed that the PCSK9 protein promotes the degradation of low-density lipoprotein receptors (LDLR), thereby affecting cholesterol levels in the blood.
Prof. Horton elaborated on the mechanism of action of PCSK9. Research found that PCSK9 binds to the epidermal growth factor-like domain A (EGF-A) of LDLR, promoting LDLR degradation. This discovery provided an important basis for developing therapeutic strategies targeting PCSK9.
Notably, Prof. Horton emphasized that the catalytic activity of PCSK9 is not necessary for its degradation of LDLR. This finding opened new avenues for developing PCSK9 inhibitors.
In terms of clinical applications, Prof. Horton introduced two monoclonal antibody drugs targeting PCSK9: Alirocumab and Evolocumab. These drugs were approved by the FDA in 2015 for treating familial hypercholesterolemia and atherosclerotic heart disease patients. Clinical trial results showed that these antibody drugs can significantly lower patients' LDL cholesterol levels.
Prof. Horton pointed out that it took only about 12 years from the discovery of the PCSK9 gene to its clinical application, which is remarkably fast in the history of drug development. This successful case not only brings new treatment options for patients with hypercholesterolemia but also provides valuable experience for the future development of targeted therapies.
黄恺教授：中国心血管疾病死亡率上升的隐形推手——糖尿病
黄恺教授就中国心血管死亡率中糖尿病负担的最新研究成果进行了分享。研究显示，糖尿病和糖尿病前期正在成为中国心血管疾病死亡的主要风险因素。
黄教授指出，心血管疾病已成为中国居民的首要死因，且死亡率持续上升。从1990年到2013年，心血管疾病死亡人数增加了46%。同时，中国糖尿病患病率在过去40年间增长了20倍，目前约有1.4亿中国成年人患有糖尿病。黄教授的研究团队分析了来自中国慢性病人群队列的17万多名参与者的数据。数年的随访调查结果显示，糖尿病与全因死亡、心血管疾病死亡和癌症死亡风险增加显著相关。在总死亡人数中，糖尿病前期人群相比糖尿病人群，与全因死亡和心血管疾病死亡风险增加相关，总死亡占比超过70%。这些结果提示我们糖代谢异常会对身体健康带来极大危害。
基于这些发现，黄教授呼吁加强糖尿病和糖尿病前期的预防和治疗，并强调需要开发针对性干预措施，以减轻糖尿病及其并发症在中国的疾病负担。
Professor Huang Kai shared the latest findings on the diabetes burden of cardiovascular mortality. The research shows that diabetes and prediabetes are becoming major risk factors for cardiovascular disease mortality in China.
Prof. Huang pointed out that cardiovascular disease has become the leading cause of death among Chinese residents, with mortality rates continuing to rise. From 1990 to 2013, the number of cardiovascular disease deaths increased by 46%. Meanwhile, the prevalence of diabetes in China has grown 20-fold over the past 40 years, with approximately 140 million Chinese adults now living with diabetes.
Prof. Huang's research team analysed the data of more than 170,000 participants from the chronic patient cohort in China. The results of several years of follow-up survey show that diabetes is significantly related to all-cause death, cardiovascular disease death and increased risk of cancer death. Among the total number of deaths, compared with people with diabetes, the pre-diabetic population is associated with the increased risk of all-cause death and cardiovascular disease death, accounting for more than 70% of the total deaths. These results suggest that our abnormal sugar metabolism will bring great harm to our health.
Based on these findings, Prof. Huang called for strengthening the prevention and treatment of diabetes and pre-diabetes. He stressed the need to develop targeted interventions to reduce the disease burden of diabetes and its complications in China.
本次学术会议汇聚了国内外顶尖专家，聚焦代谢疾病的最新研究进展及其对国民健康的深远影响。这些突破性研究不仅深化了我们对代谢疾病的认识，也为制定更有针对性的公共卫生政策和个体化治疗方案提供了科学依据，对提升国民健康水平具有重要意义。
This academic conference brought together top experts from home and abroad, focusing on the latest research progress in metabolic diseases and their profound impact on national health. These breakthrough studies not only deepened our understanding of metabolic diseases but also provided scientific basis for formulating more targeted public health policies and individualized treatment plans, which are of great significance for improving the health level of the nation.
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