1. 引言
近年来，生酮饮食（Ketogenic Diet, KD）作为一种极低碳水化合物、高脂肪、适量蛋白质的饮食模式，因其在体重管理、血糖控制、癫痫治疗乃至神经退行性疾病（如阿尔茨海默病）中的潜在益处而广受欢迎 12345。这种饮食通过显著限制碳水化合物摄入（通常低于50克/天），促使身体从葡萄糖代谢转向脂肪代谢，进而产生酮体（如β-羟丁酸、乙酰乙酸和丙酮）作为主要的能量来源，实现“营养性酮症”状态 6。与糖尿病酮症酸中毒这一危及生命的病理状态不同，营养性酮症通常是安全的生理适应过程 6。
与此同时，心脏功能在维持整体健康，特别是在应对代谢性疾病方面扮演着核心角色。肥胖、2型糖尿病和代谢综合征等疾病在全球范围内迅速蔓延，这些代谢紊乱不仅直接损害心血管健康，还是心力衰竭（特别是射血分数保留性心力衰竭, HFpEF）、冠心病及心律失常等多种心脏疾病的独立危险因素 7891011。心脏作为高耗能器官，其能量代谢模式对心肌功能至关重要。在病理状态下，心肌能量底物利用的改变常导致心功能受损 11。
鉴于生酮饮食对全身代谢的深远影响及其日益增长的普及性，系统性地评估其对心脏功能的影响变得尤为重要。本综述旨在全面梳理生酮饮食与心脏功能关联的最新研究进展，深入探讨其潜在的分子机制、现有临床证据以及仍存在的争议与风险。通过整合现有知识，本综述将为理解生酮饮食在心血管健康中的作用提供一个清晰的框架，并展望未来的研究方向，以期为临床实践和公众健康提供科学依据。
2. 生酮饮食的代谢特征与心脏能量代谢基础
2.1 生酮饮食的定义与代谢适应
生酮饮食是一种严格限制碳水化合物摄入（通常占总能量的5%-10%）、高脂肪（70%-75%）和适量蛋白质（15%-20%）的饮食模式 12。经典的生酮饮食配比，例如“6.6:1”或“3.0:1”，指的是脂肪与蛋白质加碳水化合物的重量比，通常用于癫痫治疗等更严格的临床干预 13。这种饮食模式的核心在于通过极低的碳水化合物摄入量（通常每日低于20-50克），迫使身体从以葡萄糖为主要能量来源的代谢模式转向以脂肪为主要能量来源。
当碳水化合物摄入量极低时，肝脏储存的糖原耗尽，血糖水平下降，胰岛素分泌减少，而胰高血糖素和儿茶酚胺等激素水平升高，从而激活脂肪分解和β-氧化过程。肝脏线粒体将脂肪酸转化为乙酰辅酶A，进而生成酮体，包括β-羟丁酸（β-HB）、乙酰乙酸（AcAc）和丙酮 14。这些酮体被释放到血液中，作为葡萄糖的替代燃料，供给大脑、心脏、骨骼肌等葡萄糖依赖性组织使用。当血酮浓度达到一定阈值（通常为0.5 mM以上，高可达3-5 mM）时，即进入“营养性酮症”状态 14。这一过程是身体对碳水化合物限制的正常生理适应，而非病理性的酮症酸中毒。例如，在长期禁食或饥饿状态下，身体也会通过生成酮体来维持能量供应 15。
2.2 心脏正常能量代谢模式
心脏是体内代谢最活跃的器官之一，每时每刻都在进行收缩泵血，对能量的需求巨大且持续。心脏的正常能量代谢具有高度的灵活性和适应性，能够根据可用的营养底物（如脂肪酸、葡萄糖、乳酸和酮体）动态调整其燃料利用比例 1617。在生理条件下，心肌约60%-90%的ATP（三磷酸腺苷）由脂肪酸氧化提供，而葡萄糖氧化则提供约10%-40%的ATP 18。乳酸和酮体在正常情况下也是次要但重要的能量来源 16。心肌能够优先利用脂肪酸，但当葡萄糖供应充足或心肌负荷增加时，也会增加葡萄糖的利用。
这种代谢灵活性对于维持心脏功能至关重要。例如，在运动或应激状态下，心肌能够迅速切换能量底物，以满足不断变化的能量需求。然而，在病理状态下，如心力衰竭、肥胖或糖尿病，心肌的能量代谢模式会发生显著改变，这种改变被称为“代谢重构” 16。例如，在心力衰竭时，心肌的线粒体氧化磷酸化功能下降，导致能量合成受损，同时葡萄糖氧化减少而糖酵解可能增加，或脂肪酸氧化改变（HFpEF中脂肪酸氧化增加，HFrEF中则可能减少或不变） 18。此时，酮体的利用在某些类型的心力衰竭中可能增加，以弥补能量不足 1619。心肌的这种代谢重构不仅影响ATP的生成效率，还会通过改变代谢中间产物和信号分子，影响基因表达、蛋白质功能和细胞信号通路，从而进一步加剧心脏病理进程 1720。因此，理解生酮饮食如何影响这些复杂的代谢通路，对于评估其对心脏功能的影响至关重要。
3. 生酮饮食影响心脏功能的分子机制
生酮饮食通过其独特的代谢途径，特别是酮体的生成和利用，对心脏功能产生多方面的分子影响。这些影响既包括潜在的心脏保护作用，也可能涉及一些复杂的调节和潜在风险。
3.1 酮体的直接心脏保护作用
β-羟丁酸（β-HB）是生酮饮食诱导的营养性酮症中最主要的酮体，被认为是心脏保护的关键介质之一。β-HB的心脏保护作用主要体现在以下几个方面：
首先，β-HB能够抑制NLRP3（NOD样受体家族、含有PYRIN结构域3）炎症小体的激活。NLRP3炎症小体是先天免疫系统的重要组成部分，其过度激活与多种心血管疾病的发生发展密切相关，包括心肌梗死、心力衰竭和动脉粥样硬化 2122。研究表明，在射血分数保留性心力衰竭（HFpEF）的小鼠模型中，线粒体过度乙酰化会加剧IL-1β/IL-18的过量产生和组织纤维化，而增加酮体（特别是β-HB）的可用性能够逆转这些表型 21。β-HB通过抑制NLRP3炎症小体的形成，减弱促炎细胞因子的释放，从而减轻心肌炎症反应 2122。此外，β-HB还被发现能够下调乙酰辅酶A池和线粒体乙酰化，部分通过激活柠檬酸合酶（CS）和抑制脂肪酸摄取来发挥作用，这进一步抑制了炎症的发生 21。在脓毒症模型中，外源性酮酯（可提高血酮水平）显著减轻了LPS诱导的全身性炎症反应和器官损伤，包括对心脏功能的保护作用，这进一步支持了酮体抗炎的特性 23。
其次，β-HB可能通过激活GPR109A受体发挥作用。GPR109A（也称为烟酸受体1）是一种G蛋白偶联受体，主要表达在脂肪组织和免疫细胞上。虽然GPR109A在心肌细胞中的直接作用尚未完全阐明，但已知其激活可以介导抗炎和血管保护作用。β-HB作为GPR109A的内源性配体，其激活该受体可能通过调节下游信号通路，如抑制NF-κB信号，从而减少促炎基因的表达，进而对心脏产生保护效应。
再者，β-HB具有增强线粒体抗氧化能力的作用。心脏作为高代谢器官，其线粒体不断产生活性氧（ROS），适量的ROS是信号分子，但过量的ROS则会导致氧化应激，损伤心肌细胞。β-HB能够提升心肌细胞的抗氧化酶活性，例如超氧化物歧化酶（SOD）活性，特别是铜/锌超氧化物歧化酶（Cu/Zn-SOD） 24。研究发现，在链脲佐菌素诱导的糖尿病大鼠模型和高糖处理的人心脏微血管内皮细胞中，β-HB通过促进Cu/Zn-SOD的生成，减少过氧亚硝酸盐的产生，从而抑制心脏微血管胶原蛋白IV的积累和纤维化 24。这种抗氧化特性有助于保护心肌细胞免受氧化损伤。此外，乙酰乙酸，作为另一种酮体，也被证实能够通过抗氧化机制增强心肌的β-肾上腺素能正性肌力作用，提示酮体在恢复缺血再灌注心肌功能中的潜在益处 2526。
总而言之，β-HB通过抑制炎症小体激活、潜在的受体介导作用以及增强抗氧化防御，共同构成了其对心脏的直接保护机制，这为生酮饮食在改善心脏健康方面的应用提供了分子层面的解释。
3.2 脂肪酸代谢通路的双向调节
生酮饮食以其高脂肪摄入为特征，这不可避免地会对心肌的脂肪酸代谢通路产生深远影响。心脏是脂肪酸氧化的主要器官，其大部分能量来源于此。在生酮饮食下，循环中的脂肪酸水平升高，直接促进了心肌对脂肪酸的利用和氧化，这一过程主要通过线粒体脂肪酸β-氧化来完成。
核心的调节因子是肉碱棕榈酰转移酶1A（CPT1A）和过氧化物酶体增殖物激活受体α（PPARα）。CPT1A是脂肪酸进入线粒体进行β-氧化的限速酶，生酮饮食通过增加脂肪酸供应和改变激素环境（如胰岛素下降）来上调CPT1A的活性，从而增强心肌对长链脂肪酸的摄取和线粒体转运。PPARα则是一个核受体，广泛分布于心肌细胞中，它在脂肪酸代谢中发挥着关键的转录调控作用。当脂肪酸及其衍生物作为配体结合PPARα时，它会激活一系列参与脂肪酸摄取、转运和氧化的基因表达，包括CPT1A、脂肪酸转运蛋白（FAT/CD36）和多种β-氧化酶的基因。因此，生酮饮食可以有效激活心肌的PPARα信号通路，导致脂肪酸氧化能力显著增强。
然而，脂肪酸氧化的过度增强并非总是带来益处，甚至可能导致“代谢解偶联”现象，从而降低心肌的能量效率。代谢解偶联是指线粒体氧化磷酸化过程中，电子传递链与ATP合成的偶联程度降低，导致更多的能量以热量的形式耗散，而不是有效地用于ATP的合成。虽然高脂肪酸氧化提供了充足的能量底物，但在某些情况下，过度依赖脂肪酸氧化会抑制葡萄糖氧化。例如，一项研究指出，在缺血性心力衰竭的小鼠模型中，生酮饮食虽然增加了血酮水平，但并没有改善心功能，反而显著降低了心脏的葡萄糖氧化率，并且心脏的酮体氧化率并未增加，这可能是由于关键酮体氧化酶表达的降低。相反，心肌对脂肪酸氧化的依赖性增加，导致心力衰竭小鼠在生酮饮食下心脏效率下降 27。这种现象可能是由于高脂肪酸氧化产生的乙酰辅酶A和NADH/FADH2累积，反馈性抑制糖酵解和葡萄糖氧化关键酶的活性（如丙酮酸脱氢酶复合体），即著名的“葡萄糖-脂肪酸循环”或Randle循环。长期或过度地抑制葡萄糖氧化，尤其是在心肌应激或缺血再灌注等需要高效率能量供应的病理生理状态下，可能导致心肌无法灵活适应能量需求的变化，从而损害心功能。
此外，过度的脂肪酸氧化也可能导致活性氧（ROS）的产生增加。尽管酮体本身具有抗氧化作用，但如果脂肪酸氧化超出了线粒体的处理能力，或电子传递链出现功能障碍，ROS的生成可能会抵消部分抗氧化益处，甚至加剧氧化应激，长期来看可能对心肌细胞造成损伤。因此，生酮饮食对心脏脂肪酸代谢的双向调节效应需要更深入的评估，尤其是在不同生理和病理背景下的长期影响。
3.3 离子通道与电生理特性改变
心脏的正常功能高度依赖于心肌细胞精确的离子通道活动和电生理特性。任何对这些特性的干扰都可能导致心律失常。生酮饮食，特别是长期酮症状态，已被动物实验和临床观察提示可能对心肌的离子通道功能产生影响，进而影响心脏的电生理稳定性。
一项针对糖尿病大鼠心脏的研究发现，生酮饮食能够纠正糖尿病引起的QTc间期延长和动作电位时程延长，并改善了心肌细胞内的钙稳态。具体而言，生酮饮食治疗的糖尿病大鼠心肌表现出细胞内钙瞬变、肌浆网钙含量以及L-型钙通道和肌浆网钙ATP酶（SERCA2a）含量的升高。同时，其雷诺定受体2（RyR2）、磷酸肌醇磷酸酶（PLB）和钙调蛋白依赖性蛋白激酶II（CaMKII）等钙处理蛋白的磷酸化水平异常升高得到纠正。这些改变提示生酮饮食可能通过调节钙处理蛋白，从而改善糖尿病心肌病中的心肌收缩功能和防止心律失常的发生 28。此外，该研究还观察到生酮饮食可能减轻糖尿病引起的钠/氢交换电流和晚期钠电流的失调，这些也与心律失常的发生密切相关 28。
然而，也有其他研究或假说提出，在某些情况下，长期酮症可能与心律失常风险的潜在关联。例如，虽然β-HB可以改善钙稳态，但酮体本身对心肌细胞离子通道（如钠通道、钾通道，特别是人乙醚-à-go-go相关基因（hERG）钾通道）的直接作用尚不完全清楚。hERG通道是心脏复极的关键通道，其功能障碍与长QT综合征及室性心律失常相关。理论上，代谢产物的改变可能影响离子通道的构象或功能，或通过影响细胞内pH值和ATP/AMP比率间接影响通道活性。此外，生酮饮食导致的电解质紊乱（如低钾、低镁）本身也是心律失常的已知风险因素，尽管这并非酮体本身的直接效应，但却是生酮饮食干预中需要密切监测的方面。
尽管上述动物实验结果表明生酮饮食对糖尿病引起的心脏电生理异常具有改善作用 28，但这些发现在健康个体或不同病理状态下的普适性以及长期效应仍需更多临床研究验证。未来研究需要更深入地探讨酮体及其代谢产物对各类心肌离子通道的直接作用，以及生酮饮食引起的宏观代谢变化（如血糖、胰岛素水平和脂肪酸氧化状态）如何共同影响心脏的电生理稳定性和心律失常风险。
4. 临床研究中的心脏功能结局证据
4.1 健康人群的短期干预结果
在健康人群中评估生酮饮食对心脏功能的影响，是理解其潜在益处和风险的关键一步，尤其是在排除其他疾病混杂因素的情况下。目前，针对健康个体短期（通常3-6个月）生酮饮食干预的随机对照试验（RCTs）已积累了一些证据，这些研究主要关注心功能相关的生理指标，如心脏射血分数、左室舒张功能以及运动耐量。
在关于射血分数（Ejection Fraction, EF）的研究中，现有数据多表明短期生酮饮食对健康成年人的左心室射血分数没有显著的负面影响，通常保持在正常范围内。射血分数是衡量心脏泵血能力的重要指标，其稳定提示生酮饮食在短期内不损害心脏的收缩功能。一项心脏MRI调查显示，摄入生酮促进性饮料后，健康成年人的心输出量（CO）和心肌血流量（MBF）在急性期显著升高，这主要是由于射血量（stroke volume）和心率（heart rate）的增加，表明酮体可能对心脏功能有即时促进作用 29。然而，这并非长期饮食干预下的结果，且心率的持续升高在长期效应中需要被进一步评估。
左室舒张功能，常用E/A比值（二尖瓣口早期舒张期血流速度E峰与晚期舒张期血流速度A峰的比值）来评估，反映了左心室在舒张期充盈血液的能力。尽管在健康人群中进行生酮饮食干预的随机对照试验中，直接报告E/A比值变化的数据相对较少，但已有研究表明，体重减轻本身能够改善高血压患者的左心室舒张功能 30。考虑到生酮饮食在健康超重或肥胖个体中常能带来体重减轻，因此其对舒张功能的间接益处是可能的。然而，需要指出的是，并非所有体重减轻都能归因于生酮饮食，因此直接评估生酮饮食本身对舒张功能的影响仍需更多专门的RCTs。
运动耐量是衡量心血管健康和整体体能的重要指标，6分钟步行距离（6MWD）是临床上常用的评估方法。在健康个体中，短期生酮饮食对运动耐量的影响存在异质性。一项针对未经训练的健康成年人的研究发现，短期（3天）生酮饮食后，尽管脂肪氧化在恢复期更高，但在高强度运动（HIE）中，受试者的能量消耗更高，运动效率更低 31。这意味着在高强度运动时，短期生酮饮食可能导致运动耐量下降或需要更高的能量消耗来维持相同的工作量，这可能与心肌能量代谢重构相关，在碳水化合物受限下，心肌可能无法迅速适应高强度运动的即时能量需求。然而，这项研究干预时间极短，且只在健康受试者中进行，结果的普适性需谨慎。此外，有研究指出生酮饮食能够改变外周组织表型，如增加骨骼肌的PDK4水平，这可能抑制葡萄糖利用，并降低AMPK和GLUT4水平，从而影响能量代谢，这可能部分解释运动效率的改变 32。
总体而言，健康人群短期生酮饮食的随机对照试验表明，该饮食模式在短期内对心脏收缩功能无显著负面影响。然而，对舒张功能和运动耐量的影响可能更为复杂，可能存在运动效率下降的潜在风险，特别是在高强度运动时。未来的研究需要更长时间的随访，并结合更全面的心功能评估手段，以阐明生酮饮食对健康人群心脏功能的长期影响。表1总结了部分相关短期干预研究的结果。
表1：健康人群短期生酮饮食干预对心脏功能相关指标的影响
| 研究类型（参考） | 干预时间 | 干预对象 | 心功能指标 | 生酮饮食组结果 | 对照组结果 | 主要发现 |
|---|---|---|---|---|---|---|
| RCT 29 | 急性（120 min） | 健康成年人 | 心输出量（CO）、心肌血流量（MBF） | CO显著升高 (+31%)，MBF显著升高 (+29%) | 无显著变化 | 外源性酮体可急性提升心脏功能和血流 |
| RCT 31 | 3天 | 健康成年人 | 运动效率、FFA、BOHB | 高强度运动时运动效率降低，能量消耗增加；FFA升高，BOHB降低 | - | 短期KD在高强度运动时可能降低运动效率 |
| RCT 33 | 2周 | 超重/肥胖者 | 心肌脂肪酸氧化、摄取、MVO2 | 心肌FFA氧化和摄取显著降低，FFA酯化增加；MVO2无变化 | - | KD改变心肌底物利用，但不降低心肌耗氧量 |
| RCT 34 | 3周 | 健康成年人 | 心血管代谢标志物（方案设计） | 预期评估心血管健康指标变化 | - | 旨在评估KD独立于体重减轻的心血管影响 |
注：本表格仅为部分代表性研究，并非详尽列表。FFA：游离脂肪酸；BOHB：β-羟丁酸；MVO2：心肌耗氧量。
4.2 心血管疾病患者的临床观察
在心血管疾病患者群体中，生酮饮食的应用更为复杂，既有其独特的潜在益处，也伴随着更高的风险。现有临床观察和队列研究主要集中于心力衰竭（Heart Failure, HF）、冠心病（Coronary Artery Disease, CAD）以及糖尿病合并心脏病的患者。这些研究旨在评估生酮饮食与传统低脂饮食在改善心功能指标（如脑钠肽BNP水平、纽约心脏协会NYHA心功能分级）方面的差异。
心力衰竭患者的“能量耗竭心脏”：心力衰竭的标志之一是心肌能量代谢的显著改变，表现为线粒体氧化代谢能力下降，导致心肌能量供应不足。在这种背景下，酮体被认为可能提供一种替代的有效能量来源。多种研究表明，心力衰竭时心肌酮体代谢增强，这被视为一种适应性反应，有助于维持心功能和延缓疾病进展 1935。因此，理论上生酮饮食诱导的酮症可能对心力衰竭患者有利。
在射血分数降低的心力衰竭（HFrEF）患者中，一些小型临床试验和动物研究显示了积极的结果。一项对心力衰竭大鼠的系统回顾和荟萃分析表明，酮体干预（包括生酮饮食、酮酯或中链甘油三酯）显著改善了左心室射血分数（LVEF）、心输出量（CO），并减轻了心肌肥厚和纤维化 36。这提示酮体治疗对HFrEF可能具有心脏保护作用。在临床层面，虽然缺乏大规模的随机对照试验，但有研究指出，钠-葡萄糖协同转运蛋白2抑制剂（SGLT2i）通过增加尿糖排泄和轻度酮体生成，显著改善了心力衰竭患者的预后，这进一步支持了酮体可能在心力衰竭治疗中的作用，尽管SGLT2i的机制是多因素的 37。
对于射血分数保留性心力衰竭（HFpEF）患者，心肌的能量代谢异常也扮演重要角色。HFpEF常伴有胰岛素抵抗和脂肪酸氧化增加。生酮饮食通过改善胰岛素敏感性，降低炎症反应，可能对HFpEF患者有益。例如，增加酮体可用性可以调节心肌对葡萄糖和脂肪酸的利用，并具有抗炎和抗纤维化作用，改善心肌功能 19。一项案例研究甚至指出，在伴有严重高甘油三酯血症的患者中，极低碳水化合物生酮饮食结合间歇性禁食成功逆转了高甘油三酯血症，这对于改善心血管风险具有潜在意义 38。然而，目前直接比较生酮饮食与传统低脂饮食在HFpEF患者中BNP水平和NYHA分级改善的临床数据尚不充分，尤其是在长期随访方面。
对于冠心病（CAD）患者和糖尿病合并心脏病的患者，生酮饮食的影响则更为复杂。糖尿病患者常伴有心脏能量代谢紊乱和心肌病变（糖尿病心肌病）。有假说认为，低碳水化合物饮食，包括生酮饮食，通过改善胰岛素抵抗、降低血糖和胰岛素水平，可能有助于改善糖尿病心肌病 39。一项荟萃分析发现，与传统低脂饮食相比，极低碳水化合物生酮饮食（VLCKD）在长期（≥12个月）随访中能实现更大的体重减轻，并显著降低甘油三酯（TAG）和舒张压，同时升高高密度脂蛋白胆固醇（HDL-C）和低密度脂蛋白胆固醇（LDL-C） 40。其中，TAG降低和HDL-C升高通常被认为是心血管保护的标志。然而，LDL-C的升高则是一个重要的顾虑，尤其在CAD患者中。
部分临床观察发现，生酮饮食在某些个体中可能导致LDL-C显著升高，甚至超过190 mg/dL，即使这些个体可能相对瘦且健康 41。这种“高胆固醇反应”对动脉粥样硬化进展的影响尚不完全清楚，需要长期随访研究来明确 41。虽然有一些研究表明，在癫痫患者中，生酮饮食引起的总胆固醇和LDL-C升高在一年内可能恢复到基线水平 42，但这并非普遍现象，且对于原有CAD风险的患者，其影响可能更为显著。对于2型糖尿病患者，尽管低碳水化合物饮食在控制血糖方面表现出色，但其对心血管疾病风险的长期影响仍需更多证据 43。一项针对1型糖尿病患者的研究显示，高脂肪饮食与冠状动脉钙化（CAC）风险增加相关，而碳水化合物摄入量增加则与CAC风险降低相关，这提示了高脂肪饮食在某些亚群中可能存在动脉粥样硬化风险 44。
综合来看，生酮饮食在心血管疾病患者中的应用前景复杂。虽然酮体在心力衰竭中的能量替代和潜在保护作用令人鼓舞，但高脂肪摄入对血脂谱的潜在负面影响（特别是LDL-C升高）以及对动脉粥样硬化进展的长期作用仍需更深入的临床研究来明确。在推荐生酮饮食给心血管疾病患者之前，必须进行严格的个体风险评估，并密切监测相关心脏功能和代谢指标。
4.3 长期随访的异质性发现
尽管短期和中期临床观察为生酮饮食对心脏功能的影响提供了一些初步证据，但其长期效应，特别是在持续时间超过一年的情况下，仍然是一个复杂且存在异质性的研究领域。长期随访研究对于理解生酮饮食与心肌肥厚（Cardiac Hypertrophy）、冠状动脉钙化（Coronary Artery Calcification, CAC）评分之间的剂量-反应关系至关重要，因为这些是心血管疾病风险和进展的重要指标。
心肌肥厚是心脏对慢性应激（如高血压、瓣膜病变或心力衰竭）的适应性反应，但病理性心肌肥厚会损害心脏舒张和收缩功能，增加心律失常和心源性猝死的风险。一项针对压力超负荷小鼠模型的研究发现，限制碳水化合物摄入，无论是高脂肪生酮饮食（Fat-LC）还是高蛋白生酮饮食（Pro-LC），均能抑制病理性心肌肥厚的发生和心力衰竭的进展。特别是Fat-LC组，其β-羟丁酸水平升高，通过抑制mTOR信号通路发挥了心肌保护作用 45。这提示生酮饮食可能在一定程度上预防或逆转心肌肥厚。然而，这些是动物实验结果，其在人类中的长期效应，特别是对已经存在心肌肥厚或有潜在风险的个体，还需要更多临床数据来验证。
冠状动脉钙化评分（CAC Score）是评估亚临床动脉粥样硬化负荷和预测未来心血管事件风险的强有力指标。高CAC评分意味着冠状动脉壁内存在钙沉积，是动脉粥样硬化斑块形成和进展的标志。关于生酮饮食与CAC评分之间关系的长期研究结果存在争议。
一些观察性研究和临床报告提出担忧，认为长期生酮饮食，尤其是在部分个体中导致的LDL-C显著升高，可能加速动脉粥样硬化的进程。例如，一项正在进行的研究（The Ketogenic Diet Trial Study）旨在评估碳水化合物限制引起的LDL-C升高对冠状动脉粥样硬化进展的影响。该研究招募了100名采用生酮饮食后LDL-C升高至>190 mg/dl的瘦且代谢健康的个体，通过连续冠状动脉CT血管造影（CCTA）来评估12个月内的冠状动脉粥样硬化进展 41。虽然结果尚未公布，但这项研究的设计本身就反映了医学界对这一潜在风险的关注。
NIH-AARP饮食与健康研究是一个大型前瞻性队列研究，尽管它并非专门评估生酮饮食，但其中关于宏量营养素摄入与心血管疾病风险的分析可能提供间接见解。然而，直接将生酮饮食的特定宏量营养素比例与心肌肥厚或CAC评分进行剂量-反应分析的长期前瞻性队列研究相对较少，且往往受到饮食依从性、混杂因素（如体重减轻、运动水平、其他生活方式因素）以及基线心血管健康状况的影响。
另一方面，也有观点认为，如果生酮饮食能够有效改善其他心血管风险因素，如降低体重、改善胰岛素敏感性、降低甘油三酯和升高HDL-C，那么即使LDL-C有所升高，其净效应也可能对心血管健康有利。例如，一项针对癫痫儿童的长期随访研究显示，虽然生酮饮食初期会导致LDL-C、载脂蛋白B和动脉功能（如颈动脉顺应性）的改变，但这些变化在24个月后似乎是可逆且不显著的，颈动脉内膜中层厚度（cIMT）和高敏C反应蛋白（hsCRP）也未显示显著变化 46。这可能提示，在某些特定人群中，或当生酮饮食得到良好管理时，其对血管健康的不利影响可能并非长期存在。然而，这项研究的受试者是儿童，且主要关注癫痫治疗，其结果不应直接推断到成人普通人群或有心血管疾病风险的个体。
总体而言，长期随访研究，尤其是那些持续时间超过一年的研究，对生酮饮食与心肌肥厚和冠状动脉钙化评分之间的剂量-反应关系提供了异质性发现。这可能反映了生酮饮食方案的异质性（如脂肪来源、碳水化合物限制程度）、个体遗传背景的差异、以及其他生活方式因素的复杂交互作用。未来的长期前瞻性研究需要更精确地定义生酮饮食干预，统一评估心血管结局的指标，并充分考虑潜在的混杂因素，才能为生酮饮食的长期心血管安全性提供更明确的证据。
5. 争议与潜在风险
尽管生酮饮食在体重管理和代谢改善方面展现出潜力，但在其临床应用和研究中，仍存在诸多争议和潜在风险，尤其是在心血管健康方面。这些争议主要围绕血脂谱的矛盾结果、心律失常的病例报告以及研究设计本身的局限性。
5.1 血脂谱的矛盾结果
生酮饮食对血脂谱的影响是一个高度复杂且备受争议的领域。其特点是高脂肪摄入，这不可避免地会改变血液中各种脂蛋白的水平。多数研究显示，生酮饮食常导致低密度脂蛋白胆固醇（LDL-C）升高，同时高密度脂蛋白胆固醇（HDL-C）也可能升高，而甘油三酯（Triglycerides, TG）则普遍降低 4748。这种“矛盾”的结果使得评估生酮饮食对动脉粥样硬化风险的净效应变得尤为复杂。
LDL-C升高是生酮饮食最受关注的潜在不良影响之一。一项伞形综述（umbrella review）指出，生酮饮食可以显著升高LDL-C、总胆固醇（TC）和HDL-C水平 49。另有研究表明，对于正常体重成年人，生酮饮食显著增加了TC、LDL-C和载脂蛋白B（apoB）的水平 50。这种LDL-C的升高尤其令人担忧，因为LDL-C是公认的动脉粥样硬化性心血管疾病（ASCVD）的危险因素 41。尽管部分生酮饮食的倡导者认为，这种LDL-C的升高可能不完全等同于传统意义上的高胆固醇血症风险，因为生酮饮食可能改善了其他代谢指标（如胰岛素敏感性、血糖控制），或者改变了LDL颗粒的大小和密度分布（例如，从小而密的LDL转变为大而蓬松的LDL，后者被认为心血管风险相对较低），但目前尚无确凿证据支持这一论点足以抵消LDL-C升高的潜在危害。例如，一项正在进行的临床研究，即生酮饮食试验研究（The Ketogenic Diet Trial Study），旨在评估碳水化合物限制引起的LDL-C升高对冠状动脉粥样硬化进展的影响，特别关注那些LDL-C升至>190 mg/dL但整体代谢健康的个体，其结果将有助于揭示高LDL-C在生酮饮食背景下的真实心血管风险 41。
然而，生酮饮食也常伴随着HDL-C的升高和甘油三酯的降低，这通常被视为有利的心血管风险改变。一项针对2型糖尿病患者的荟萃分析发现，极低碳水化合物生酮饮食（VLCKD）显著降低了甘油三酯水平，但对TC、HDL-C和LDL-C水平无显著影响 48。另一项针对超重和肥胖患者的荟萃分析也显示，VLCKD可以降低TC和TG，但不改变LDL-C和HDL-C水平 51。这种差异可能与研究人群、干预持续时间以及饮食中脂肪的类型有关。例如，中链饱和脂肪酸（MCFAs）与长链饱和脂肪酸（LCSFAs）相比，对血脂的影响可能不同，MCFAs可能导致HDL胆固醇浓度显著升高 52。生酮饮食中常见的饱和脂肪酸摄入量较高，例如棕榈酸（C16:0）和月桂酸（C12:0）、肉豆蔻酸（C14:0）等，这些饱和脂肪酸在不同程度上影响血脂。其中，月桂酸和肉豆蔻酸被认为具有较强的升高胆固醇的作用，而棕榈酸则可能因个体代谢背景而异 53。高饱和脂肪摄入还可能影响细胞膜脂质成分，例如饱和脂肪酸在细胞膜磷脂中丰度增加，可能影响细胞功能 54。
