bims-hafaim Biomed News
on Heart failure metabolism
Issue of 2026–05–03
six papers selected by
Kyle McCommis, Saint Louis University
  1. The Medium Chain Fatty Acid Octanoate is a Beneficial Fuel for the Failing Heart.
  2. Unrestrained fatty acid oxidation triggers heart failure in mice via cardiolipin loss and mitochondrial dysfunction.
  3. Running rich: how excess fatty acid oxidation drains the cardiac engine.
  4. Mitochondria-lipid droplet communication remodels bioenergetic metabolism in cardiovascular diseases.
  5. Systems Biology Identifies TARS2 as a Cardiomyocyte Regulator of Mitochondrial Oxidative Stress in Dilated Cardiomyopathy.
  6. Targeting the ALCAT1 enzyme for the treatment of pressure- overload hypertrophy.
  1. Am J Physiol Heart Circ Physiol. 2026 Apr 30.
    The Medium Chain Fatty Acid Octanoate is a Beneficial Fuel for the Failing Heart.
    Nikoloz Gorgodze, Timothy R Matsuura, Noemi Nisini, Remus Berretta, Alessandra Recchia, Alisha Werlen, Tao Wang, Kirill Batmanov, Steven Houser, Daniel P Kelly, Fabio A Recchia.
      The failing heart displays marked alterations of energy substrate metabolism, with a reduced oxidation of long chain fatty acids (FA) associated with increased glucose oxidation. Recent pre-clinical and human studies have shown that the delivery of ketone bodies as an alternative substrate reduces pathologic cardiac remodeling and dysfunction in heart failure. However, chronic administration of ketone bodies is challenging. Therefore, using a clinically relevant canine model of tachypacing-induced dilated cardiomyopathy, we tested the hypothesis that other shorter chain FA may also be beneficial. Seven dogs received cardiac tachypacing and continuous infusion of sodium octanoate, a medium-chain FA, starting after 2 weeks of pacing when cardiac dysfunction was still moderate. Six dogs received cardiac pacing with no octanoate infusion. Octanoate did not significantly alter circulating levels of ketone bodies, while it still exerted protection resulting in a delayed progression of systolic and diastolic cardiac dysfunction and normalized myocardial metabolism. These results identify the delivery of medium-chain FA as a potential actionable therapeutic for heart failure with reduced ejection fraction. Octanoate has translational promise due to proven methods of dietary supplementation with no need for parenteral administration.
    Keywords:  Cardiac metabolism; Heart Failure; Ketones; Octanoate; Tachypacing
    DOI:  https://doi.org/10.1152/ajpheart.00153.2026
  2. J Clin Invest. 2026 May 01. pii: e202528. [Epub ahead of print]136(9):
    Unrestrained fatty acid oxidation triggers heart failure in mice via cardiolipin loss and mitochondrial dysfunction.
    Chai-Wan Kim, Goncalo Vale, Xiaorong Fu, Jeffrey G McDonald, Chongshan Dai, Chao Li, Zhao V Wang, Gaurav Sharma, Chalermchai Khemtong, Craig R Malloy, Stanislaw Deja, Shawn C Burgess, Matthew A Mitsche, Jay D Horton.
      Cardiomyocytes primarily rely on fatty acid oxidation (FAO), which provides more than 70% of their energy. However, excessive FAO can disrupt cardiac metabolism by increasing oxygen demand and suppressing glucose utilization through the Randle cycle. Although inhibition of FAO has been investigated in heart failure, its overall therapeutic impact remains uncertain. To determine the consequences of enhanced FAO, we generated cardiomyocyte-specific ACC1 and ACC2 double-knockout (ACC dHKO) mice, which exhibit constitutively elevated FAO. ACC dHKO mice developed dilated cardiomyopathy and heart failure. Lipidomic analysis revealed marked depletion of cardiolipin caused by reduced linoleic acid, a direct consequence of excessive FAO. This cardiolipin deficiency impaired mitochondrial electron transport chain (ETC) activity, leading to mitochondrial dysfunction. Pharmacologic inhibition of FAO with etomoxir or oxfenicine restored cardiolipin levels, normalized ETC activity, and prevented cardiac dysfunction in ACC dHKO mice. These findings demonstrate that unrestrained FAO disrupts both lipid and energy homeostasis, culminating in heart failure in this model. Collectively, these results indicate that although FAO is essential for cardiac energy production, therapeutic strategies aimed at stimulating cardiac FAO may be detrimental rather than beneficial in heart failure.
    Keywords:  Cardiology; Fatty acid oxidation; Heart failure; Metabolism
    DOI:  https://doi.org/10.1172/JCI202528
  3. J Clin Invest. 2026 May 01. pii: e204459. [Epub ahead of print]136(9):
    Running rich: how excess fatty acid oxidation drains the cardiac engine.
    Steven M Claypool, Carla M Koehler.