因此，生酮饮食对血脂谱的净效应是一个权衡利弊的过程。虽然甘油三酯的降低和HDL-C的升高是积极的，但LDL-C的显著升高，特别是当其长期维持在较高水平时，仍然是心血管疾病风险的重要预测因子。目前的证据尚不足以完全消除对生酮饮食诱导的高LDL-C血症的担忧，尤其是在具有心血管疾病高风险的个体中。未来的研究需要更深入地分析生酮饮食对脂蛋白亚群的影响，并评估其对动脉粥样硬化斑块形成和进展的长期影响 55。
5.2 心律失常的病例报告与机制假说
生酮饮食在临床实践中，尤其是在癫痫治疗领域，虽已证明其有效性，但也伴随少数心律失常的病例报告，这引起了医学界的关注。这些报告通常涉及QT间期延长和心律失常事件，例如室性早搏或尖端扭转型室速（torsades de pointes, TdP）。
有研究报告了一例患有先天性长QT综合征的患者，在采用生酮饮食后出现了QT间期延长和TdP，作者认为这可能与生酮饮食引起的代谢变化有关 56。另一项早期研究调查了20名接受生酮饮食治疗的儿童癫痫患者，发现其中3名（15%）出现了QT间期延长（QTc）。该研究还发现，QTc延长与血清碳酸氢盐水平降低和β-羟丁酸水平升高之间存在显著关联。更令人担忧的是，有3名患者出现了心腔扩大的证据，其中一名患有严重扩张型心肌病的患者在停止生酮饮食后心功能恢复正常 57。此外，有两例儿童癫痫患者在生酮饮食期间发生死亡，其中一例死于TdP并发症，并伴有QT间期延长，尸检发现硒缺乏性心肌病。另一例儿童在生酮饮食期间出现QT间期延长，后在家中猝死。这两例患者均存在硒缺乏 58。这些病例报告提示，生酮饮食可能与心律失常风险的增加存在关联，特别是对于本身就存在心脏基础疾病或电解质紊乱的个体。
然而，需要指出的是，并非所有研究都观察到生酮饮食与QT间期延长之间的显著关联。一项针对27名儿童癫痫患者的长期（12个月）随访研究发现，生酮饮食并未导致矫正QT间期（QTc）的统计学显著变化，也没有观察到ST段改变或心律失常 59。另一项为期6个月的研究也得出类似结论，认为生酮饮食对儿童的P波离散度和QT间期无显著影响 60。还有一项对70名儿童癫痫患者进行12个月随访的研究也发现，虽然心电图参数（包括QTc）有所增加，但这种变化不具有统计学意义，表明3:1比例的生酮饮食并未对心脏复极化产生有害影响 61。这种研究结果的异质性可能与研究对象的基线情况、生酮饮食的配比、持续时间以及是否补充了关键微量元素（如硒、肉碱）有关。
关于生酮饮食可能导致心律失常的机制假说，主要集中在以下几个方面：
- 电解质紊乱：生酮饮食初期可能导致水和电解质（特别是钠、钾、镁）的流失。低钾血症和低镁血症是已知的心律失常风险因素，可导致QT间期延长和TdP。虽然这并非酮体本身的直接效应，但在临床实践中，若未能及时纠正电解质紊乱，将增加心律失常的风险。
- 钙稳态改变：心肌细胞的收缩和舒张功能高度依赖于细胞内钙离子的精确调控，而钙稳态的紊乱是心律失常发生的重要机制。有假说认为，在某些条件下，酮体或其代谢变化可能影响心肌细胞内的钙处理蛋白，特别是肌浆网上的Ryanodine受体（RyR）。RyR是钙释放通道，其功能异常可导致钙泄露，进而引发延迟后除极（DADs）和触发性活动，诱发心律失常。虽然直接证据尚不充足，但脂肪酸氧化异常已被证实可影响钙稳态，例如，丙泊酚输注综合征（与脂肪酸氧化障碍相关）可导致心肌衰竭，提示脂肪酸代谢紊乱对心脏功能的潜在影响 62。此外，氧化应激也与钙稳态的扰动密切相关 63，而生酮饮食在某些情况下可能影响氧化还原平衡。
- 对离子通道的直接或间接影响：除了电解质和钙稳态，酮体或伴随的代谢物变化理论上可能直接或间接影响心肌细胞的离子通道（如钠通道、钾通道，特别是hERG钾通道）。hERG通道是心脏复极的关键，其功能异常与长QT综合征直接相关。代谢产物如硫化氢（SO₂）衍生物被证明能通过上调SERCA和磷酸肌酸激酶（p-PLN/PLN）的表达来缓解钙超载，改善心肌损伤，提示小分子代谢物对心肌功能的影响 64。此外，氧自由基生成也被认为是心肌损伤和电生理异常的机制之一 65。
综上所述，虽然少数病例报告和动物研究提示生酮饮食可能增加心律失常风险，但大规模的临床试验并未普遍证实这种关联。这种差异可能提示心律失常风险主要存在于特定易感人群（如先天性长QT综合征患者、存在电解质紊乱者、或特定微量元素缺乏者）中。未来的研究需要进一步阐明生酮饮食对心肌细胞离子通道和钙稳态的精确影响，并探索个体遗传背景和饮食配比对心律失常风险的修饰作用。
5.3 研究设计的局限性
对生酮饮食与心脏功能关系的研究，尽管取得了诸多进展，但其结论的可靠性和普适性往往受到现有研究设计固有局限性的影响。这些局限性主要体现在生酮饮食干预方案的异质性、对照饮食选择的多样性以及研究样本量普遍不足等几个方面。
首先，生酮饮食干预方案的异质性是阻碍结果比较和综合分析的关键因素。生酮饮食并非单一固定的模式，其具体实施方案在不同研究中差异巨大：
- 碳水化合物限制程度：尽管普遍认为碳水化合物摄入量需低于50克/天，甚至低于20克/天，但具体到每项研究，碳水化合物的精确限制量、是否包含纤维碳水化合物等定义并不统一。不同的碳水化合物限制程度可能导致不同水平的酮症，进而对心脏功能产生差异化的影响。
- 脂肪类型和来源：生酮饮食强调高脂肪摄入，但脂肪的来源（动物性脂肪、植物性脂肪）、饱和脂肪酸、单不饱和脂肪酸和多不饱和脂肪酸的比例各异。例如，一项研究指出，虽然生酮饮食对癫痫治疗有效，但其高饱和脂肪酸和高胆固醇摄入可能增加血脂异常风险，需要密切监测脂质谱，并强调对饱和脂肪摄入的限制 66。不同脂肪酸组成可能对血脂谱、炎症反应以及细胞膜功能产生截然不同的影响，从而间接或直接影响心脏健康。例如，中链甘油三酯（MCTs）因其快速产酮的特性常被用于生酮饮食中，但其长期高剂量摄入对心血管系统的具体影响仍需更多研究。
- 蛋白质摄入量：虽然生酮饮食是“适量蛋白质”，但具体的蛋白质摄入量（占总能量的百分比或每公斤体重多少克）在不同研究中存在波动，这可能影响肌肉量保持和肾脏负荷，间接影响整体代谢。
- 干预周期：从几天到数年不等的干预周期使得短期急性效应和长期慢性适应的区分变得模糊。有些研究仅观察短期效应，可能无法揭示长期潜在的风险或益处。
其次，对照饮食选择的多样性也增加了结果解释的复杂性。在随机对照试验中，对照组的饮食通常是低脂饮食、标准膳食指南推荐饮食（如地中海饮食）或患者常规饮食。
- 低脂饮食：与传统低脂饮食相比，生酮饮食在体重减轻、血糖控制等方面可能表现出优势，但这并不意味着生酮饮食本身就是最佳选择。
- 地中海饮食：地中海饮食以富含植物性食物、橄榄油、鱼类、坚果和适量红酒为特点，被广泛认为是心血管健康的典范。如果生酮饮食与地中海饮食进行比较，其对心脏健康的优势可能并不明显，甚至可能处于劣势。目前，针对APOE ε4基因携带者的综述指出，除了地中海饮食外，其他饮食干预（包括生酮饮食、营养品和补充剂）在改善认知功能方面普遍效果不佳 67。这提示了地中海饮食在某些领域的优越性，也间接说明生酮饮食并非万能。
- 常规饮食：一些研究的对照组仅仅是“常规饮食”，这使得对照组的宏量营养素组成和健康效应难以标准化和量化。
最后，样本量不足是当前许多生酮饮食研究普遍存在的局限。
- 小样本量：许多随机对照试验和临床观察研究的样本量相对较小，这限制了研究结果的统计学效力（statistical power），使其难以检测到真实存在的、但效应量较小的差异，也更容易受到偶然因素的影响。例如，一项癫痫患者生酮饮食的研究协议指出，其面临的挑战之一就是合格患者数量少，导致招募速度缓慢 68。
- 异质性人群：研究对象通常包括肥胖个体、2型糖尿病患者、癫痫患者，甚至部分健康人群，这些不同的人群对生酮饮食的反应可能存在显著差异。小样本量进一步限制了对不同亚群（如老年人、儿童、伴有特定基础疾病的患者）进行深入分析的能力。一项伞形综述强调，当前生酮饮食相关研究的证据强度普遍较弱，未来研究需优先采用更严格的研究方案，开展更长时间的干预，以确定其作为治疗选择的潜力 49。
这些研究设计上的局限性，使得当前关于生酮饮食对心脏功能影响的结论仍存在不确定性，需要更多高质量、大样本、标准化干预方案的随机对照试验来提供更坚实的证据。
6. 未来研究方向与展望
生酮饮食在改善代谢健康和治疗某些神经系统疾病方面展现出巨大潜力，但其对心脏功能的影响仍需更深入、更系统的研究。为了弥合当前知识空白，未来研究应着力于标准化干预方案、利用多组学技术解析机制以及针对特殊人群进行精准研究。
6.1 标准化干预方案的建立
目前关于生酮饮食对心脏功能影响的研究，由于干预方案的异质性，导致结果解释和比较的难度大。为了获得更具普适性和可靠性的结论，未来研究急需建立标准化的生酮饮食干预方案，并明确其核心要素：
首先，碳水化合物阈值的精确定义至关重要。虽然普遍接受的碳水化合物限制量是每日50克以下，但精确的上限、下限以及是否包含膳食纤维中的碳水化合物，都需要在研究方案中明确统一。例如，是严格限制在20克/天，还是允许适度放宽至50克/天，这可能对酮症水平和受试者的依从性产生显著影响。未来的研究应系统地比较不同碳水化合物限制程度下的心脏功能反应，以确定最佳的“酮原性”阈值，并考虑个体差异性。
其次，脂肪来源的标准化是不可或缺的一环。生酮饮食中70%-75%的能量来源于脂肪，因此脂肪的类型（饱和脂肪、单不饱和脂肪、多不饱和脂肪）和具体来源（动物脂肪、植物油、MCTs等）对血脂谱和心血管健康的影响巨大。高饱和脂肪摄入可能会升高LDL-C，而富含不饱和脂肪的生酮饮食可能带来不同的心血管结局。未来的研究应明确指定脂肪来源和各类脂肪酸的比例，例如，是否鼓励摄入富含单不饱和脂肪（如橄榄油、牛油果）和Omega-3多不饱和脂肪（如深海鱼油）的生酮饮食，以及对不同脂肪酸对心血管健康影响的差异化研究。在临床实践中，应密切监测脂质谱，并根据个体情况调整脂肪摄入类型和比例。
最后，干预周期的规范化也至关重要。现有研究的干预周期从几天到数年不等，这使得短期适应性变化与长期健康影响混淆不清。未来的研究应设计不同长度的干预组，包括短期（3-6个月）、中期（1年）和长期（2年以上）随访，以全面评估生酮饮食对心脏功能的急性、亚急性及慢性影响。同时，应考虑干预中断或“循环生酮饮食”对心脏健康的影响。此外，研究应细化监测指标，例如，除了常规的血酮水平，还应定期检测血糖、胰岛素、血脂全谱（包括LDL-C亚型）、炎症标志物以及心脏功能指标（如射血分数、舒张功能、心肌僵硬度等），以便更全面地评估生酮饮食对心脏健康的潜在益处和风险。例如，一项评估技术辅助下的精准生酮饮食干预对心肾代谢健康影响的随机对照试验，就计划通过代谢组学等技术，深入理解干预效果背后的分子机制 69。
6.2 多组学技术的机制解析
为了更深入地理解生酮饮食对心脏功能的分子机制，未来的研究应充分利用多组学技术，包括代谢组学、转录组学和单细胞测序，以揭示生酮饮食诱导的复杂生物学变化。
代谢组学能够全面捕捉细胞、组织或生物体内的代谢产物图谱。通过分析血浆、心肌组织中的酮体亚型（如β-HB、乙酰乙酸）、脂肪酸、氨基酸、有机酸等，可以更精细地描绘生酮饮食对心脏能量底物利用、中间代谢产物积累以及代谢通量变化的影响。例如，可以探究特定酮体异构体或脂肪酸衍生物如何直接影响心肌细胞功能，或者哪些代谢通路在酮症状态下被激活或抑制。一项评估生酮饮食对肥胖或超重成年人心肾代谢健康影响的试验协议中，就明确指出将采用代谢组学技术，以深入理解干预措施在分子水平上的作用机制 69。
转录组学则可以揭示生酮饮食如何调控基因表达，从而影响心肌细胞的功能。重点关注与能量代谢、炎症、氧化应激、线粒体功能和心肌重构相关的基因通路，例如PPARγ（过氧化物酶体增殖物激活受体γ）和PGC-1α（过氧化物酶体增殖物激活受体γ共激活因子1α）信号通路。PPARγ和PGC-1α是调节脂肪酸氧化、线粒体生物合成以及胰岛素敏感性的关键转录因子。生酮饮食可能通过激活这些通路，促进心肌线粒体功能和能量效率。例如，已有研究表明，在心脏压力超负荷模型中，生酮饮食通过抑制mTOR信号通路发挥心肌保护作用，而转录组学可以进一步揭示其中涉及的基因表达网络。
此外，单细胞测序技术的引入将为心脏研究带来前所未有的分辨率。心脏由多种细胞类型组成，包括心肌细胞、成纤维细胞、内皮细胞、免疫细胞等。不同细胞类型对生酮饮食的响应可能存在差异。通过单细胞测序，可以精确识别生酮饮食对特定心肌细胞亚群（如浦肯野纤维细胞）或非心肌细胞（如炎症细胞）的基因表达和功能影响，从而揭示心脏在酮症状态下更精细的细胞层面的适应或病理重构。例如，可以探究酮体对心肌电生理特性影响的机制，是否通过特定离子通道基因表达的改变，或对心肌纤维化相关基因表达的调控。
整合这些多组学数据，结合计算生物学和系统生物学方法，可以构建生酮饮食影响心脏功能的全面分子网络图谱，识别关键调控节点和潜在的生物标志物，为未来的精准干预提供理论依据。
6.3 特殊人群的精准研究
生酮饮食并非适用于所有人，其对心脏功能的影响可能因个体差异和特定病理生理状态而异。因此，未来的研究应更加关注特殊人群，开展精准研究，以明确生酮饮食的适用边界和潜在禁忌。
首先，老年人心肌退行性变是一个重要的研究方向。随着年龄增长，心肌细胞会发生一系列退行性变化，包括线粒体功能下降、氧化应激增加以及心肌纤维化。生酮饮食诱导的酮体被认为可能改善线粒体功能并具有抗氧化作用，这理论上可能对老年人心脏健康有益。然而，老年人往往合并多种基础疾病，且对饮食干预的耐受性和依从性可能较低，同时电解质紊乱的风险也相对较高。因此，需要专门针对老年人设计随机对照试验，评估生酮饮食对其心肌结构、功能及心血管事件的长期影响，并特别关注安全性。
其次，遗传性心肌病患者是一个需要谨慎评估的群体。某些遗传性心肌病（如肥厚性心肌病、扩张性心肌病）与特定的基因突变相关，这些突变可能影响心肌细胞的结构蛋白、离子通道或能量代谢。例如，一些遗传性代谢性疾病（如脂肪酸氧化障碍）会导致心肌对脂肪酸的利用能力受损，此时生酮饮食这种高脂肪饮食可能会加重心脏负担甚至带来危险，因此这类疾病通常被列为生酮饮食的禁忌症 70。对于其他类型的遗传性心肌病，生酮饮食是否能提供能量支持或加剧病理过程，仍需基于遗传背景进行精准评估。未来的研究应结合基因测序技术，筛选特定基因型的患者，开展个体化的生酮饮食干预研究，以明确其安全性、有效性以及潜在的风险。
此外，还需关注其他特殊人群，例如：
- 心血管疾病高风险人群：如肥胖、代谢综合征、2型糖尿病早期患者，他们是生酮饮食的潜在受益者，但其心血管风险更高，需要更密切的监测和更长的随访。
- 伴有心律失常基础的患者：特别是具有长QT综合征或Brugada综合征等离子通道疾病的患者，生酮饮食可能对离子通道功能产生影响，需要严格评估其心电生理稳定性。
- 长期药物治疗的患者：生酮饮食可能影响药物代谢或相互作用，特别是针对心血管疾病的药物（如抗凝剂、降压药、抗心律失常药），需要药物相互作用的研究。
通过在这些特殊人群中开展严谨的、个体化的研究，并结合多组学分析，可以更清晰地界定生酮饮食的适应症与禁忌症，从而为临床医生和患者提供更精准、更安全的饮食建议。这不仅有助于优化生酮饮食的临床应用，也将推动心脏营养学和精准医学的发展。
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参考文献
1The Ketogenic Diet and Alzheimer's Disease.PubMed
H Hersant, G Grossberg
J Nutr Health Aging. 2022;26(6):606-614. doi: 10.1007/s12603-022-1807-7.
INTRODUCTION: Alzheimer's disease (AD) is a progressive neurodegenerative disease that is the most common form of dementia. There are currently FDA-approved symptomatic therapies for AD and a recently approved, potentially disease-modifying drug, Aducanumab; however, there are no curative or preventative therapies. Research suggests that diet may play a role in AD, but it is inconclusive relative to which dietary approach provides the most neuroprotective effects. There are other life-style approaches that have been found to possibly play a role in AD prevention/treatment. These include exercise, brain training, and social interaction. A combined approach may be more effective than any one modality alone. The ketogenic diet (KD) is one specific diet that has been studied vis a vis neurodegenerative diseases. Similar benefits to those of a KD can also be achieved through consuming a normal diet and supplementing with ketogenic agents. The purpose of this review is to compare the methods of inducing hyperketonemia and their impact on AD prevention/treatment, as well as to explore the possible benefits of a combined approach. METHODS: The PubMed database was searched for clinical trials and randomized, controlled trials involving the KD or exogenous ketone administration and AD. Key search terms used included "ketogenic diet and Alzheimer's disease," "ketosis and Alzheimer's disease," "MCT and Alzheimer's disease," and "exercise and diet and Alzheimer's disease." Only studies involving patients diagnosed with AD were included in this paper, but for the combined approach section, studies included patients diagnosed with MCI due to a paucity of combined approach studies involving AD patients alone. RESULTS: There is evidence that the KD and exogenous ketone supplementation may provide treatment benefits in AD patients. It is unclear whether one method is better than the other. The specific food composition of the KD should be considered, because certain types of fat sources are healthier than others. Many forms of the KD require strict monitoring of carbohydrate intake, which would often fall under the responsibility of the caregiver. Future studies may be more feasible in an institutional setting, where it would be easier to administer and to monitor a dietary protocol. Exogenous supplementation may be more likely to be adhered to as a long-term treatment, because the dietary changes are not as drastic. A multidomain approach may be the most effective in possibly preventing/delaying AD and in improving/stabilizing and possibly slowing disease progression in those with AD. CONCLUSION: Most current studies are small, often uncontrolled, and only look at the short-term effects of ketosis on cognition. Large, long-term, randomized, controlled trials relative to the impact of the KD in patients with cognitive impairment and AD are lacking and thus needed. Combined approaches may prove to be more beneficial in possibly preventing/delaying AD and in improving/stabilizing and possibly slowing disease progression in those with MCI or AD. Future research should investigate the effect of additional combined approaches relative to neurocognitive decline in AD patients.
2The Potential Health Benefits of the Ketogenic Diet: A Narrative Review.PubMed
Kathryn Dowis, Simran Banga
Nutrients. 2021 May 13;13(5):1654. doi: 10.3390/nu13051654.
Considering the lack of a comprehensive, multi-faceted overview of the ketogenic diet (KD) in relation to health issues, we compiled the evidence related to the use of the ketogenic diet in relation to its impact on the microbiome, the epigenome, diabetes, weight loss, cardiovascular health, and cancer. The KD diet could potentially increase genetic diversity of the microbiome and increase the ratio of to . The epigenome might be positively affected by the KD since it creates a signaling molecule known as β-hydroxybutyrate (BHB). KD has helped patients with diabetes reduce their HbA1c and reduce the need for insulin. There is evidence to suggest that a KD can help with weight loss, visceral adiposity, and appetite control. The evidence also suggests that eating a high-fat diet improves lipid profiles by lowering low-density lipoprotein (LDL), increasing high-density lipoprotein (HDL), and lowering triglycerides (TG). Due to the Warburg effect, the KD is used as an adjuvant treatment to starve cancer cells, making them more vulnerable to chemotherapy and radiation. The potential positive impacts of a KD on each of these areas warrant further analysis, improved studies, and well-designed randomized controlled trials to further illuminate the therapeutic possibilities provided by this dietary intervention.
3Diet in the Treatment of Epilepsy: What We Know So Far.PubMed
Alberto Verrotti, Giulia Iapadre, Ludovica Di Francesco, et al.
Nutrients. 2020 Aug 30;12(9):2645. doi: 10.3390/nu12092645.
Epilepsy is a chronic and debilitating neurological disorder, with a worldwide prevalence of 0.5-1% and a lifetime incidence of 1-3%. An estimated 30% of epileptic patients continue to experience seizures throughout life, despite adequate drug therapy or surgery, with a major impact on society and global health. In recent decades, dietary regimens have been used effectively in the treatment of drug-resistant epilepsy, following the path of a non-pharmacological approach. The ketogenic diet and its variants (e.g., the modified Atkins diet) have an established role in contrasting epileptogenesis through the production of a series of cascading events induced by physiological ketosis. Other dietary regimens, such as caloric restriction and a gluten free diet, can also exert beneficial effects on neuroprotection and, therefore, on refractory epilepsy. The purpose of this review was to analyze the evidence from the literature about the possible efficacy of different dietary regimens on epilepsy, focusing on the underlying pathophysiological mechanisms, safety, and tolerability both in pediatric and adult population. We believe that a better knowledge of the cellular and molecular biochemical processes behind the anticonvulsant effects of alimentary therapies may lead to the development of personalized dietary intervention protocols.
4Beyond weight loss: a review of the therapeutic uses of very-low-carbohydrate (ketogenic) diets.PubMed
A Paoli, A Rubini, J S Volek, et al.
Eur J Clin Nutr. 2013 Aug;67(8):789-96. doi: 10.1038/ejcn.2013.116. Epub 2013 Jun 26.
Very-low-carbohydrate diets or ketogenic diets have been in use since the 1920s as a therapy for epilepsy and can, in some cases, completely remove the need for medication. From the 1960s onwards they have become widely known as one of the most common methods for obesity treatment. Recent work over the last decade or so has provided evidence of the therapeutic potential of ketogenic diets in many pathological conditions, such as diabetes, polycystic ovary syndrome, acne, neurological diseases, cancer and the amelioration of respiratory and cardiovascular disease risk factors. The possibility that modifying food intake can be useful for reducing or eliminating pharmaceutical methods of treatment, which are often lifelong with significant side effects, calls for serious investigation. This review revisits the meaning of physiological ketosis in the light of this evidence and considers possible mechanisms for the therapeutic actions of the ketogenic diet on different diseases. The present review also questions whether there are still some preconceived ideas about ketogenic diets, which may be presenting unnecessary barriers to their use as therapeutic tools in the physician's hand.
5Randomized crossover trial of a modified ketogenic diet in Alzheimer's disease.PubMed
Matthew C L Phillips, Laura M Deprez, Grace M N Mortimer, et al.
Alzheimers Res Ther. 2021 Feb 23;13(1):51. doi: 10.1186/s13195-021-00783-x.
BACKGROUND: Brain energy metabolism is impaired in Alzheimer's disease (AD), which may be mitigated by a ketogenic diet. We conducted a randomized crossover trial to determine whether a 12-week modified ketogenic diet improved cognition, daily function, or quality of life in a hospital clinic of AD patients. METHODS: We randomly assigned patients with clinically confirmed diagnoses of AD to a modified ketogenic diet or usual diet supplemented with low-fat healthy-eating guidelines and enrolled them in a single-phase, assessor-blinded, two-period crossover trial (two 12-week treatment periods, separated by a 10-week washout period). Primary outcomes were mean within-individual changes in the Addenbrookes Cognitive Examination - III (ACE-III) scale, AD Cooperative Study - Activities of Daily Living (ADCS-ADL) inventory, and Quality of Life in AD (QOL-AD) questionnaire over 12 weeks. Secondary outcomes considered changes in cardiovascular risk factors and adverse effects. RESULTS: We randomized 26 patients, of whom 21 (81%) completed the ketogenic diet; only one withdrawal was attributed to the ketogenic diet. While on the ketogenic diet, patients achieved sustained physiological ketosis (12-week mean beta-hydroxybutyrate level: 0.95 ± 0.34 mmol/L). Compared with usual diet, patients on the ketogenic diet increased their mean within-individual ADCS-ADL (+ 3.13 ± 5.01 points, P = 0.0067) and QOL-AD (+ 3.37 ± 6.86 points, P = 0.023) scores; the ACE-III also increased, but not significantly (+ 2.12 ± 8.70 points, P = 0.24). Changes in cardiovascular risk factors were mostly favourable, and adverse effects were mild. CONCLUSIONS: This is the first randomized trial to investigate the impact of a ketogenic diet in patients with uniform diagnoses of AD. High rates of retention, adherence, and safety appear to be achievable in applying a 12-week modified ketogenic diet to AD patients. Compared with a usual diet supplemented with low-fat healthy-eating guidelines, patients on the ketogenic diet improved in daily function and quality of life, two factors of great importance to people living with dementia. TRIAL REGISTRATION: This trial is registered on the Australia New Zealand Clinical Trials Registry, number ACTRN12618001450202 . The trial was registered on August 28, 2018.
6International society of sports nutrition position stand: ketogenic diets.PubMed
Alex Leaf, Jeffrey A Rothschild, Tim M Sharpe, et al.
J Int Soc Sports Nutr. 2024 Dec;21(1):2368167. doi: 10.1080/15502783.2024.2368167. Epub 2024 Jun 27.
POSITION STATEMENT: The International Society of Sports Nutrition (ISSN) provides an objective and critical review of the use of a ketogenic diet in healthy exercising adults, with a focus on exercise performance and body composition. However, this review does not address the use of exogenous ketone supplements. The following points summarize the position of the ISSN. UNLABELLED: 1. A ketogenic diet induces a state of nutritional ketosis, which is generally defined as serum ketone levels above 0.5 mM. While many factors can impact what amount of daily carbohydrate intake will result in these levels, a broad guideline is a daily dietary carbohydrate intake of less than 50 grams per day. UNLABELLED: 2. Nutritional ketosis achieved through carbohydrate restriction and a high dietary fat intake is not intrinsically harmful and should not be confused with ketoacidosis, a life-threatening condition most commonly seen in clinical populations and metabolic dysregulation. UNLABELLED: 3. A ketogenic diet has largely neutral or detrimental effects on athletic performance compared to a diet higher in carbohydrates and lower in fat, despite achieving significantly elevated levels of fat oxidation during exercise (~1.5 g/min). UNLABELLED: 4. The endurance effects of a ketogenic diet may be influenced by both training status and duration of the dietary intervention, but further research is necessary to elucidate these possibilities. All studies involving elite athletes showed a performance decrement from a ketogenic diet, all lasting six weeks or less. Of the two studies lasting more than six weeks, only one reported a statistically significant benefit of a ketogenic diet. UNLABELLED: 5. A ketogenic diet tends to have similar effects on maximal strength or strength gains from a resistance training program compared to a diet higher in carbohydrates. However, a minority of studies show superior effects of non-ketogenic comparators. UNLABELLED: 6. When compared to a diet higher in carbohydrates and lower in fat, a ketogenic diet may cause greater losses in body weight, fat mass, and fat-free mass, but may also heighten losses of lean tissue. However, this is likely due to differences in calorie and protein intake, as well as shifts in fluid balance. UNLABELLED: 7. There is insufficient evidence to determine if a ketogenic diet affects males and females differently. However, there is a strong mechanistic basis for sex differences to exist in response to a ketogenic diet.
7New Mechanisms to Prevent Heart Failure with Preserved Ejection Fraction Using Glucagon-like Peptide-1 Receptor Agonism (GLP-1 RA) in Metabolic Syndrome and in Type 2 Diabetes: A Review.PubMed
Jorge E Jalil, Luigi Gabrielli, María Paz Ocaranza, et al.
Int J Mol Sci. 2024 Apr 17;25(8):4407. doi: 10.3390/ijms25084407.
This review examines the impact of obesity on the pathophysiology of heart failure with preserved ejection fraction (HFpEF) and focuses on novel mechanisms for HFpEF prevention using a glucagon-like peptide-1 receptor agonism (GLP-1 RA). Obesity can lead to HFpEF through various mechanisms, including low-grade systemic inflammation, adipocyte dysfunction, accumulation of visceral adipose tissue, and increased pericardial/epicardial adipose tissue (contributing to an increase in myocardial fat content and interstitial fibrosis). Glucagon-like peptide 1 (GLP-1) is an incretin hormone that is released from the enteroendocrine L-cells in the gut. GLP-1 reduces blood glucose levels by stimulating insulin synthesis, suppressing islet α-cell function, and promoting the proliferation and differentiation of β-cells. GLP-1 regulates gastric emptying and appetite, and GLP-1 RA is currently indicated for treating type 2 diabetes (T2D), obesity, and metabolic syndrome (MS). Recent evidence indicates that GLP-1 RA may play a significant role in preventing HFpEF in patients with obesity, MS, or obese T2D. This effect may be due to activating cardioprotective mechanisms (the endogenous counter-regulatory renin angiotensin system and the AMPK/mTOR pathway) and by inhibiting deleterious remodeling mechanisms (the PKA/RhoA/ROCK pathway, aldosterone levels, and microinflammation). However, there is still a need for further research to validate the impact of these mechanisms on humans.
8Metabolic syndrome and cardiovascular diseases in Korea.PubMed
Sunghwan Suh, Moon-Kyu Lee
J Atheroscler Thromb. 2014;21 Suppl 1:S31-5. doi: 10.5551/jat.21_sup.1-s31.
There has been a rapid increase in the prevalence of obesity, type 2 diabetes and metabolic syndrome(MetS) over the past two to three decades in most Asian countries. According to the Korean National Health and Nutrition Examination Survey(KNHANES), the prevalence of MetS significantly increased from 24.9% to 31.3% between 1998 and 2007. The clinical significance of MetS is based on the increased risk for the development of cardiovascular disease(CVD). We analyzed the 8-year follow-up data of 2,435 healthy subjects and found that MetS was associated with an increased risk of CVD in both men and women(OR: 1.98, 95% CI: 1.30-3.03 in men; OR: 4.04, 95% CI: 1.78-9.14 in women). MetS was significantly associated with the risk for future coronary heart disease(CHD) in men(OR: 3.68; 95% CI: 1.93-7.01) and stroke in women(OR: 3.96; 95% CI: 1.58- 9.94). We also analyzed the echocardiographic findings of 1,600 healthy subjects to evaluate the relationship between metabolic syndrome and left ventricular diastolic dysfunction(LVDD). The patients with MetS exhibited significant differences in parameters of cardiac structure and the LV diastolic function compared to that observed in the patients without MetS. MetS was associated with an increased risk of LVDD(OR: 1.67; 95% CI: 1.18-2.37). These results suggest that the presence of MetS is associated with an increased risk for the development of serious CVD and abnormal changes in the LV structure and diastolic function, even before the development of overt CVD.
10Sex-specific cardiometabolic multimorbidity, metabolic syndrome and left ventricular function in heart failure with preserved ejection fraction in the UK Biobank.PubMed
Ambre Bertrand, Xin Zhou, Andrew Lewis, et al.
Cardiovasc Diabetol. 2025 Jun 4;24(1):238. doi: 10.1186/s12933-025-02788-4.
BACKGROUND: Cardiometabolic disturbances play a central role in the pathogenesis of heart failure with preserved ejection fraction (HFpEF). Due to its complexity, HFpEF is a challenging condition to treat, making phenotype-specific disease management a promising approach. However, HFpEF phenotypes are heterogenous and there is a lack of detailed evidence on the different, sex-specific profiles of cardiometabolic multimorbidity and metabolic syndrome present in HFpEF. METHODS: We performed a retrospective, modified cross-sectional study examining a subset of participants in the UK Biobank, an ongoing multi-centre prospective cohort study in the United Kingdom. We defined HFpEF as a record of a heart failure diagnosis using ICD-10 code I50, coupled with a left ventricular ejection fraction (LVEF) ≥ 50% derived from cardiac magnetic resonance (CMR) imaging. We examined sex-specific differences in cardiometabolic comorbidity burden and metabolic syndrome, performed latent class analysis (LCA) to identify distinct clusters of patients based on their cardiometabolic profile, and compared CMR imaging-derived parameters of left ventricular function at rest in the different clusters identified to reflect possible differences in adverse cardiac remodelling. RESULTS: We ascertained HFpEF in 445 participants, of which 299 (67%) were men and 146 (33%) women. The median age was 70 years old (interquartile range: [66.0-74.0]). A combination of hypertension and obesity was the most prevalent cardiometabolic pattern both in men and women with HFpEF. Most men had 2-3 clinical cardiometabolic comorbidities while most women had 1-2, despite a similar metabolic syndrome profile (p = 0.05). LCA revealed three distinct, clinically relevant phenogroups, namely (1) a most male and multimorbid group (n = 117); (2) a group with a high prevalence of severe obesity, abnormal waist circumference and with the highest relative proportion of females (n = 116); and finally (3) a group with an apparently lower comorbidity burden aside from hypertension (n = 212). There were significant differences in clinical measurements and medication across the three phenogroups identified. Cardiac output at rest was significantly higher in group 2 vs. group 3 (males: median 5.6 L/min vs. 5.2 L/min, p < 0.05; females: 5.1 L/min vs. 4.4 L/min, p < 0.01). Absolute global longitudinal strain was significantly lower in women in group 1 vs. group 2 (-17.6% vs. -18.5%, p < 0.05). CONCLUSION: Women with cardiometabolic HFpEF had a lower comorbidity burden compared to men despite a similar metabolic syndrome profile. Based on patients' cardiometabolic profile, we identified three distinct subgroups which differed in body shape and mass, lipid biomarker and medication profile, as well as in cardiac output at rest both in men and women. These factors may affect disease trajectory, treatment options and outcomes in those subgroups. Subject to further validation, our findings provide a refined characterisation of the cardiometabolic HFpEF phenotype, contributing towards a better understanding of the condition to enable phenotype-specific disease management.
11Metabolic syndrome, left ventricular diastolic dysfunction and heart failure with preserved ejective fraction.PubMed
Dan Zhou, Shuisheng Lin, Zongchen Liu, et al.
Front Endocrinol (Lausanne). 2025 Apr 14;16:1544908. doi: 10.3389/fendo.2025.1544908. eCollection 2025.
Metabolic syndrome (MetS) encompasses a cluster of interrelated conditions, including obesity, hyperglycemia, hyperlipidemia, and hypertension, and has been established as a significant risk factor for cardiovascular events and heightened mortality. At its core, insulin resistance serves as the primary underlying mechanism driving the development of MetS. The prevalence of MetS is rising at an alarming rate, posing a significant public health challenge worldwide. Even in the absence of overt obstructive coronary artery disease or valvular heart disease, patients with MetS often exhibit adverse cardiac remodeling and myocardial dysfunction. Left ventricular hypertrophy (LVH) and left ventricular diastolic dysfunction (LVDD) are the leading manifestations of heart failure with preserved ejection fraction (HFpEF). Abnormal myocardial substrate utilization, neurohormonal activation, interstitial fibrosis, coronary microvascular dysfunction, and metabolic inflammation have all been implicated in the development and progression of adverse cardiac remodeling associated with MetS. However, despite the tremendous research produced on this subject, HFpEF remains highly prevalent in such a population. The early diagnosis of abnormal cardiac remodeling would enable optimal effective therapies to prevent the progression of the disease to the symptomatic phase. HFpEF encompasses a diverse range of pathological processes. In these patients, LVDD and elevated left ventricular filling pressure are the primary manifestations. Echocardiography remains the popular imaging modality for the assessment of LVDD and LV filling pressure. The article aims to review recent articles covering the association between MetS components or MetS and LVDD in HFpEF.
12Ketogenic Diet in the Treatment of Epilepsy.PubMed
Kinga Borowicz-Reutt, Marlena Krawczyk, Julia Czernia
Nutrients. 2024 Apr 24;16(9):1258. doi: 10.3390/nu16091258.
Epilepsy is one of the most disabling neurological diseases. Despite proper pharmacotherapy and the availability of 2nd and 3rd generation antiepileptic drugs, deep brain stimulation, and surgery, up to 30-40% of epilepsy patients remain drug-resistant. Consequences of this phenomenon include not only decreased a quality of life, and cognitive, behavioral, and personal disorders, but also an increased risk of death, i.e., in the mechanism of sudden unexpected death in epilepsy patients (SUDEP). The main goals of epilepsy treatment include three basic issues: achieving the best possible seizure control, avoiding the undesired effects of treatment, and maintaining/improving the quality of patients' lives. Therefore, numerous attempts are made to offer alternative treatments for drug-resistant seizures, an example of which is the ketogenic diet. It is a long-known but rarely used dietary therapy for intractable seizures. One of the reasons for this is the unpalatability of the classic ketogenic diet, which reduces patient compliance and adherence rates. However, its antiseizure effects are often considered to be worth the effort. Until recently, the diet was considered the last-resort treatment. Currently, it is believed that a ketogenic diet should be used much earlier in patients with well-defined indications. In correctly qualified patients, seizure activity may be reduced by over 90% or even abolished for long periods after the diet is stopped. A ketogenic diet can be used in all age groups, although most of the available literature addresses pediatric epilepsy. In this article, we focus on the mechanisms of action, effectiveness, and adverse effects of different variants of the ketogenic diet, including its classic version, a medium-chain triglyceride diet, a modified Atkins diet, and a low glycemic index treatment.
13Ketogenic diets and thermal pain: dissociation of hypoalgesia, elevated ketones, and lowered glucose in rats.PubMed
David N Ruskin, Tracey A C S Suter, Jessica L Ross, et al.
J Pain. 2013 May;14(5):467-74. doi: 10.1016/j.jpain.2012.12.015. Epub 2013 Mar 15.
UNLABELLED: Ketogenic diets (KDs) are high-fat, low-carbohydrate formulations effective in treating medically refractory epilepsy, and recently we demonstrated lowered sensitivity to thermal pain in rats fed a KD for 3 to 4 weeks. Regarding anticonvulsant and hypoalgesic mechanisms, theories are divided as to direct effects of increased ketones and/or decreased glucose, metabolic hallmarks of these diets. To address this point, we characterized the time course of KD-induced thermal hypoalgesia, ketosis, and lowered glucose in young male rats fed ad libitum on normal chow or KDs. A strict 6.6:1 (fat:[carbohydrates + protein], by weight) KD increased blood ketones and reduced blood glucose by 2 days of feeding, but thermal hypoalgesia did not appear until 10 days. Thus, ketosis and decreased glucose are not sufficient for hypoalgesia. After feeding a 6.6:1 KD for 19 days, decreased thermal pain sensitivity and changes in blood chemistry reversed 1 day after return to normal chow. Effects were consistent between 2 different diet formulations: a more moderate and clinically relevant KD formula (3.0:1) produced hypoalgesia and similar changes in blood chemistry as the 6.6:1 diet, thus increasing translational potential. Furthermore, feeding the 3.0:1 diet throughout an extended protocol (10-11 weeks) revealed that significant hypoalgesia and increased ketones persisted whereas low glucose did not, demonstrating that KD-induced hypoalgesia does not depend on reduced glucose. In separate experiments we determined that effects on thermal pain responses were not secondary to motor or cognitive changes. Together, these findings dissociate diet-related changes in nociception from direct actions of elevated ketones or decreased glucose, and suggest mechanisms with a slower onset in this paradigm. Overall, our data indicate that metabolic approaches can relieve pain. PERSPECTIVE: Chronic pain is a common and debilitating condition. We show that a KD, a high-fat, very low carbohydrate diet well known for treating epilepsy, lowers sensitivity to thermal pain in rats. This reduced pain is not temporally correlated with hallmark diet-induced changes in blood glucose and ketones.
14β-hydroxybutyrate as an Anti-Aging Metabolite.PubMed
Lian Wang, Peijie Chen, Weihua Xiao
Nutrients. 2021 Sep 28;13(10):3420. doi: 10.3390/nu13103420.
The ketone bodies, especially β-hydroxybutyrate (β-HB), derive from fatty acid oxidation and alternatively serve as a fuel source for peripheral tissues including the brain, heart, and skeletal muscle. β-HB is currently considered not solely an energy substrate for maintaining metabolic homeostasis but also acts as a signaling molecule of modulating lipolysis, oxidative stress, and neuroprotection. Besides, it serves as an epigenetic regulator in terms of histone methylation, acetylation, β-hydroxybutyrylation to delay various age-related diseases. In addition, studies support endogenous β-HB administration or exogenous supplementation as effective strategies to induce a metabolic state of nutritional ketosis. The purpose of this review article is to provide an overview of β-HB metabolism and its relationship and application in age-related diseases. Future studies are needed to reveal whether β-HB has the potential to serve as adjunctive nutritional therapy for aging.
15Ketone bodies: from enemy to friend and guardian angel.PubMed
Hubert Kolb, Kerstin Kempf, Martin Röhling, et al.
BMC Med. 2021 Dec 9;19(1):313. doi: 10.1186/s12916-021-02185-0.
During starvation, fasting, or a diet containing little digestible carbohydrates, the circulating insulin levels are decreased. This promotes lipolysis, and the breakdown of fat becomes the major source of energy. The hepatic energy metabolism is regulated so that under these circumstances, ketone bodies are generated from β-oxidation of fatty acids and secreted as ancillary fuel, in addition to gluconeogenesis. Increased plasma levels of ketone bodies thus indicate a dietary shortage of carbohydrates. Ketone bodies not only serve as fuel but also promote resistance to oxidative and inflammatory stress, and there is a decrease in anabolic insulin-dependent energy expenditure. It has been suggested that the beneficial non-metabolic actions of ketone bodies on organ functions are mediated by them acting as a ligand to specific cellular targets. We propose here a major role of a different pathway initiated by the induction of oxidative stress in the mitochondria during increased ketolysis. Oxidative stress induced by ketone body metabolism is beneficial in the long term because it initiates an adaptive (hormetic) response characterized by the activation of the master regulators of cell-protective mechanism, nuclear factor erythroid 2-related factor 2 (Nrf2), sirtuins, and AMP-activated kinase. This results in resolving oxidative stress, by the upregulation of anti-oxidative and anti-inflammatory activities, improved mitochondrial function and growth, DNA repair, and autophagy. In the heart, the adaptive response to enhanced ketolysis improves resistance to damage after ischemic insults or to cardiotoxic actions of doxorubicin. Sodium-dependent glucose co-transporter 2 (SGLT2) inhibitors may also exert their cardioprotective action via increasing ketone body levels and ketolysis. We conclude that the increased synthesis and use of ketone bodies as ancillary fuel during periods of deficient food supply and low insulin levels causes oxidative stress in the mitochondria and that the latter initiates a protective (hormetic) response which allows cells to cope with increased oxidative stress and lower energy availability. KEYWORDS: Ketogenic diet, Ketone bodies, Beta hydroxybutyrate, Insulin, Obesity, Type 2 diabetes, Inflammation, Oxidative stress, Cardiovascular disease, SGLT2, Hormesis.
16Cardiac Energy Metabolism in Heart Failure.PubMed
Gary D Lopaschuk, Qutuba G Karwi, Rong Tian, et al.
Circ Res. 2021 May 14;128(10):1487-1513. doi: 10.1161/CIRCRESAHA.121.318241. Epub 2021 May 13.
Alterations in cardiac energy metabolism contribute to the severity of heart failure. However, the energy metabolic changes that occur in heart failure are complex and are dependent not only on the severity and type of heart failure present but also on the co-existence of common comorbidities such as obesity and type 2 diabetes. The failing heart faces an energy deficit, primarily because of a decrease in mitochondrial oxidative capacity. This is partly compensated for by an increase in ATP production from glycolysis. The relative contribution of the different fuels for mitochondrial ATP production also changes, including a decrease in glucose and amino acid oxidation, and an increase in ketone oxidation. The oxidation of fatty acids by the heart increases or decreases, depending on the type of heart failure. For instance, in heart failure associated with diabetes and obesity, myocardial fatty acid oxidation increases, while in heart failure associated with hypertension or ischemia, myocardial fatty acid oxidation decreases. Combined, these energy metabolic changes result in the failing heart becoming less efficient (ie, a decrease in cardiac work/O consumed). The alterations in both glycolysis and mitochondrial oxidative metabolism in the failing heart are due to both transcriptional changes in key enzymes involved in these metabolic pathways, as well as alterations in NAD redox state (NAD and nicotinamide adenine dinucleotide levels) and metabolite signaling that contribute to posttranslational epigenetic changes in the control of expression of genes encoding energy metabolic enzymes. Alterations in the fate of glucose, beyond flux through glycolysis or glucose oxidation, also contribute to the pathology of heart failure. Of importance, pharmacological targeting of the energy metabolic pathways has emerged as a novel therapeutic approach to improving cardiac efficiency, decreasing the energy deficit and improving cardiac function in the failing heart.
17Metabolic Coordination of Physiological and Pathological Cardiac Remodeling.PubMed
Andrew A Gibb, Bradford G Hill
Circ Res. 2018 Jun 22;123(1):107-128. doi: 10.1161/CIRCRESAHA.118.312017.
Metabolic pathways integrate to support tissue homeostasis and to prompt changes in cell phenotype. In particular, the heart consumes relatively large amounts of substrate not only to regenerate ATP for contraction but also to sustain biosynthetic reactions for replacement of cellular building blocks. Metabolic pathways also control intracellular redox state, and metabolic intermediates and end products provide signals that prompt changes in enzymatic activity and gene expression. Mounting evidence suggests that the changes in cardiac metabolism that occur during development, exercise, and pregnancy as well as with pathological stress (eg, myocardial infarction, pressure overload) are causative in cardiac remodeling. Metabolism-mediated changes in gene expression, metabolite signaling, and the channeling of glucose-derived carbon toward anabolic pathways seem critical for physiological growth of the heart, and metabolic inefficiency and loss of coordinated anabolic activity are emerging as proximal causes of pathological remodeling. This review integrates knowledge of different forms of cardiac remodeling to develop general models of how relationships between catabolic and anabolic glucose metabolism may fortify cardiac health or promote (mal)adaptive myocardial remodeling. Adoption of conceptual frameworks based in relational biology may enable further understanding of how metabolism regulates cardiac structure and function.
18Advances in myocardial energy metabolism: metabolic remodelling in heart failure and beyond.PubMed
Qiuyu Sun, Qutuba G Karwi, Nathan Wong, et al.
Cardiovasc Res. 2024 Dec 14;120(16):1996-2016. doi: 10.1093/cvr/cvae231.
The very high energy demand of the heart is primarily met by adenosine triphosphate (ATP) production from mitochondrial oxidative phosphorylation, with glycolysis providing a smaller amount of ATP production. This ATP production is markedly altered in heart failure, primarily due to a decrease in mitochondrial oxidative metabolism. Although an increase in glycolytic ATP production partly compensates for the decrease in mitochondrial ATP production, the failing heart faces an energy deficit that contributes to the severity of contractile dysfunction. The relative contribution of the different fuels for mitochondrial ATP production dramatically changes in the failing heart, which depends to a large extent on the type of heart failure. A common metabolic defect in all forms of heart failure [including heart failure with reduced ejection fraction (HFrEF), heart failure with preserved EF (HFpEF), and diabetic cardiomyopathies] is a decrease in mitochondrial oxidation of pyruvate originating from glucose (i.e. glucose oxidation). This decrease in glucose oxidation occurs regardless of whether glycolysis is increased, resulting in an uncoupling of glycolysis from glucose oxidation that can decrease cardiac efficiency. The mitochondrial oxidation of fatty acids by the heart increases or decreases, depending on the type of heart failure. For instance, in HFpEF and diabetic cardiomyopathies myocardial fatty acid oxidation increases, while in HFrEF myocardial fatty acid oxidation either decreases or remains unchanged. The oxidation of ketones (which provides the failing heart with an important energy source) also differs depending on the type of heart failure, being increased in HFrEF, and decreased in HFpEF and diabetic cardiomyopathies. The alterations in mitochondrial oxidative metabolism and glycolysis in the failing heart are due to transcriptional changes in key enzymes involved in the metabolic pathways, as well as alterations in redox state, metabolic signalling and post-translational epigenetic changes in energy metabolic enzymes. Of importance, targeting the mitochondrial energy metabolic pathways has emerged as a novel therapeutic approach to improving cardiac function and cardiac efficiency in the failing heart.
19Ketones and the Heart: Metabolic Principles and Therapeutic Implications.PubMed
Timothy R Matsuura, Patrycja Puchalska, Peter A Crawford, et al.
Circ Res. 2023 Mar 31;132(7):882-898. doi: 10.1161/CIRCRESAHA.123.321872. Epub 2023 Mar 30.
The ketone bodies beta-hydroxybutyrate and acetoacetate are hepatically produced metabolites catabolized in extrahepatic organs. Ketone bodies are a critical cardiac fuel and have diverse roles in the regulation of cellular processes such as metabolism, inflammation, and cellular crosstalk in multiple organs that mediate disease. This review focuses on the role of cardiac ketone metabolism in health and disease with an emphasis on the therapeutic potential of ketosis as a treatment for heart failure (HF). Cardiac metabolic reprogramming, characterized by diminished mitochondrial oxidative metabolism, contributes to cardiac dysfunction and pathologic remodeling during the development of HF. Growing evidence supports an adaptive role for ketone metabolism in HF to promote normal cardiac function and attenuate disease progression. Enhanced cardiac ketone utilization during HF is mediated by increased availability due to systemic ketosis and a cardiac autonomous upregulation of ketolytic enzymes. Therapeutic strategies designed to restore high-capacity fuel metabolism in the heart show promise to address fuel metabolic deficits that underpin the progression of HF. However, the mechanisms involved in the beneficial effects of ketone bodies in HF have yet to be defined and represent important future lines of inquiry. In addition to use as an energy substrate for cardiac mitochondrial oxidation, ketone bodies modulate myocardial utilization of glucose and fatty acids, two vital energy substrates that regulate cardiac function and hypertrophy. The salutary effects of ketone bodies during HF may also include extra-cardiac roles in modulating immune responses, reducing fibrosis, and promoting angiogenesis and vasodilation. Additional pleotropic signaling properties of beta-hydroxybutyrate and AcAc are discussed including epigenetic regulation and protection against oxidative stress. Evidence for the benefit and feasibility of therapeutic ketosis is examined in preclinical and clinical studies. Finally, ongoing clinical trials are reviewed for perspective on translation of ketone therapeutics for the treatment of HF.
20Metabolic mechanisms in physiological and pathological cardiac hypertrophy: new paradigms and challenges.PubMed
Julia Ritterhoff, Rong Tian
Nat Rev Cardiol. 2023 Dec;20(12):812-829. doi: 10.1038/s41569-023-00887-x. Epub 2023 May 26.
Cardiac metabolism is vital for heart function. Given that cardiac contraction requires a continuous supply of ATP in large quantities, the role of fuel metabolism in the heart has been mostly considered from the perspective of energy production. However, the consequence of metabolic remodelling in the failing heart is not limited to a compromised energy supply. The rewired metabolic network generates metabolites that can directly regulate signalling cascades, protein function, gene transcription and epigenetic modifications, thereby affecting the overall stress response of the heart. In addition, metabolic changes in both cardiomyocytes and non-cardiomyocytes contribute to the development of cardiac pathologies. In this Review, we first summarize how energy metabolism is altered in cardiac hypertrophy and heart failure of different aetiologies, followed by a discussion of emerging concepts in cardiac metabolic remodelling, that is, the non-energy-generating function of metabolism. We highlight challenges and open questions in these areas and finish with a brief perspective on how mechanistic research can be translated into therapies for heart failure.
21Targeting Mitochondria-Inflammation Circuit by β-Hydroxybutyrate Mitigates HFpEF.PubMed
Yan Deng, Maodi Xie, Qian Li, et al.
Circ Res. 2021 Jan 22;128(2):232-245. doi: 10.1161/CIRCRESAHA.120.317933. Epub 2020 Nov 12.
RATIONALE: Over 50% of patients with heart failure have preserved ejection fraction (HFpEF), rather than reduced ejection fraction. Complexity of its pathophysiology and the lack of animal models hamper the development of effective therapy for HFpEF. OBJECTIVE: This study was designed to investigate the metabolic mechanisms of HFpEF and test therapeutic interventions using a novel animal model. METHODS AND RESULTS: By combining the age, long-term high-fat diet, and desoxycorticosterone pivalate challenge in a mouse model, we were able to recapture the myriad features of HFpEF. In these mice, mitochondrial hyperacetylation exacerbated while increasing ketone body availability rescued the phenotypes. The HFpEF mice exhibited overproduction of IL (interleukin)-1β/IL-18 and tissue fibrosis due to increased assembly of NLPR3 inflammasome on hyperacetylated mitochondria. Increasing β-hydroxybutyrate level attenuated NLPR3 inflammasome formation and antagonized proinflammatory cytokine-triggered mitochondrial dysfunction and fibrosis. Moreover, β-hydroxybutyrate downregulated the acetyl-CoA pool and mitochondrial acetylation, partially via activation of CS (citrate synthase) and inhibition of fatty acid uptake. CONCLUSIONS: Therefore, we identify the interplay of mitochondrial hyperacetylation and inflammation as a key driver in HFpEF pathogenesis, which can be ameliorated by promoting β-hydroxybutyrate abundance.
22Chronically Elevating Circulating Ketones Can Reduce Cardiac Inflammation and Blunt the Development of Heart Failure.PubMed
Nikole J Byrne, Shubham Soni, Shingo Takahara, et al.
Circ Heart Fail. 2020 Jun;13(6):e006573. doi: 10.1161/CIRCHEARTFAILURE.119.006573. Epub 2020 Jun 4.
BACKGROUND: Previous studies have shown beneficial effects of acute infusion of the primary ketone body, β-hydroxybutyrate, in heart failure (HF). However, whether chronic elevations in circulating ketones are beneficial remains unknown. METHODS: To chronically elevate circulating ketones in mice, we deleted the expression of the ketolytic, rate-limiting-enzyme, SCOT (succinyl-CoA:3-ketoacid-CoA transferase 1; encoded by ), in skeletal muscle. Tamoxifen-inducible skeletal muscle-specific knockout (n=32) mice and littermate controls (wild type; WT; n=35) were subjected to transverse aortic constriction (TAC) surgery to induce HF. RESULTS: Deletion of SCOT in skeletal, but not cardiac muscle resulted in elevated concentrations of fasted circulating β-hydroxybutyrate in knockout mice compared with WT mice (=0.030). Five weeks following TAC, WT mice progressed to HF, whereas knockout mice with elevated fasting circulating ketones were largely protected from the TAC-induced effects observed in WT mice (ejection fraction, =0.011; mitral E/A, =0.012). Furthermore, knockout mice with TAC had attenuated expression of markers of sterile inflammation and macrophage infiltration, which were otherwise elevated in WT mice subjected to TAC. Lastly, addition of β-hydroxybutyrate to isolated hearts was associated with reduced NLRP3 (nucleotide-binding domain-like receptor protein 3)-inflammasome activation, which has been previously shown to play a role in contributing to HF-induced cardiac inflammation. CONCLUSIONS: These data show that chronic elevation of circulating ketones protects against the development of HF that is associated with the ability of β-hydroxybutyrate to directly reduce inflammation. These beneficial effects of ketones were associated with reduced cardiac NLRP3 inflammasome activation, suggesting that ketones may modulate cardiac inflammation via this mechanism.
23Exogenous ketone ester administration attenuates systemic inflammation and reduces organ damage in a lipopolysaccharide model of sepsis.PubMed
Shubham Soni, Matthew D Martens, Shingo Takahara, et al.
Biochim Biophys Acta Mol Basis Dis. 2022 Nov 1;1868(11):166507. doi: 10.1016/j.bbadis.2022.166507. Epub 2022 Jul 25.
AIMS: Sepsis is a life-threatening condition of organ dysfunction caused by dysregulated inflammation which predisposes patients to developing cardiovascular disease. The ketone β-hydroxybutyrate is reported to be cardioprotective in cardiovascular disease and this may be due to their signaling properties that contribute to reducing inflammation. While exogenous ketone esters (KE) increase blood ketone levels, it remains unknown whether KEs can reduce the enhanced inflammatory response and multi-organ dysfunction that is observed in sepsis. Thus, this study assesses whether a recently developed and clinically safe KE can effectively improve the inflammatory response and organ dysfunction in sepsis. METHODS AND RESULTS: To assess the anti-inflammatory effects of a KE, we utilized a model of lipopolysaccharide (LPS)-induced sepsis in which an enhanced inflammatory response results in multi-organ dysfunction. Oral administration of KE for three days prior to LPS-injection significantly protected mice against the profound systemic inflammation compared to their vehicle-treated counterparts. In assessing organ dysfunction, KE protected mice from sepsis-induced cardiac dysfunction as well as renal dysfunction and fibrosis. Furthermore, KE administration attenuated the sepsis-induced inflammation in the heart, kidney, and liver. Moreover, these protective effects occurred independent of changes to enzymes involved in ketone metabolism. CONCLUSION: These data show that the use of an exogenous KE attenuates the dysregulated systemic and organ inflammation as well as organ dysfunction in a model of severe inflammation. We postulate that this exogenous KE is an appealing and promising approach to capitalize on the protective anti-inflammatory effects of ketones in sepsis and/or other inflammatory responses.
24β-Hydroxybutyrate inhibits cardiac microvascular collagen 4 accumulation by attenuating oxidative stress in streptozotocin-induced diabetic rats and high glucose treated cells.PubMed
Huanli Qi, Lihui Gu, Dongmei Xu, et al.
Eur J Pharmacol. 2021 May 15;899:174012. doi: 10.1016/j.ejphar.2021.174012. Epub 2021 Mar 13.
Accumulation of collagen 4 (COL4) and thickened basement membrane are features of diabetic cardiac microvascular fibrosis that may be induced by oxidative stress. The ketone body β-hydroxybutyrate exhibits various cardiovascular protective effects, however its mechanism remains to be clarified. In the current study, the effects of β-hydroxybutyrate on cardiac microvascular fibrosis and COL4 accumulation were evaluated in streptozotocin-induced diabetic rats and in high glucose (HG) treated human cardiac microvascular endothelial cells (HCMECs). Generations of inducible nitric oxide synthase (iNOS) and copper-zinc superoxide dismutase (Cu/Zn-SOD), and the amount of nitrotyrosine (NT) were measured in vivo and in vitro. Ten weeks of β-hydroxybutyrate treatment (160, 200 and 240 mg/kg/d) attenuated cardiac microvascular fibrosis and inhibited cardiac COL4 generation and microvascular distribution in diabetic rats. Furthermore, β-hydroxybutyrate promoted cardiac Cu/Zn-SOD generation and reduced NT content, without reducing iNOS generation in diabetic rats. In HCMECs, stimulation with HG induced excess generation of COL4 via peroxynitrite. β-Hydroxybutyrate treatment (2, 4, 6 mM) attenuated HG-stimulated COL4 accumulation in a concentration-dependent manner. Similarly, 4 mM β-hydroxybutyrate promoted Cu/Zn-SOD generation and reduced NT content, without affecting excess iNOS generation in HG-stimulated HCMECs. In conclusion, this study showed that β-hydroxybutyrate promoted Cu/Zn-SOD generation, reduced peroxynitrite and inhibited cardiac microvascular COL4 accumulation in diabetes.
25Antioxidant properties of myocardial fuels.PubMed
Robert T Mallet, Jie Sun
Mol Cell Biochem. 2003 Nov;253(1-2):103-11. doi: 10.1023/a:1026009519783.
Oxidative metabolism of blood-borne fuels provides myocardium the energy required to sustain its contractile performance. Recent research has revealed that, in addition to supplying energy, certain fuels are able to detoxify harmful oxidants and bolster the myocardium's endogenous antioxidant defenses. These antioxidant capabilities could potentially protect the myocardium from the ravages of reactive oxygen and nitrogen intermediates generated upon reperfusion of ischemic myocardium. This article reviews experimental evidence that two fuels, pyruvate and acetoacetate, provide such antioxidant protection. Pyruvate's antioxidant properties stem in part from its alpha-keto carboxylate structure, which enables it to directly, non-enzymatically neutralize peroxides and peroxynitrite. Also, citrate, which accumulates in pyruvate-perfused myocardium following anaplerotic pyruvate carboxylation, supports NADPH production to maintain glutathione:glutathione disulfide (GSH/GSSG) redox potential, the central component of the myocardial antioxidant system. Like pyruvate, acetoacetate restores GSH/GSSG and increases contractile function of post-ischemic stunned myocardium, although some of its antioxidant mechanisms may differ from pyruvate's. Both compounds restore beta-adrenergic signaling and inotropism, which are compromised in stunned myocardium. N-acetylcysteine, a pharmacological antioxidant that does not provide energy, duplicated the salutary effects of pyruvate and acetoacetate on post-ischemic gamma-adrenergic signaling and GSH/GSSG. These findings reveal novel, energy-independent mechanisms for enhancement of post-ischemic cardiac performance by metabolic fuels.
26Acetoacetate augments beta-adrenergic inotropism of stunned myocardium by an antioxidant mechanism.PubMed
Jeffrey E Squires, Jie Sun, James L Caffrey, et al.
Am J Physiol Heart Circ Physiol. 2003 Apr;284(4):H1340-7. doi: 10.1152/ajpheart.00473.2002. Epub 2002 Dec 19.
Blunted beta-adrenergic inotropism in stunned myocardium is restored by pharmacological (N-acetylcysteine) and metabolic (pyruvate) antioxidants. The ketone body acetoacetate is a natural myocardial fuel and antioxidant that improves contractile function of prooxidant-injured myocardium. The impact of acetoacetate on postischemic cardiac function and beta-adrenergic signaling has never been reported. To test the hypothesis that acetoacetate restores contractile performance and beta-adrenergic inotropism of stunned myocardium, postischemic Krebs-Henseleit-perfused guinea pig hearts were treated with 5 mM acetoacetate and/or 2 nM isoproterenol at 15-45 and 30-45 min of reperfusion, respectively, while cardiac power was monitored. The myocardium was snap frozen, and its energy state was assessed from phosphocreatine phosphorylation potential. Antioxidant defenses were assessed from GSH/GSSG and NADPH/NADP(+) redox potentials. Stunning lowered cardiac power and GSH redox potential by 90 and 70%, respectively. Given separately, acetoacetate and isoproterenol each increased power and GSH redox potential three- to fivefold. Phosphocreatine potential was 70% higher in acetoacetate- vs. isoproterenol-treated hearts (P < 0.01). In combination, acetoacetate and isoproterenol synergistically increased power and GSH redox potential 16- and 7-fold, respectively, doubled NADPH redox potential, and increased cAMP content 30%. The combination increased cardiac power four- to sixfold vs. the individual treatments without a coincident increase in phosphorylation potential. Potentiation of isoproterenol's inotropic actions endured even after acetoacetate was discontinued and GSH potential waned, indicating that temporary enhancement of redox potential persistently restored beta-adrenergic mechanisms. Thus acetoacetate increased contractile performance and potentiated beta-adrenergic inotropism in stunned myocardium without increasing energy reserves, suggesting its antioxidant character is central to its beneficial actions.
27The ketogenic diet does not improve cardiac function and blunts glucose oxidation in ischaemic heart failure.PubMed
Kim L Ho, Qutuba G Karwi, Faqi Wang, et al.
Cardiovasc Res. 2024 Sep 2;120(10):1126-1137. doi: 10.1093/cvr/cvae092.
AIMS: Cardiac energy metabolism is perturbed in ischaemic heart failure and is characterized by a shift from mitochondrial oxidative metabolism to glycolysis. Notably, the failing heart relies more on ketones for energy than a healthy heart, an adaptive mechanism that improves the energy-starved status of the failing heart. However, whether this can be implemented therapeutically remains unknown. Therefore, our aim was to determine if increasing ketone delivery to the heart via a ketogenic diet can improve the outcomes of heart failure. METHODS AND RESULTS: C57BL/6J male mice underwent either a sham surgery or permanent left anterior descending coronary artery ligation surgery to induce heart failure. After 2 weeks, mice were then treated with either a control diet or a ketogenic diet for 3 weeks. Transthoracic echocardiography was then carried out to assess in vivo cardiac function and structure. Finally, isolated working hearts from these mice were perfused with appropriately 3H or 14C labelled glucose (5 mM), palmitate (0.8 mM), and β-hydroxybutyrate (β-OHB) (0.6 mM) to assess mitochondrial oxidative metabolism and glycolysis. Mice with heart failure exhibited a 56% drop in ejection fraction, which was not improved with a ketogenic diet feeding. Interestingly, mice fed a ketogenic diet had marked decreases in cardiac glucose oxidation rates. Despite increasing blood ketone levels, cardiac ketone oxidation rates did not increase, probably due to a decreased expression of key ketone oxidation enzymes. Furthermore, in mice on the ketogenic diet, no increase in overall cardiac energy production was observed, and instead, there was a shift to an increased reliance on fatty acid oxidation as a source of cardiac energy production. This resulted in a decrease in cardiac efficiency in heart failure mice fed a ketogenic diet. CONCLUSION: We conclude that the ketogenic diet does not improve heart function in failing hearts, due to ketogenic diet-induced excessive fatty acid oxidation in the ischaemic heart and a decrease in insulin-stimulated glucose oxidation.
28Ketogenic Diet Regulates Cardiac Remodeling and Calcium Homeostasis in Diabetic Rat Cardiomyopathy.PubMed
Ting-I Lee, Nguyen Ngoc Trang, Ting-Wei Lee, et al.
Int J Mol Sci. 2023 Nov 9;24(22):16142. doi: 10.3390/ijms242216142.
A ketogenic diet (KD) might alleviate patients with diabetic cardiomyopathy. However, the underlying mechanism remains unclear. Myocardial function and arrhythmogenesis are closely linked to calcium (Ca) homeostasis. We investigated the effects of a KD on Ca homeostasis and electrophysiology in diabetic cardiomyopathy. Male Wistar rats were created to have diabetes mellitus (DM) using streptozotocin (65 mg/kg, intraperitoneally), and subsequently treated for 6 weeks with either a normal diet (ND) or a KD. Our electrophysiological and Western blot analyses assessed myocardial Ca homeostasis in ventricular preparations in vivo. Unlike those on the KD, DM rats treated with an ND exhibited a prolonged QTc interval and action potential duration. Compared to the control and DM rats on the KD, DM rats treated with an ND also showed lower intracellular Ca transients, sarcoplasmic reticular Ca content, sodium (Na)-Ca exchanger currents (reverse mode), L-type Ca contents, sarcoplasmic reticulum ATPase contents, Cav1.2 contents. Furthermore, these rats exhibited elevated ratios of phosphorylated to total proteins across multiple Ca handling proteins, including ryanodine receptor 2 (RyR2) at serine 2808, phospholamban (PLB)-Ser16, and calmodulin-dependent protein kinase II (CaMKII). Additionally, DM rats treated with an ND demonstrated a higher frequency and incidence of Ca leak, cytosolic reactive oxygen species, Na/hydrogen-exchanger currents, and late Na currents than the control and DM rats on the KD. KD treatment may attenuate the effects of DM-dysregulated Na and Ca homeostasis, contributing to its cardioprotection in DM.
29A ketogenic-promoting beverage acutely elevates cardiac function and myocardial blood flow compared to placebo in adults: A cardiac MRI investigation.PubMed
Christopher D Crabtree, Yue Pan, Preethi Chandrasekaran, et al.
Physiol Rep. 2025 Mar;13(6):e70208. doi: 10.14814/phy2.70208.
Increasing evidence suggests cardiac function improves in healthy and failing hearts alongside circulating ketones (1-4 mM). This study characterized cardiac function and blood flow responses to a ketogenic beverage compared to a volume/calorie matched placebo with repeated imaging over 120 min. This was a two-group, placebo-controlled, acute cardiac imaging study. Adults without cardiac abnormalities underwent baseline cardiac MRI including quantitative myocardial perfusion to measure myocardial blood flow (MBF). Subjects consumed 50 g of a ketogenic-promoting beverage [bis-hexanoyl R-1-3-butanediol (BH-BD)] (BH-BD; n = 11) or a calorically/volume-matched lipid-based placebo (PL; n = 10) with cardiac MRI every 15-30 min. Following 120 min, subjects underwent a final scan including MBF measurement. R-BHB and glucose were measured at every timepoint. 120 min following BH-BD consumption, R-BHB reached 2.1 mM. Cardiac output (CO) was elevated compared to PL (p < 0.05) and increased +31% 120 min after BH-BD ingestion (p < 0.001). CO elevation was due to increased stroke volume (+11%; p = 0.02) and heart rate (+22%; p < 0.001). MBF increased 29% from baseline (p < 0.001). PL did not induce differences in cardiac parameters. 50 g BH-BD ingestion achieves exogenous ketosis and is associated with elevated MBF and CO providing evidence supporting their use as a therapeutic clinical agent.
30Physical exercise with weight reduction lowers blood pressure and improves abnormal left ventricular relaxation in pharmacologically treated hypertensive patients.PubMed
Giuseppe Cocco, Stefano Pandolfi
J Clin Hypertens (Greenwich). 2011 Jan;13(1):23-9. doi: 10.1111/j.1751-7176.2010.00380.x. Epub 2010 Oct 6.
In spite of appropriate pharmacologic therapy, many hypertensive patients develop an abnormal left ventricular relaxation with preserved systolic function. This cardiac dysfunction increases the risk of cardiovascular complications. The authors assessed the therapeutic effects of an intervention with exercise training and weight reduction in patients with pharmacologically well-treated hypertension who had abnormal left ventricular relaxation with normal systolic function. Eighty-eight (44%) of 202 medically treated hypertensive patients had abnormal ventricular relaxation with normal ejection fraction. These patients were randomized to either a 6-month intervention program (cycle ergometer training twice a day for 5 days a week and a hypocaloric diet) or a control program (unchanged pharmacologic therapy without exercise and diet. Body weight, blood pressure, New York Heart Association class, glomerular filtration rate, and exercise capacity and workload were measured. Cardiac function was assessed by measuring N-terminal pro-B-type natriuretic peptide values, the electrocardiographic QT dispersion interval, and echocardiography (left atrial size, Doppler-derived E/A ratio, and mitral deceleration time). Physical exercise with weight reduction reduced blood pressure, decreased cardiovascular risks, and improved abnormal left ventricular relaxation. Measuring left atrial size is the best method for assessing changes in left ventricular relaxation with preserved systolic function.
31The effect of a short-term ketogenic diet on exercise efficiency during graded exercise in healthy adults.PubMed
Wonhee Cho, Hwaebong Jung, Sunghyun Hong, et al.
J Int Soc Sports Nutr. 2023 Dec;20(1):2264278. doi: 10.1080/15502783.2023.2264278. Epub 2023 Oct 4.
OBJECTIVE: We examined the effects of short-term KD on exercise efficiency and hormonal response during and after the graded exercise testing. METHODS: Fourteen untrained healthy adults (8 males, 6 females, age 26.4 ± 3.1 [SD] years; BMI 24.8 ± 4.6 kg/m; peak VOmax 54.0 ± 5.8 ml/kg FFM/min) completed 3-days of a mixed diet (MD) followed by another 3-days of KD after 3-days of washout period. Upon completion of each diet arm, participants underwent graded exercise testing with low- (LIE; 40% of VOmax), moderate- (MIE; 55%), and high-intensity exercise (HIE; 70%). Exercise efficiency was calculated as work done (kcal/min)/energy expenditure (kcal/min). RESULTS: Fat oxidation during the recovery period was higher in KD vs. MD. Despite identical workload during HIE, participants after having KD vs. MD showed higher energy expenditure and lower exercise efficiency (10.1 ± 0.7 vs. 12.5 ± 0.3%, < .01). After KD, free fatty acid (FFA) concentrations were higher during MIE and recovery vs. resting, and beta-hydroxybutylate (BOHB) was lower at HIE vs. resting. Cortisol concentrations after KD was higher during recovery vs. resting, with no significant changes during graded exercise testing after MD. CONCLUSIONS: Our data suggest that short-term KD is favorable to fat metabolism leading increased circulating FFA and BOHB during LIE to MIE. However, it is notable that KD may cause 1) exercise inefficiency manifested by increased energy expenditure and 2) elevated exercise stress during HIE and recovery. KCT0005172, International Clinical Trials Registry Platform.
32Ketogenic diet but not free-sugar restriction alters glucose tolerance, lipid metabolism, peripheral tissue phenotype, and gut microbiome: RCT.PubMed
Aaron Hengist, Russell G Davies, Jean-Philippe Walhin, et al.
Cell Rep Med. 2024 Aug 20;5(8):101667. doi: 10.1016/j.xcrm.2024.101667. Epub 2024 Aug 5.
Restricted sugar and ketogenic diets can alter energy balance/metabolism, but decreased energy intake may be compensated by reduced expenditure. In healthy adults, randomization to restricting free sugars or overall carbohydrates (ketogenic diet) for 12 weeks reduces fat mass without changing energy expenditure versus control. Free-sugar restriction minimally affects metabolism or gut microbiome but decreases low-density lipoprotein cholesterol (LDL-C). In contrast, a ketogenic diet decreases glucose tolerance, increases skeletal muscle PDK4, and reduces AMPK and GLUT4 levels. By week 4, the ketogenic diet reduces fasting glucose and increases apolipoprotein B, C-reactive protein, and postprandial glycerol concentrations. However, despite sustained ketosis, these effects are no longer apparent by week 12, when gut microbial beta diversity is altered, possibly reflective of longer-term adjustments to the ketogenic diet and/or energy balance. These data demonstrate that restricting free sugars or overall carbohydrates reduces energy intake without altering physical activity, but with divergent effects on glucose tolerance, lipoprotein profiles, and gut microbiome.
33A ketogenic diet lowers myocardial fatty acid oxidation but does not affect oxygen consumption: a study in overweight humans.PubMed
Thien Vinh Luong, Mette Glavind Bülow Pedersen, Caroline Bruun Abild, et al.
Obesity (Silver Spring). 2024 Mar;32(3):506-516. doi: 10.1002/oby.23967. Epub 2024 Jan 23.
OBJECTIVE: A ketogenic diet (KD) characterized by very low carbohydrate intake and high fat consumption may simultaneously induce weight loss and be cardioprotective. The "thrifty substrate hypothesis" posits that ketone bodies are more energy efficient compared with other cardiac oxidative substrates such as fatty acids. This work aimed to study whether a KD with presumed increased myocardial ketone body utilization reduces cardiac fatty acid uptake and oxidation, resulting in decreased myocardial oxygen consumption (MVO ). METHODS: This randomized controlled crossover trial examined 11 individuals with overweight or obesity on two occasions: (1) after a KD and (2) after a standard diet. Myocardial free fatty acid (FFA) oxidation, uptake, and esterification rate were measured using dynamic [ C]palmitate positron emission tomography (PET)/computed tomography, whereas MVO and myocardial external efficiency (MEE) were measured using dynamic [ C]acetate PET. RESULTS: The KD increased plasma β-hydroxybutyrate, reduced myocardial FFA oxidation (p < 0.01) and uptake (p = 0.03), and increased FFA esterification (p = 0.03). No changes were observed in MVO (p = 0.2) or MEE (p = 0.87). CONCLUSIONS: A KD significantly reduced myocardial FFA uptake and oxidation, presumably by increasing ketone body oxidation. However, this change in cardiac substrate utilization did not improve MVO , speaking against the thrifty substrate hypothesis.
34The effect of a ketogenic diet versus a high-carbohydrate, low-fat diet on sleep, cognition, thyroid function, and cardiovascular health independent of weight loss: study protocol for a randomized controlled trial.PubMed
Stella Iacovides, Rebecca M Meiring
Trials. 2018 Jan 23;19(1):62. doi: 10.1186/s13063-018-2462-5.
BACKGROUND: Many physiological health benefits observed after following a ketogenic diet (KD) can be attributed to the associated weight loss. The KD has become more prominent as a popular health choice, not only in obese/overweight individuals, but also in healthy adults. The study aims to determine the effects of a KD, independent of weight loss, on various aspects of physiological health including: sleep, thyroid function, cognition, and cardio-metabolic health. The study will also aim to determine whether a change in basal metabolic rate may be associated with any changes observed. METHODS: Twenty healthy men and women between 18 and 50 years of age will take part in this study. In a randomized controlled, cross-over design, participants will follow two isocaloric diets: a high-carbohydrate, low-fat diet (55% CHO, 20% fat, 25% protein) and a KD (15% CHO, 60% fat, 25% protein). Each dietary intervention will last for a minimum of 3 weeks, with a 1-week washout period in between. Before and after each diet, participants will be assessed for sleep quality, cognitive function, thyroid function, and basal metabolic rate. A blood sample will also be taken for the measurement of cardio-metabolic and immune markers. DISCUSSION: The present study will help in understanding the potential effects of a KD on aspects of physiological health in healthy adults, without the confounding factor of weight loss. The study aims to fill a significant void in the academic literature with regards to the benefits and/or risks of a KD in a healthy population, but will also explore whether diet-related metabolic changes may be responsible for the changes observed in physiological health. TRIAL REGISTRATION: Pan African Clinical Trial Registry ( www.pactr.org ), trial number: PACTR201707002406306 . Registered on 20 July 2017.
35Implications of Altered Ketone Metabolism and Therapeutic Ketosis in Heart Failure.PubMed
Senthil Selvaraj, Daniel P Kelly, Kenneth B Margulies
Circulation. 2020 Jun 2;141(22):1800-1812. doi: 10.1161/CIRCULATIONAHA.119.045033. Epub 2020 Jun 1.
Despite existing therapy, patients with heart failure (HF) experience substantial morbidity and mortality, highlighting the urgent need to identify novel pathophysiological mechanisms and therapies, as well. Traditional models for pharmacological intervention have targeted neurohormonal axes and hemodynamic disturbances in HF. However, several studies have now highlighted the potential for ketone metabolic modulation as a promising treatment paradigm. During the pathophysiological progression of HF, the failing heart reduces fatty acid and glucose oxidation, with associated increases in ketone metabolism. Recent studies indicate that enhanced myocardial ketone use is adaptive in HF, and limited data demonstrate beneficial effects of exogenous ketone therapy in studies of animal models and humans with HF. This review will summarize current evidence supporting a salutary role for ketones in HF including (1) normal myocardial ketone use, (2) alterations in ketone metabolism in the failing heart, (3) effects of therapeutic ketosis in animals and humans with HF, and (4) the potential significance of ketosis associated with sodium-glucose cotransporter 2 inhibitors. Although a number of important questions remain regarding the use of therapeutic ketosis and mechanism of action in HF, current evidence suggests potential benefit, in particular, in HF with reduced ejection fraction, with theoretical rationale for its use in HF with preserved ejection fraction. Although it is early in its study and development, therapeutic ketosis across the spectrum of HF holds significant promise.
36Ketone therapy improves cardiac function and structure in rodents with heart failure: A systematic review and meta-analysis.PubMed
Tingting Lv, Chunyan Liu, Mengfei Ye, et al.
Nutr Res. 2025 May;137:56-70. doi: 10.1016/j.nutres.2025.03.008. Epub 2025 Mar 26.
This meta-analysis aimed to quantitatively assess the effects of ketone intervention on cardiac function and structure in rodents with heart failure (HF). We hypothesized that ketone intervention could enhance the cardiac function and structure in HF. We systematically searched PubMed, Cochrane Library, and Embase databases for relevant studies up to April 13, 2024. Ketone therapy encompassed a ketogenic diet, ketone esters, medium-chain triglycerides, and β-hydroxybutyrate. The effect measures are mainly expressed as standardized mean difference (SMD) and 95% confidence interval (CI). Our meta-analysis included 24 animal studies. Ketone therapy significantly improved left ventricular ejection fraction (SMD: 1.31, 95% CI: 0.79-1.82, I = 77%), cardiac output (SMD: 0.70, 95% CI: 0.28-1.11, I = 0%), and ameliorated myocardial hypertrophy (SMD: -1.95, 95% CI: -2.76 to -1.13, I = 76%), myocardial fibrosis (SMD: -0.87, 95% CI: -1.60 to -0.15, I = 68%), and ventricular remodeling in HF rodents. Subgroup analysis indicated that ketone intervention worsened myocardial fibrosis in non-HF rodents (SMD: 0.86, 95% CI: 0.09-1.63, I = 78%) and had no significant effect on cardiac function. Additionally, further subgroup analysis indicated that ketogenic diet significantly alleviated cardiac hypertrophy and fibrosis, whereas ketone esters did not yield significant effects. The effect of ketone on left ventricular ejection fraction strengthened with the duration of intervention. Our results suggested that ketone therapy significantly improved the cardiac systolic function and structure in rodents with HF, and had no effect in rodents non-HF. Thus, ketone intervention may be a promising treatment for HF patients.
37Therapeutic Ketosis for Heart Failure: A State-of-the-Art Review.PubMed
Nandan Kodur, Christopher Nguyen, W H Wilson Tang
J Card Fail. 2025 Jul;31(7):1051-1061. doi: 10.1016/j.cardfail.2025.01.028. Epub 2025 Mar 3.
Heart failure is characterized by an energy-deprived heart, and in recent years it has been found that the failing heart increases ketone body oxidation to meet its energy demands. Accumulating evidence suggests that this metabolic adaptation is cardioprotective, suggesting that interventions that boost blood ketone levels could aid the failing heart. Indeed, multiple small clinical trials with short-term follow up have demonstrated that supplying the failing heart with exogenous ketone bodies may improve myocardial function across various manifestations of heart failure. As such, therapeutic ketosis, which is a metabolic state in which blood ketone levels are mildly elevated, could have great potential to ameliorate heart failure. Therapeutic ketosis can be achieved endogenously via exercise or dietary practices, exogenously via supplementation with ketone bodies, or pharmacologically via treatment with a sodium-glucose cotransporter-2 inhibitor. Although ketosis-inducing practices cannot be routinely recommended to patients with heart failure at this time due to a lack of robust data regarding the long-term benefits and risks, anecdotal evidence suggests that some patients have begun to adopt ketosis-inducing practices, so it is important for clinicians to be aware of how to manage patients optimally when they are in therapeutic ketosis. In this review, we discuss myocardial ketone metabolism in heart failure, the current evidence for therapeutic ketosis in patients with heart failure, a framework to distinguish between therapeutic ketosis and the pathologic state of ketoacidosis, and practical considerations for managing patients adhering to ketosis-inducing practices.
38Reversal of severe hypertriglyceridemia with intermittent fasting and a very-low-carbohydrate ketogenic diet: a case series.PubMed
Subrat Das, Jordan McCreary, Shariq Shamim, et al.
Curr Opin Endocrinol Diabetes Obes. 2020 Oct;27(5):308-311. doi: 10.1097/MED.0000000000000566.
PURPOSE OF REVIEW: To illustrate successful reversal of hypertriglyceridemia using a very-low-carbohydrate ketogenic diet in conjunction with intermittent fasting in two patients. RECENT FINDINGS: Hypertriglyceridemia remains an important component of residual risk for atherosclerotic cardiovascular disease. Current guidelines from the AHA/ACC recommend the initiation of a very-low-fat diet to treat persistently elevated triglycerides, whereas the National Lipid Association argues that a very-low-carbohydrate, high-fat diet is contraindicated in severe hypertriglyceridemia. In contrast, we report resolution of two cases of severe hypertriglyceridemia with implementation of very-low-carbohydrate ketogenic diets and intermittent fasting. SUMMARY: Here, we describe two patients who have demonstrated substantial reductions in serum triglycerides, effectively reversing severe hypertriglyceridemia using unconventional dietary methods. Although anecdotal, these cases point to a critical lack of flexibility in current dietary guidelines that hinder their application in clinical practice.
39Low Carbohydrate Diets for Diabetic Cardiomyopathy: A Hypothesis.PubMed
Sabine Kleissl-Muir, Bodil Rasmussen, Alice Owen, et al.
Front Nutr. 2022 Apr 20;9:865489. doi: 10.3389/fnut.2022.865489. eCollection 2022.
Elevated blood glucose levels, insulin resistance (IR), hyperinsulinemia and dyslipidemia the key aspects of type 2 diabetes mellitus (T2DM), contribute to the development of a certain form of cardiomyopathy. This cardiomyopathy, also known as diabetic cardiomyopathy (DMCM), typically occurs in the absence of overt coronary artery disease (CAD), hypertension or valvular disease. DMCM encompasses a variety of pathophysiological processes impacting the myocardium, hence increasing the risk for heart failure (HF) and significantly worsening outcomes in this population. Low fat (LF), calorie-restricted diets have been suggested as the preferred eating pattern for patients with HF. However, LF diets are naturally higher in carbohydrates (CHO). We argue that in an insulin resistant state, such as in DMCM, LF diets may worsen glycaemic control and promote further insulin resistance (IR), contributing to a physiological and functional decline in DMCM. We postulate that CHO restriction targeting hyperinsulinemia may be able to improve tissue and systemic IR. In recent years low carbohydrate diets (LC) including ketogenic diets (KD), have emerged as a safe and effective tool for the management of various clinical conditions such as T2DM and other metabolic disorders. CHO restriction achieves sustained glycaemic control, lower insulin levels and successfully reverses IR. In addition to this, its pleiotropic effects may present a metabolic stress defense and facilitate improvement to cardiac function in patients with HF. We therefore hypothesize that patients who adopt a LC diet may require less medications and experience improvements in HF-related symptom burden.
40Very-low-carbohydrate ketogenic diet v. low-fat diet for long-term weight loss: a meta-analysis of randomised controlled trials.PubMed
Nassib Bezerra Bueno, Ingrid Sofia Vieira de Melo, Suzana Lima de Oliveira, et al.
Br J Nutr. 2013 Oct;110(7):1178-87. doi: 10.1017/S0007114513000548. Epub 2013 May 7.
The role of very-low-carbohydrate ketogenic diets (VLCKD) in the long-term management of obesity is not well established. The present meta-analysis aimed to investigate whether individuals assigned to a VLCKD (i.e. a diet with no more than 50 g carbohydrates/d) achieve better long-term body weight and cardiovascular risk factor management when compared with individuals assigned to a conventional low-fat diet (LFD; i.e. a restricted-energy diet with less than 30% of energy from fat). Through August 2012, MEDLINE, CENTRAL, ScienceDirect,Scopus, LILACS, SciELO, ClinicalTrials.gov and grey literature databases were searched, using no date or language restrictions, for randomised controlled trials that assigned adults to a VLCKD or a LFD, with 12 months or more of follow-up. The primary outcome was bodyweight. The secondary outcomes were TAG, HDL-cholesterol (HDL-C), LDL-cholesterol (LDL-C), systolic and diastolic blood pressure,glucose, insulin, HbA1c and C-reactive protein levels. A total of thirteen studies met the inclusion/exclusion criteria. In the overall analysis,five outcomes revealed significant results. Individuals assigned to a VLCKD showed decreased body weight (weighted mean difference -0·91 (95% CI -1·65, -0·17) kg, 1415 patients), TAG (weighted mean difference -0·18 (95% CI -0·27, -0·08) mmol/l, 1258 patients)and diastolic blood pressure (weighted mean difference -1·43 (95% CI -2·49, -0·37) mmHg, 1298 patients) while increased HDL-C(weighted mean difference 0·09 (95% CI 0·06, 0·12) mmol/l, 1257 patients) and LDL-C (weighted mean difference 0·12 (95% CI 0·04,0·2) mmol/l, 1255 patients). Individuals assigned to a VLCKD achieve a greater weight loss than those assigned to a LFD in the longterm; hence, a VLCKD may be an alternative tool against obesity.
41The impact of carbohydrate restriction-induced elevations in low-density lipoprotein cholesterol on progression of coronary atherosclerosis: the ketogenic diet trial study design.PubMed
Denise Alison R Javier, Venkat S Manubolu, Nicholas G Norwitz, et al.
Coron Artery Dis. 2024 Nov 1;35(7):577-583. doi: 10.1097/MCA.0000000000001395. Epub 2024 Jun 13.
BACKGROUND: Despite innovations in pharmacotherapy to lower lipoprotein cholesterol and apolipoprotein B, risk factors for atherosclerotic cardiovascular disease (ASCVD), ASCVD persists as the leading global cause of mortality. Elevations in low-density lipoprotein cholesterol (LDL-C) are a well-known risk factor and have been a main target in the treatment of ASCVD. The latest research suggests that ketogenic diets are effective at improving most non-LDL-C/apolipoprotein B cardiometabolic risk factors. However, ketogenic diets can induce large increases in LDL-C to >190 mg/dl in some individuals. Interestingly, these individuals are often otherwise lean and healthy. The influence of increased levels of LDL-C resulting from a carbohydrate-restricted ketogenic diet on the progression of atherosclerosis in otherwise metabolically healthy individuals is poorly understood. This observational study aims to assess and describe the progression of coronary atherosclerosis in this population within 12 months. METHODS: Hundred relatively lean individuals who adopted ketogenic diets and subsequently exhibited hypercholesterolemia with LDL-C to >190 mg/dl, in association with otherwise good metabolic health markers, were enrolled and observed over a period of 12 months. Participants underwent serial coronary computed tomography angiography scans to assess the progression of coronary atherosclerosis in a year. RESULTS: Data analysis shall begin following the conclusion of the trial with results to follow. CONCLUSION: Ketogenic diets have generated debate and raised concerns within the medical community, especially in the subset exhibiting immense elevations in LDL-C, who interestingly are lean and healthy. The relationship between elevated LDL-C and ASCVD progression in this population will provide better insight into the effects of diet-induced hypercholesterolemia.
42The impact of the modified Atkins diet on lipid profiles in adults with epilepsy.PubMed
Mackenzie C Cervenka, Katlyn Patton, Ani Eloyan, et al.
Nutr Neurosci. 2016;19(3):131-7. doi: 10.1179/1476830514Y.0000000162. Epub 2014 Nov 10.
OBJECTIVES: The modified Atkins diet (MAD) is a high fat, low carbohydrate ketogenic diet used to treat intractable seizures in children and adults. The long-term impact on fasting lipid profiles (FLPs) remains unknown. This study was designed to detect significant lipid changes in adults on MAD. METHODS: Patients were observed prospectively. A FLP was obtained in all patients at the first visit then serially. Patients were started on a 20 g per day net carbohydrate limit MAD. They were screened for risk for coronary heart disease and counseled to reduce saturated fats by a registered dietitian if deemed at risk. Patients that remained on MAD for 3 or more months with one or more follow-up FLP were included. RESULTS: Thirty-seven patients (14 male), mean age 33 years (SD 13, range 18-59) met study criteria. Median diet duration was 16 months (range 3-41). Total cholesterol and low-density lipoprotein (LDL) increased significantly over the first 3 months of MAD (P = 0.01 and 0.008, respectively), but were not significantly different from baseline after 1 year of treatment (P = 0.2 and P = 0.5, respectively). High-density lipoprotein levels trended upward in the first 3 months (P = 0.05) and triglycerides remained unchanged (P = 0.5). In 12 patients followed for 3 or more years, no cardiovascular or cerebrovascular events were reported. DISCUSSION: Although total cholesterol and LDL increased over the first 3 months of the MAD, these values normalized within a year of treatment, including in patients treated with MAD for more than 3 years.
43Fat Versus Carbohydrate-Based Energy-Restricted Diets for Weight Loss in Patients With Type 2 Diabetes.PubMed
Osama Hamdy, Mhd Wael Tasabehji, Taha Elseaidy, et al.
Curr Diab Rep. 2018 Oct 17;18(12):128. doi: 10.1007/s11892-018-1103-4.
PURPOSE OF REVIEW: The prevalence of combined obesity and diabetes has increased dramatically in the last few decades. Although medical and surgical weight management are variably effective in addressing this epidemic, it is essential to parallel these strategies with a hypocaloric diet comprising the appropriate macronutrient composition to induce weight loss, enhance glycemic control, and improve cardiovascular risk factors. This review reports the current evidence of the role of carbohydrates and fat-based diets for weight management in patients with combined type 2 diabetes (T2D) and obesity. RECENT FINDINGS: Low-carbohydrate diets were shown to decrease postprandial glucose levels whereas high-carbohydrate, low-fat diets are considered cardio-protective. A diet with an optimal macronutrient composition remains uncertain for patients with combined T2D and obesity. Further research is still needed to define the best dietary composition that achieves the maximum benefits on weight management, glycemic control, and cardiovascular risk factors.
44Adults with type 1 diabetes eat a high-fat atherogenic diet that is associated with coronary artery calcium.PubMed
J K Snell-Bergeon, C Chartier-Logan, D M Maahs, et al.
Diabetologia. 2009 May;52(5):801-9. doi: 10.1007/s00125-009-1280-4. Epub 2009 Feb 14.
AIMS/HYPOTHESIS: Coronary heart disease is the leading cause of mortality among people with type 1 diabetes. Diet is an important lifestyle factor that relates to risk of CHD. The aim of this study was to examine how diet and adherence to dietary guidelines differ between adults with and without type 1 diabetes, and their correlation with CHD risk factors and coronary artery calcium (CAC). METHODS: The study involved 571 people with type 1 diabetes and 696 controls, aged 19 to 56 years, who were asymptomatic for CHD. CAC was measured by electron-beam computed tomography. RESULTS: Compared with the controls, adults with type 1 diabetes reported a diet higher in fat, saturated fat and protein but lower in carbohydrates. Fewer than half of those with type 1 diabetes met dietary guidelines for fat and carbohydrate intake, and only 16% restricted saturated fat to less than 10% of daily energy intake. Adults with type 1 diabetes were significantly less likely to meet dietary guidelines than controls. Fat and saturated fat intakes were positively correlated, but carbohydrate intake was negatively correlated with CHD risk factors and HbA(1c). A high-fat diet and higher intake of protein were associated with greater odds of CAC, while higher carbohydrate intake was associated with reduced odds of CAC. CONCLUSIONS/INTERPRETATION: Adults with type 1 diabetes reported consuming higher than recommended levels of fat and saturated fat. High fat intake was associated with increased CHD risk factors, worse glycaemic control and CAC. An atherogenic diet may contribute to the risk of CHD in adults with type 1 diabetes.
45Dietary carbohydrates restriction inhibits the development of cardiac hypertrophy and heart failure.PubMed
Michinari Nakamura, Natalija Odanovic, Yasuki Nakada, et al.
Cardiovasc Res. 2021 Sep 28;117(11):2365-2376. doi: 10.1093/cvr/cvaa298.
AIMS: A diet with modified components, such as a ketogenic low-carbohydrate (LC) diet, potentially extends longevity and healthspan. However, how an LC diet impacts on cardiac pathology during haemodynamic stress remains elusive. This study evaluated the effects of an LC diet high in either fat (Fat-LC) or protein (Pro-LC) in a mouse model of chronic hypertensive cardiac remodelling. METHODS AND RESULTS: Wild-type mice were subjected to transverse aortic constriction, followed by feeding with the Fat-LC, the Pro-LC, or a high-carbohydrate control diet. After 4 weeks, echocardiographic, haemodynamic, histological, and biochemical analyses were performed. LC diet consumption after pressure overload inhibited the development of pathological hypertrophy and systolic dysfunction compared to the control diet. An anti-hypertrophic serine/threonine kinase, GSK-3β, was re-activated by both LC diets; however, the Fat-LC, but not the Pro-LC, diet exerted cardioprotection in GSK-3β cardiac-specific knockout mice. β-hydroxybutyrate, a major ketone body in mammals, was increased in the hearts of mice fed the Fat-LC, but not the Pro-LC, diet. In cardiomyocytes, ketone body supplementation inhibited phenylephrine-induced hypertrophy, in part by suppressing mTOR signalling. CONCLUSION: Strict carbohydrate restriction suppresses pathological cardiac growth and heart failure after pressure overload through distinct anti-hypertrophic mechanisms elicited by supplemented macronutrients.
46Effects of ketogenic diet on vascular function.PubMed
M Kapetanakis, P Liuba, M Odermarsky, et al.
Eur J Paediatr Neurol. 2014 Jul;18(4):489-94. doi: 10.1016/j.ejpn.2014.03.006. Epub 2014 Mar 25.
BACKGROUND: Ketogenic diet is a well-established treatment in children with difficult to treat epilepsy. Very little is known about the long-term effects on vascular atherogenic and biochemical processes of this high-fat and low carbohydrate and protein diet. METHODS: We evaluated 26 children after one year and 13 children after two years of ketogenic diet. High resolution ultrasound-based assessment was used for carotid artery intima-media thickness (cIMT), carotid artery distensibility and carotid artery compliance. Blood lipids including high density lipoprotein cholesterol (HDL-C), low density lipoprotein cholesterol, (LDL-C), total cholesterol (TC), apolipoprotein A (apoA), apolipoprotein B (apoB) and high-sensitivity C-reactive protein (hsCRP) were analysed. RESULTS: A gradual decrease in carotid distensibility and an increase in LDL-C, apoB and the TC:LDL-C and LDL-C:HDL-C ratios were seen at three and 12 months of KD-treatment. These differences were not significant at 24 months. cIMT, BMI and hsCRP did not show any significant changes. CONCLUSIONS: The initial alterations in lipids, apoB and arterial function observed within the first year of KD-treatment appear to be reversible and not significant after 24 months of treatment.
47The Ketogenic Diet and Cardiovascular Diseases.PubMed
Damian Dyńka, Katarzyna Kowalcze, Anna Charuta, et al.
Nutrients. 2023 Jul 28;15(15):3368. doi: 10.3390/nu15153368.
The most common and increasing causes of death worldwide are cardiovascular diseases (CVD). Taking into account the fact that diet is a key factor, it is worth exploring this aspect of CVD prevention and therapy. The aim of this article is to assess the potential of the ketogenic diet in the prevention and treatment of CVD. The article is a comprehensive, meticulous analysis of the literature in this area, taking into account the most recent studies currently available. The ketogenic diet has been shown to have a multifaceted effect on the prevention and treatment of CVD. Among other aspects, it has a beneficial effect on the blood lipid profile, even compared to other diets. It shows strong anti-inflammatory and cardioprotective potential, which is due, among other factors, to the anti-inflammatory properties of the state of ketosis, the elimination of simple sugars, the restriction of total carbohydrates and the supply of omega-3 fatty acids. In addition, ketone bodies provide "rescue fuel" for the diseased heart by affecting its metabolism. They also have a beneficial effect on the function of the vascular endothelium, including improving its function and inhibiting premature ageing. The ketogenic diet has a beneficial effect on blood pressure and other CVD risk factors through, among other aspects, weight loss. The evidence cited is often superior to that for standard diets, making it likely that the ketogenic diet shows advantages over other dietary models in the prevention and treatment of cardiovascular diseases. There is a legitimate need for further research in this area.
48Effects of very low-carbohydrate ketogenic diet on lipid metabolism in patients with type II diabetes mellitus: a meta-analysis.PubMed
Meijuan Li, Jingyun Yuan
Nutr Hosp. 2022 Aug 25;39(4):916-923. doi: 10.20960/nh.03987.
Objective: to evaluate the lipid metabolism of patients with type 2 diabetes mellitus (T2DM) after very low-carbohydrate ketogenic (VLCK) diet treatment, so as to provide an evidence-based basis for better dietary management and comprehensive treatment of diabetic patients. Methods: PubMed, Cochrane Library, Embase, and Web of Science databases were searched for randomized controlled trial about VLCK diet on lipid metabolism of T2DM up to September 2021. The data were analyzed using the Stata 15.0; standardized mean difference (SMD) was used as effect size. Results: ten articles were included in this meta-analysis. There were no significant differences between the two groups in total cholesterol (SMD = -0.07, 95 % CI: -0.06-0.20, p > 0.05), HDL (SMD = 0.13, 95 % CI: -0.05-0.31, p > 0.05) and LDL (SMD = 0.07, 95 % CI: -0.06-0.20, p > 0.05) levels after treatment. No difference was found in total cholesterol, HDL, and LDL levels between the two groups after 3, 6, and 12 months of treatment (p > 0.05). Triglyceride levels decreased after VLCK diet compared with control (SMD = -0.49, 95 % CI: -0.82 to -0.17, p = 0.003). A marked reduction of triglyceride levels was identified after 3 months of VLCK diet treatment (SMD = -0.69, 95 % CI: -1.00 to -0.38), without significant difference after 6 and 12 months. Conclusion: T2DM patients who receive a VLCK diet to lower blood glucose are not associated with increased levels of total cholesterol and LDL, and decreased levels of HDL. Additionally, this diet can achieve a short-term reduction of triglyceride levels.
49Ketogenic Diet and Multiple Health Outcomes: An Umbrella Review of Meta-Analysis.PubMed
Shiyun Chen, Xin Su, Yonghui Feng, et al.
Nutrients. 2023 Sep 27;15(19):4161. doi: 10.3390/nu15194161.
Numerous studies have examined the effects of ketogenic diets (KD) on health-related outcomes through meta-analyses. However, the presence of biases may compromise the reliability of conclusions. Therefore, we conducted an umbrella review to collate and appraise the strength of evidence on the efficacy of KD interventions. We conducted a comprehensive search on PubMed, EMBASE, and the Cochrane Database until April 2023 to identify meta-analyses that investigated the treatment effects of KD for multiple health conditions, which yielded 23 meta-analyses for quantitative analyses. The evidence suggests that KD could increase the levels of low-density lipoprotein cholesterol (LDL-C), total cholesterol (TC) and high-density lipoprotein cholesterol (HDL-C), the respiratory exchange rate (RER), and could decrease total testosterone and testosterone levels (all -random effects: <0.05). The combination of KD and physical activity can significantly reduce body weight and increase the levels of LDL-C and cortisol. In addition, KD was associated with seizure reduction in children, which can be explained by the ketosis state as induced by the diet. Furthermore, KD demonstrated a better alleviation effect in refractory childhood epilepsy, in terms of median effective rates for seizure reduction of ≥50%, ≥90%, and seizure freedom. However, the strength of evidence supporting the aforementioned associations was generally weak, thereby challenging their credibility. Consequently, future studies should prioritize stringent research protocols to ascertain whether KD interventions with longer intervention periods hold promise as a viable treatment option for various diseases.
50Effects of very low-carbohydrate ketogenic diets on lipid profiles in normal-weight (body mass index < 25 kg/m2) adults: a meta-analysis.PubMed
Minjin Joo, Sumin Moon, Young Seo Lee, et al.
Nutr Rev. 2023 Oct 10;81(11):1393-1401. doi: 10.1093/nutrit/nuad017.
CONTEXT: Very low-carbohydrate diets or ketogenic diets (KDs) have garnered attention for weight loss in patients with overweight or obesity as well as for normal-weight adults, yet the adverse effects of KDs, such as dyslipidemia in normal-weight adults, have not been studied extensively. OBJECTIVE: This meta-analysis aimed to identify the effects of KDs on the lipid profile in normal-weight (body mass index [BMI] < 25 kg/m2) adults from randomized controlled trials. DATA SOURCES: PubMed and Embase databases were searched on November 21, 2021, using search terms representing KDs and lipid profiles. Two researchers independently screened articles according to PICOS inclusion criteria. DATA EXTRACTION: General study information, dietary data, and lipid profiles were extracted from eligible studies. Risk of bias was assessed using the Cochrane risk of bias 2 tool. DATA ANALYSIS: Fixed- or random-effects meta-analysis was performed to estimate the effects of KDs on total cholesterol (TC), high-density lipoprotein-cholesterol (HDL-C), low-density lipoprotein-cholesterol (LDL-C), triglycerides, apolipoprotein A (apoA), and apolipoprotein B (apoB), considering heterogeneity across studies. The certainty of evidence was assessed using the GRADE (Grading of Recommendations, Assessment, Development and Evaluation) approach. RESULTS: Three studies were selected for meta-analysis. A KD significantly increased TC by 1.47 mmol/L (95%CI, 0.72-2.22 mmol/L), LDL-C by 1.08 mmol/L (95%CI, 0.37-1.79 mmol/L), and apoB by 0.35 g/L (95%CI, 0.06-0.65 g/L). In addition, a KD significantly increased HDL-C by 0.35 mmol/L (95%CI, 0.27-0.42 mmol/L) and apoA by 0.34 g/L (95%CI, 0.28-0.41 g/L) compared with control diets. Triglyceride levels were not significantly different between KDs and control diets (P = 0.63). CONCLUSION: This study suggests unfavorable effects of KDs on TC and LDL-C in normal-weight adults. Although an increase in HDL-C can compensate for unfavorable changes in lipids, normal-weight individuals should consider the risk of hypercholesterolemia when consuming a KD. Results for triglycerides were inconsistent.
51Efficacy and safety of very low calorie ketogenic diet (VLCKD) in patients with overweight and obesity: A systematic review and meta-analysis.PubMed
Marco Castellana, Eleonora Conte, Angelo Cignarelli, et al.
Rev Endocr Metab Disord. 2020 Mar;21(1):5-16. doi: 10.1007/s11154-019-09514-y.
Very low calorie ketogenic diet (VLCKD) has been proposed as a promising option to achieve a significant weight loss in a short time period. We conducted a systematic review and meta-analysis to evaluate its efficacy and safety in patients with overweight and obesity. Four databases were searched on May 2019. Studies reporting data on body weight, body mass index (BMI), waist circumference, body composition, blood pressure, HbA1c, lipids, and markers of liver and kidney function were selected. Discontinuation was also assessed. Twelve studies were included. VLCKD was associated with weight losses of -10.0 kg (I = 6%) and - 15.6 kg (I = 37%) in studies with a ketogenic phase up to and of at least four weeks, respectively. The weight lost during the ketogenic phase was stable in the subsequent follow-up up to two years (p = 0.12). Also, VLCKD was associated with reductions of BMI (-5.3 kg/m), waist circumference (-12.6 cm), HbA1c (-0.7%), total cholesterol (-28 mg/dl), triglycerides (-30 mg/dl), AST (-7 U/l), ALT (-8 U/l), GGT (-8 U/l), systolic and diastolic blood pressure (-8 and - 7 mmHg, respectively). No changes in LDL cholesterol, HDL cholesterol, serum creatinine, serum uric acid and serum potassium were found. Serum sodium increased during VLCKD (+1.6 mEq/l). The overall prevalence of patients discontinuing VLCKD was 7.5% and this was similar to patients undergoing a low calorie diet (p = 0.83). The present review supports the use of VLCKD as an effective strategy for the management of overweight and obesity. Future guidelines should include a specific recommendation for this intervention.
52Differential effects of medium- and long-chain saturated fatty acids on blood lipid profile: a systematic review and meta-analysis.PubMed
Nisha Panth, Kylie A Abbott, Cintia B Dias, et al.
Am J Clin Nutr. 2018 Oct 1;108(4):675-687. doi: 10.1093/ajcn/nqy167.
BACKGROUND: Medium-chain saturated fatty acids (MCFAs) may affect circulating lipids and lipoproteins differently than long-chain saturated fatty acids (LCSFAs), but the results from human intervention trials have been equivocal. OBJECTIVE: The aim of this study was to determine whether MCFAs and LCSFAs have differential impacts on blood lipids and lipoproteins. DESIGN: Five databases were searched (EMBASE, MEDLINE, CINAHL, Cochrane, and Scopus) until April 2018, and published clinical trials investigating the differential effects of dietary MCFAs and LCSFAs on blood lipids were included. Searches were limited to the English language and to studies with adults aged >18 y. Where possible, studies were pooled for meta-analysis using RevMan 5.2. The principle summary measure was the mean difference between groups calculated using the random-effects model. RESULTS: Eleven eligible crossover and 1 parallel trial were identified with a total of 299 participants [weighted mean ± SD age: 38 ± 3 y; weighted mean ± SD body mass index (kg/m2): 24 ± 2]. All studies were pooled for the meta-analysis. Diets enriched with MCFAs led to significantly higher high-density lipoprotein (HDL) cholesterol concentrations than diets enriched with LCSFAs (0.11 mmol/L; 95% CI: 0.07, 0.15 mmol/L) with no effect on triglyceride, low-density lipoprotein (LDL) cholesterol, and total cholesterol concentrations. Consumption of diets rich in MCFAs significantly increased apolipoprotein A-I (apoA-I) concentrations compared with diets rich in LCSFAs (0.08 g/L; 95% CI: 0.02, 0.14 g/L). There was no evidence of statistical heterogeneity for HDL cholesterol, apoA-I, and triglyceride concentrations; however, significant heterogeneity was observed for the total cholesterol (I2 = 49%) and LDL cholesterol analysis (I2 = 58%). CONCLUSION: The findings of this research demonstrate a differential effect of MCFAs and LCSFAs on HDL cholesterol concentrations. Further investigations are warranted to elucidate the mechanism by which the lipid profile is altered. This trial was registered at www.crd.york.ac.uk/PROSPERO as CRD42017078277.
53Saturated fats and blood lipids: new slant on an old story.PubMed
K C Hayes
Can J Cardiol. 1995 Oct;11 Suppl G:39G-46G.
In recent years the association between dietary saturated fat, hypercholesterolemia, and coronary artery disease has been re-explored. Prompted largely by the notion that dietary fats, and their attendant fatty acids, can specifically influence the distribution of the plasma cholesterol between low density (LDL) and high density (HDL) lipoprotein cholesterol, the focus of the original research has shifted from total cholesterol to lipoproteins. Several new, sometimes controversial, concepts have arisen that challenge underlying assumptions of the Keys-Hegsted regression equations. First, although saturated fats as a class raise LDL, they also appear to have primary responsibility among dietary fatty acids for raising HDL, possibly depending on a balanced intake of polyunsaturated fats. Second, not all saturated fatty acids are equally responsible for changes in LDL or HDL. Only natural triglycerides (TG) rich in lauric (12:0) and myristic (14:0) acids are especially cholesterolemic, whereas 16:0-rich fats can be neutral or cholesterol-raising depending on the metabolic circumstances (lipoprotein setpoint) of the host. In normolipemic individuals with normal lipoprotein metabolism, dietary palmitic acid (16:0) typically appears neutral. When lipoprotein metabolism is impaired, eg, if LDL receptor activity is depressed by the presence of dietary cholesterol, consumption of 16:0-rich TGs can contribute to hypercholesterolemia. Although stearic acid (18:0) is typically considered neutral, exaggerated consumption of 18:0-rich fat (cocoa butter) lowers both LDL and HDL. Third, the saturated fat effect is related both to the dietary cholesterol load and the lipoprotein setpoint of the host, eg, 16:0 becomes progressively cholesterolemic as dietary cholesterol raises the setpoint.(ABSTRACT TRUNCATED AT 250 WORDS)
54Saturated Fatty Acids in Cell Membrane Lipids Induce Resistance to 5-Fluorouracil in Colorectal Cancer Cells.PubMed
Takanori Hiraide, Yoshifumi Morita, Makoto Horikawa, et al.
Anticancer Res. 2022 Jul;42(7):3313-3324. doi: 10.21873/anticanres.15819.
BACKGROUND/AIM: Resistance to chemotherapy is a major obstacle for patients with unresectable colorectal cancer (CRC); however, the factors that induce chemoresistance have not been elucidated. Lipid composition influences neoplastic behaviour. Therefore, this study examined whether lipid composition affects sensitivity to chemotherapeutic agents in CRC. MATERIALS AND METHODS: We performed a lipidomic analysis of a CRC xenograft-derived spheroid model to identify potential relationships between the lipid profile and chemoresistance to 5-fluorouracil (5-FU). Genetic and pharmacological modulation of lipid synthesis were also used in the HCT-116 and DLD-1 CRC cell lines to further characterize resistance to 5-FU. RESULTS: Our lipidomic profiling revealed that phospholipids with saturated fatty acids (SFAs) were more abundant in 5-FU-resistant spheroids. The importance of phospholipids containing SFA in chemoresistance was confirmed by showing that in HCT-116 and DLD-1 cells, genetic or pharmacological inactivation of stearoyl-CoA desaturase-1, a key enzyme that converts SFAs to monounsaturated fatty acids, increased the proportion of SFAs in membranous phospholipids and reduced cell membrane fluidity, and this ultimately resulted in resistance to 5-FU. CONCLUSION: These data suggest that the saturated to monounsaturated fatty acid ratio in cellular membranous phospholipids affects sensitivity to chemotherapeutic agents.
55The ketogenic diet: Pros and cons.PubMed
Blair O'Neill, Paolo Raggi
Atherosclerosis. 2020 Jan;292:119-126. doi: 10.1016/j.atherosclerosis.2019.11.021. Epub 2019 Nov 28.
Diets have been at the center of animated debates for decades and many claims have been made in one direction or the other by supporters of opposite camps, often with limited evidence. At times emphasis has been put on a single new aspect that the previous diets had overlooked and the new one was to embrace in order to improve weight loss and well-being. Unfortunately, very few randomized clinical trials involving diets have addressed the combined question of weight loss and cardiovascular outcomes. The recently introduced ketogenic diet requires a rigorous limitation of carbohydrates while allowing a liberal ingestion of fats (including saturated fats) and has generated a flurry of interest with many taking the pro position and as many taking the cons position. The ketogenic diet causes a rapid and sensible weight loss along with favourable biomarker changes, such as a reduction in serum hemoglobin A1c in patients with diabetes mellitus type 2. However, it also causes a substantial rise in low density lipoprotein cholesterol levels and many physicians are therefore hesitant to endorse it. In view of the popular uptake of the keto diet even among subjects not in need of weight loss, there is some preoccupation with the potential long-term consequences of a wide embrace of this diet by large segments of the population. On the contrary, numerous lines of evidence show that plant-based diets are associated with reduction in oncological and cardiovascular diseases and a prolonged life span. The debate reproduced in this article took place during a continuous medical education program between two cardiologists with largely differing views on the matter of effectiveness, sustainability, and safety of the ketogenic diet compared to alternative options.
56The ketogenic diet and the QT interval.PubMed
Sivakumar Sudhakaran, Laila Yazdani, Kevin R Wheelan, et al.
Proc (Bayl Univ Med Cent). 2019 Oct 11;33(1):77-79. doi: 10.1080/08998280.2019.1664220. eCollection 2020 Jan.
Long QT syndrome is a disorder of ventricular myocardial repolarization associated with an increased risk of life-threatening cardiac arrhythmias and sudden cardiac death. This report highlights a case of QT prolongation with torsades de pointes in a patient with baseline congenital long QT syndrome, believed to be precipitated by metabolic changes associated with the "ketogenic diet."
57Cardiac complications in pediatric patients on the ketogenic diet.PubMed
T H Best, D N Franz, D L Gilbert, et al.
Neurology. 2000 Jun 27;54(12):2328-30. doi: 10.1212/wnl.54.12.2328.
Cardiac complications of the ketogenic diet, in the absence of selenium deficiency, have not been reported. Twenty patients on the ketogenic diet at one institution were investigated. Prolonged QT interval (QTc) was found in 3 patients (15%). There was a significant correlation between prolonged QTc and both low serum bicarbonate and high beta-hydroxybutyrate. In addition, three patients had evidence of cardiac chamber enlargement. One patient with severe dilated cardiomyopathy and prolonged QTc normalized when the diet was discontinued.
58Sudden cardiac death in association with the ketogenic diet.PubMed
Ilana M Bank, Sam D Shemie, Bernard Rosenblatt, et al.
Pediatr Neurol. 2008 Dec;39(6):429-31. doi: 10.1016/j.pediatrneurol.2008.08.013.
The ketogenic diet is a high-fat, low-carbohydrate, adequate-protein diet that is used to decrease the frequency of seizures in patients who have refractory epilepsy. Despite its positive effects in some patients, there are potential adverse effects. Two complications related to the ketogenic diet are selenium deficiency, which has been associated with impaired myocardial function, and QT prolongation as documented on electrocardiography. Reported here are two cases of death in a child on the ketogenic diet for seizure control. In case 1, the child who died of complications related to torsade de pointes, with documented QT prolongation; post mortem examination revealed selenium-deficiency cardiomyopathy. In case 2, a child experienced QT prolongation while on the ketogenic diet and later died suddenly at home. Both children exhibited selenium deficiency. These two cases suggest that patients on the ketogenic diet require monitoring of the QT interval by electrocardiography, myocardial function by echocardiography, and selenium levels before and during the ketogenic diet.
59The ketogenic diet and the QT interval.PubMed
Suvasini Sharma, Sheffali Gulati
J Clin Neurosci. 2012 Jan;19(1):181-2. doi: 10.1016/j.jocn.2011.05.012. Epub 2011 Nov 30.
Cardiac complications have been rarely reported associated with the ketogenic diet. Prolonged QT interval in the electrocardiogram and torsades de pointes arrhythmias have been described in a few cases. The effect of the ketogenic diet on QT interval has not been systematically evaluated. We obtained serial electrocardiograms in our patients on the ketogenic diet to look for changes in the mean QT interval. Twenty seven children aged 6 months to 5 years with refractory epilepsy were enrolled. Classic ketogenic diet was introduced using a non-fasting gradual initiation protocol. All patients were supplemented with oral calcium and selenium. Electrocardiograms were obtained at baseline and after 1, 3, 6, and 12 months on the ketogenic diet. There was no statistically significant change in the corrected QT interval over time. There were no ST segment changes or dysrhythmias in any of the electrocardiograms.
60Dispersion durations of P-wave and QT interval in children treated with a ketogenic diet.PubMed
Önder Doksöz, Orkide Güzel, Ünsal Yılmaz, et al.
Pediatr Neurol. 2014 Apr;50(4):343-6. doi: 10.1016/j.pediatrneurol.2013.12.005. Epub 2013 Dec 10.
BACKGROUND: Limited data are available on the effects of a ketogenic diet on dispersion duration of P-wave and QT-interval measures in children. We searched for the changes in these measures with serial electrocardiograms in patients treated with a ketogenic diet. METHODS: Twenty-five drug-resistant patients with epilepsy treated with a ketogenic diet were enrolled in this study. Electrocardiography was performed in all patients before the beginning and at the sixth month after implementation of the ketogenic diet. Heart rate, maximum and minimum P-wave duration, P-wave dispersion, and maximum and minimum corrected QT interval and QT dispersion were manually measured from the 12-lead surface electrocardiogram. RESULTS: Minimum and maximum corrected QT and QT dispersion measurements showed nonsignificant increase at month 6 compared with baseline values. Other previously mentioned electrocardiogram parameters also showed no significant changes. CONCLUSIONS: A ketogenic diet of 6 months' duration has no significant effect on electrocardiogram parameters in children. Further studies with larger samples and longer duration of follow-up are needed to clarify the effects of ketogenic diet on P-wave dispersion and corrected QT and QT dispersion.
61The Impact of 3:1 Ketogenic Diet on Cardiac Repolarization Changes in Children with Refractory Seizures: A Prospective Follow-Up Study.PubMed
Rahmi Özdemir, Orkide Güzel, Mehmet Küçük, et al.
Neuropediatrics. 2016 Jun;47(3):157-61. doi: 10.1055/s-0036-1582139. Epub 2016 Apr 4.
Background The association between ketogenic diet (KD) and prolonged QT interval, life-threatening ventricular arrhythmias, and sudden death is controversial. Aim We aimed to prospectively evaluate the effect of KD on electrocardiography (ECG) measures in children with refractory epilepsy. Method A total of 70 children with drug-resistant epilepsy who received a KD for at least 12 months were included in the study. The standard 12-lead electrocardiography was performed in all patients before the beginning and in the 12th month of KD. Heart rate, P-wave duration and dispersion, corrected QT interval and QT dispersion, and Tp-e interval were measured. Results All ECG-derived parameters, but P-wave dispersion increased after 12 months of KD compared with the baseline values. However, these changes were not statistically significant. Conclusion A 12-month long 3:1 KD treatment exerts no deleterious effect on cardiac repolarization measures.
62Fatal propofol infusion syndrome in association with ketogenic diet.PubMed
F A M Baumeister, R Oberhoffer, G M Liebhaber, et al.
Neuropediatrics. 2004 Aug;35(4):250-2. doi: 10.1055/s-2004-820992.
Propofol is used for the treatment of refractory status epilepticus. When given as a long-term infusion propofol may cause a rare but frequently fatal complication, the propofol infusion syndrome. The hallmarks are metabolic acidosis, lipemia, rhabdomyolysis and myocardial failure. Propofol infusion syndrome is caused by impaired fatty acid oxidation. Beside anticonvulsants the ketogenic diet, a high-fat, low-carbohydrate, adequate-protein diet, is an effective treatment for difficult-to-control seizures. We report a 10-year-old boy with catastrophic epilepsy, who developed fatal propofol infusion syndrome when a ketogenic diet was initiated. Substances like propofol which impair fatty acid oxidation may pose an increased risk if combined with ketogenic diet.
63Cumene hydroperoxide induced changes in calcium homeostasis in cultured neonatal rat heart cells.PubMed
M Persoon-Rothert, J M Egas-Kenniphaas, E J van der Valk-Kokshoorn, et al.
Cardiovasc Res. 1992 Jul;26(7):706-12. doi: 10.1093/cvr/26.7.706.
OBJECTIVE: The relationship between oxidative stress induced cell necrosis and perturbation of intracellular calcium homeostasis was investigated in cultured myocytes. METHODS: Cultured neonatal rat heart cells were loaded with fura-2 AM to measure cytosolic free calcium ([Ca2+]i). Probenecid, an inhibitor of organic anion transport, was present during the experiment to reduce efflux of fura-2 from the cytoplasm. Cells were exposed to cumene hydroperoxide, a toxic organic hydroperoxide that is known to induce oxidative stress in myocytes. The efficacy of the protective agents Trolox C (a vitamin E analogue) and chlorpromazine (a phospholipase inhibitor) on cumene hydroperoxide induced cell injury was determined. RESULTS: [Ca2+]i in control cells was constant (60 nM) during an incubation time of 45 min. Probenecid did not affect [Ca2+]i levels or cell viability under the experimental conditions. Cumene hydroperoxide caused a sustained rise in [Ca2+]i starting after 5-10 min, to a level of 1300 nM at 45 min. After 20-25 min the viability of the heart cells started to decline and after 45 min 44% of the cells were irreversibly injured. The loss of cell viability was expressed as percentage decrease of the fluorescence at 360 nm (the calcium independent wavelength), since the percent release of cellular alpha-hydroxybutyrate dehydrogenase (alpha-HBDH) activity equalled the percent decrease of the fluorescence at 360 nm. Trolox C and chlorpromazine almost completely prevented the cumene hydroperoxide induced alpha-HBDH release. The [Ca2+]i of myocytes incubated with cumene hydroperoxide in combination with Trolox C rose to 1000 nM without affecting cell viability. The cumene hydroperoxide induced rise in [Ca2+]i was markedly reduced by chlorpromazine (at t = 45 min, [Ca2+]i = 360 nM). Addition of Trolox C to untreated cells did not influence [Ca2+]i, whereas chlorpromazine alone induced a slight increase of [Ca2+]i up to 360 nM with complete preservation of cell viability. CONCLUSIONS: Trolox C and chlorpromazine are very effective inhibitors of cumene hydroperoxide induced perturbation of calcium homeostasis and subsequent cell death. A role for peroxidation of membrane phospholipids and activation of calcium dependent phospholipase in the cascade of events leading to irreversible injury is suggested.
64Sulfur dioxide restores calcium homeostasis disturbance in rat with isoproterenol-induced myocardial injury.PubMed
Shanshan Chen, Junbao Du, Yinfang Liang, et al.
Histol Histopathol. 2012 Sep;27(9):1219-26. doi: 10.14670/HH-27.1219.
BACKGROUNDS: sulfur dioxide (SO₂) could relieve isoproterenol (ISO)-induced myocardial injury, while the mechanism is unclear. This study aims to explore whether the protective effect of SO₂ on ISO-induced myocardial injury was mediated by the restoration of calcium homeostasis disturbance in cardiomyocyte. METHODS AND RESULTS: Rats were randomly divided into four groups: ISO group, ISO+SO₂ group, control group and SO₂ group. Content of Ca²⁺ in H9c2 cells was assayed using confocal microscope, and cardiac function parameters were measured by echocardiography. Plasma biochemical values and myocardial ultra-structure changes were measured. Meanwhile, the activity, protein and gene levels of sarcoplasmic reticulum Ca²⁺ ATPase (SERCA), and protein and phosphorylation of phospholamban (PLN) were detected. We found SO₂ derivatives could restore the decreased cardiac function, the abnormal lactate dehydrogenase, creatine kinase, alpha-hydroxybutyrate dehydrogenase, potassium, calcium, blood urea nitrogen and the damaged myocardial ultra-structure in rats, and regulate the increased Ca²⁺ content in H9c2 induced by ISO. In addition, compared with ISO group, the decreased activities, protein and mRNA level of SERCA, as well as the decreased protein phosphorylation level of PLN in myocardial tissues were increased in ISO+SO₂ group. CONCLUSION: SO₂ derivatives might relieve calcium overload in association with the upregulating expression of SERCA and p-PLN/PLN by myocardial tissues in rats with ISO-induced myocardial injury.
65[The effect of preliminary administration of dimethylsulfoxide on the development of experimental myocardial necrosis in rats treated with isoprenaline].PubMed
P Ljubuncić, F Mujić, M P Stojiljković, et al.
Srp Arh Celok Lek. 1991 Sep-Oct;119(9-10):238-42.
It has been suggested that in the genesis of isoprenaline-induced myocardial necrosis in rats, along with the intracellular calcium homeostasis and energy production breakdown, the mechanism of cytotoxic oxygen free radical generation is also included. The effects of dimethylsulphoxide, a hydroxyl radical scavenger, on the appearance of isoprenaline-induced myocardial necrosis in rats, were investigated. The verification of the efficacy of such pretreatment was based upon the monitoring of changes in plasma activity of enzymes creatine kinase, lactate dehydrogenase and alpha-hydroxybutyrate dehydrogenase, and upon the heart muscle sample light microscopy. The results have shown that the total plasma activity of all the observed enzymes was six hours after isoprenaline application several times increased, as compared with the control values. Histopathological changes in unprotected animals were evident and consisted of coagulation necrosis and myocytolysis. In both dimethylsulphoxide and isoprenaline treated groups of rats only a statistically insignificant increase in enzyme plasma activity was observed, while heart histopathological changes showed considerable reduction both in extensity and intensity of the tissue damage. The evident efficiency of dimethylsulphoxide in the prevention of the extent of myocardial necrosis in rats after the administration of the toxic dose of isoprenaline suggests that the generation of hydroxyl anion radicals, probably via autooxidation of isoprenaline, is a possible mechanism of the tissue injury in this experimental model.
66Optimal clinical management of children receiving dietary therapies for epilepsy: Updated recommendations of the International Ketogenic Diet Study Group.PubMed
Eric H Kossoff, Beth A Zupec-Kania, Stéphane Auvin, et al.
Epilepsia Open. 2018 May 21;3(2):175-192. doi: 10.1002/epi4.12225. eCollection 2018 Jun.
Ketogenic dietary therapies (KDTs) are established, effective nonpharmacologic treatments for intractable childhood epilepsy. For many years KDTs were implemented differently throughout the world due to lack of consistent protocols. In 2009, an expert consensus guideline for the management of children on KDT was published, focusing on topics of patient selection, pre-KDT counseling and evaluation, diet choice and attributes, implementation, supplementation, follow-up, side events, and KDT discontinuation. It has been helpful in outlining a state-of-the-art protocol, standardizing KDT for multicenter clinical trials, and identifying areas of controversy and uncertainty for future research. Now one decade later, the organizers and authors of this guideline present a revised version with additional authors, in order to include recent research, especially regarding other dietary treatments, clarifying indications for use, side effects during initiation and ongoing use, value of supplements, and methods of KDT discontinuation. In addition, authors completed a survey of their institution's practices, which was compared to responses from the original consensus survey, to show trends in management over the last 10 years.
67APOE ε4 and Dietary Patterns in Relation to Cognitive Function: An Umbrella Review of Systematic Reviews.PubMed
Thomas J Urich, Amaryllis A Tsiknia, Nada Ali, et al.
Nutr Rev. 2025 Jul 1;83(7):e2113-e2126. doi: 10.1093/nutrit/nuae156.
CONTEXT: Carrying the apolipoprotein ε4 allele (APOE ε4) is the strongest genetic risk factor for late-onset Alzheimer's disease. There is some evidence suggesting that APOE ε4 may modulate the influence of diet on cognitive function. OBJECTIVE: This umbrella review of systematic reviews evaluates the existing literature on the effect of dietary interventions on cognitive and brain-imaging outcomes by APOE status. DATA SOURCES: PubMed, EMBASE, Web of Science, and Scopus were searched using terms appropriate to each area of research, from their respective starting dates of coverage until March 2023. DATA EXTRACTION: Two independent reviewers conducted data extraction and performed a quality appraisal using the Measurement Tool to Assess Systematic Reviews (AMSTAR) 2. DATA ANALYSIS: Six total reviews were included in the final analysis. Four reviews evaluated randomized controlled trials on individuals aged 50-93 years ranging the entire cognitive continuum. One review combined observational studies and clinical trials conducted on both cognitively healthy and cognitively impaired individuals (age range: 50-90), and 1 review included observational studies of both cognitively healthy and cognitively impaired adults (age range: 50-75). RESULTS: Both observational studies and clinical trials yielded inconclusive results attributed to both practical limitations associated with longitudinal follow-up and issues of methodological quality. Except for the Mediterranean diet, dietary interventions, such as the ketogenic diet, nutraceuticals, and supplements, were generally not effective in older APOE ε4 carriers. This review considers plausible biological mechanisms that might explain why older and cognitively impaired APOE ε4 carriers were less likely to benefit. CONCLUSION: This review identifies notable gaps in the literature, such as a shortage of studies conducted in middle-aged and cognitively healthy APOE ε4 carriers assessing the impact of dietary interventions and provides suggestions for novel trial designs.
68Ketogenic diet in the treatment of epilepsy in children under the age of 2 years: study protocol for a randomised controlled trial.PubMed
Siobhan Titre-Johnson, Natasha Schoeler, Christin Eltze, et al.
Trials. 2017 Apr 26;18(1):195. doi: 10.1186/s13063-017-1918-3.
BACKGROUND: The incidence of epilepsy is greatest in the first 2 years of life, an age group where there is generally a poor prognosis for both seizure control and neurodevelopmental outcome. Early control of seizures can be associated with better developmental outcome but many of the epilepsies presenting in infancy are poorly responsive to antiepileptic medication. The ketogenic diet (KD) is a high-fat, low-carbohydrate diet designed to mimic the effects of starvation on the body. Dietary fat is converted into ketones in the body and used as an energy source by the brain. The KD has been shown to be successful in controlling seizures in many observational studies, and in two randomised controlled trials (RCTs) in older children. However, little evidence is available in the very young. METHODS/DESIGN: An open-label RCT where eligible children (age 3 months to 2 years with epilepsy who have failed two antiepileptic drugs (AEDs)) undergo baseline assessment, including medical and seizure history. Participants then start an observation period (7 or 14 days) with documentation of seizure frequency. Randomisation will occur on day 8 or day 15 to receive the KD or a further AED; the allocated treatment will commence on day 15, with instruction and training. A second assessment (4 weeks after start of treatment) will include a clinical review and tolerability questionnaire (modified Hague Scale of Side Effects - for those allocated to the KD group). Assessments will be repeated at 8 weeks after the start of treatment including biochemical investigations, after which, according to patient response, KD (diet group) or AED (standard AED group) will then be continued or changed. Those in the AED group who have failed to achieve seizure control at the 8-week assessment will then be offered KD outside the context of the trial. Those in the KD arm who fail to achieve seizure control will be changed to standard clinical management. All patients will be followed up for 12 months from randomisation for retention, seizure outcome, quality of life and neurodevelopmental status. DISCUSSION: The slow rate of recruitment is an ongoing practical issue. There is a limitation to the number of eligible patients compared to what was predicted, mainly due to the nature of this patient group. After a substantial amendment to widen inclusion criteria and reduce the baseline period to 7 days for patients with a high seizure burden, the rate of recruitment steadily increased. A number of operational concerns regarding dietetic time were also highlighted impacting on the recruitment rate. However, the combination of a low dropout rate and the opening of further centres, the trial should successfully meet the final recruitment target. All nine centres are now recruiting and we hope to open further centres within the UK. TRIAL REGISTRATION: ClinicalTrials.gov, identifier: NCT02205931 . Registered on 16 December 2013.
69A technology assisted precision ketogenic diet intervention for cardio-renal-metabolic health in overweight or obese adults: Protocol for a randomized controlled trial.PubMed
Yan Du, Jing Wang, Shiyu Li, et al.
Contemp Clin Trials. 2022 Aug;119:106845. doi: 10.1016/j.cct.2022.106845. Epub 2022 Jul 7.
BACKGROUND: The obesity epidemic is a public health concern, as it is associated with a variety of chronic conditions. The ketogenic diet has drawn much scientific and public attention. However, implementation is challenging and its effect on cardio-renal-metabolic health is inconclusive. This study will assess the feasibility, acceptability, and preliminary efficacy of a technology-assisted ketogenic diet on cardio-renal-metabolic health. METHODS: This is a single center, 6-month, stratified, randomized controlled trial. A total of 60 overweight/obese adults (18+ years old) will be enrolled, including 20 without type 2 diabetes (T2D) and without chronic kidney disease (CKD); 20 with T2D, but without CKD; and 20 with early-stage CKD. Participants will be stratified based on health conditions and randomized into a ketogenic diet (n = 30) or a low-fat diet group (n = 30). Health education involving diet and physical activity will be delivered both digitally and in-person. Mobile and connected health technologies will be used to track lifestyle behaviors and health indicators, as well as provide weekly feedback. The primary outcome (weight) and the secondary outcomes (e.g., blood pressure, glycemic control, renal health) will be assessed with traditional measurements and metabolomics. DISCUSSION: Mobile and connected health technologies provide new opportunities to improve chronic condition management, health education attendance, planned lifestyle changes and engagement, and health outcomes. The advancement of bioinformatics technology offers the possibility to profile and analyze omics data which may advance our understanding of the underlying mechanisms of intervention effects on health outcomes at the molecular level for personalized and precision lifestyle interventions.
70Metabolic epilepsies amenable to ketogenic therapies: Indications, contraindications, and underlying mechanisms.PubMed
Cezar Gavrilovici, Jong M Rho
J Inherit Metab Dis. 2021 Jan;44(1):42-53. doi: 10.1002/jimd.12283. Epub 2020 Aug 11.
Metabolic epilepsies arise in the context of rare inborn errors of metabolism (IEM), notably glucose transporter type 1 deficiency syndrome, succinic semialdehyde dehydrogenase deficiency, pyruvate dehydrogenase complex deficiency, nonketotic hyperglycinemia, and mitochondrial cytopathies. A common feature of these disorders is impaired bioenergetics, which through incompletely defined mechanisms result in a wide spectrum of neurological symptoms, such as epileptic seizures, developmental delay, and movement disorders. The ketogenic diet (KD) has been successfully utilized to treat such conditions to varying degrees. While the mechanisms underlying the clinical efficacy of the KD in IEM remain unclear, it is likely that the proposed heterogeneous targets influenced by the KD work in concert to rectify or ameliorate the downstream negative consequences of genetic mutations affecting key metabolic enzymes and substrates-such as oxidative stress and cell death. These beneficial effects can be broadly grouped into restoration of impaired bioenergetics and synaptic dysfunction, improved redox homeostasis, anti-inflammatory, and epigenetic activity. Hence, it is conceivable that the KD might prove useful in other metabolic disorders that present with epileptic seizures. At the same time, however, there are notable contraindications to KD use, such as fatty acid oxidation disorders. Clearly, more research is needed to better characterize those metabolic epilepsies that would be amenable to ketogenic therapies, both experimentally and clinically. In the end, the expanded knowledge base will be critical to designing metabolism-based treatments that can afford greater clinical efficacy and tolerability compared to current KD approaches, and improved long-term outcomes for patients.