      Fatty acid oxidation (FAO) provides the healthy heart with 60%-90% of its ATP, with the remainder coming from metabolism of glucose. Metabolic flexibility is key to heart function, ensuring an uninterrupted source of fuel. In heart failure, a shift from FAO to glucose-dependent metabolism occurs as disease progresses, supporting the widely held notion that fat is the optimal substrate in the heart. In this issue of the JCI, Kim et al. challenge this assumption. In studies of acetyl-CoA carboxylase-deficient (ACC-deficient) mice, they found that unregulated use of fat as a substrate led to cardiac damage. ACC-deficient mice developed cardiolipin deficiency as a result of excessive FAO depleting stores of linoleic acid, which is used as a substrate for cardiolipin maturation. The resulting mitochondrial dysfunction was associated with dilated cardiomyopathy and heart failure in these mice. The findings highlight potential for development of therapeutic strategies that balance energy sources and replenish cardiolipin levels.
    DOI:  https://doi.org/10.1172/JCI204459
  4. Pharmacol Res. 2026 Apr 28. pii: S1043-6618(26)00135-0. [Epub ahead of print]228 108220
    Mitochondria-lipid droplet communication remodels bioenergetic metabolism in cardiovascular diseases.
    Zhongyang Chi, Wei Deng, Saiyang Xie.
      The heart's high energy demands are primarily fulfilled through mitochondrial fatty acid (FA) β-oxidation, with lipid droplets (LDs) being the main source of FAs. Research indicates that cardiac lipid homeostasis relies on a dynamic interaction between LDs and mitochondria, facilitated by specialized membrane contact sites (MCSs). These sites are marked by essential proteins such as the Perilipin (PLIN) family, mitochondrial dynamics proteins, and Rab GTPases, forming an efficient pathway for transferring FAs from storage to mitochondrial oxidation. This protective mechanism helps to avert the accumulation of lipotoxic intermediates while supporting lipid synthesis during periods of nutrient surplus. Conversely, the dysregulation of this mitochondria-LD axis is often implicated in various metabolic cardiovascular diseases (CVDs), including heart failure, atherosclerosis, and diabetic cardiomyopathy. Such imbalances lead to interconnected pathological processes, including cardiomyocyte lipotoxicity and mitochondrial dysfunction, which ultimately contribute to myocardial injury and pathological cardiac growth and fibrosis. This review comprehensively examines the current understanding of this intricate organelle crosstalk, emphasizing its structural and functional aspects, diverse biological roles, and significant implications for CVD pathogenesis. A deeper insight into and targeted modulation of this axis could pave the way for innovative therapeutic strategies aimed at addressing metabolic CVDs.
    Keywords:  Cardiovascular diseases; Lipid droplet; Lipid metabolism; Mitochondria
    DOI:  https://doi.org/10.1016/j.phrs.2026.108220
  5. JACC Basic Transl Sci. 2026 Apr 27. pii: S2452-302X(26)00053-7. [Epub ahead of print]11(5): 101535
    Systems Biology Identifies TARS2 as a Cardiomyocyte Regulator of Mitochondrial Oxidative Stress in Dilated Cardiomyopathy.
    Liming Chen, Xuan Li, Xiaolei Sun, Xiaolin Wang, Jian Wu, Enyong Su, Shijun Wang, Huan Sun, Leilei Ma, Yunzeng Zou.
      Dilated cardiomyopathy (DCM), a leading cause of heart failure, is characterized by progressive cardiomyocyte (CM) loss and mitochondrial dysfunction; yet, the molecular drivers of mitochondrial oxidative stress (MitOS) remain unclear. By integrating bulk, single-cell, and spatial transcriptomics with machine learning, we identified threonyl-tRNA synthetase 2 (TARS2) as a CM-enriched regulator of MitOS. TARS2 was consistently up-regulated in human DCM hearts and associated with apoptotic signaling and enhanced macrophage crosstalk. Functional studies demonstrated that TARS2 overexpression disrupted mitochondrial homeostasis, triggered excessive mitochondrial reactive oxygen species, and induced CM apoptosis, whereas genetic inhibition restored mitochondrial function, reduced apoptosis, and improved cardiac performance. These findings uncover TARS2 as a novel regulator of mitochondrial dysfunction and pathological remodeling in DCM, providing both mechanistic insights and therapeutic implications, and establish a systems biology framework for translational discovery of disease targets in cardiovascular medicine.
    Keywords:  TARS2; dilated cardiomyopathy; heart failure; mitochondrial oxidative stress; transcriptomic analyses
    DOI:  https://doi.org/10.1016/j.jacbts.2026.101535
  6. Cardiovasc Res. 2026 Apr 25. pii: cvag091. [Epub ahead of print]
    Targeting the ALCAT1 enzyme for the treatment of pressure- overload hypertrophy.
    Youhua Wang, Dandan Jia, Yuguang Shi.
       AIMS: Pressure overload-induced heart failure is a major cause of fatality in patients with heart diseases. At present, there exists no highly effective treatment for this incapacitating condition. Cardiolipin (CL) is a mitochondrial specific phospholipid that plays an essential role in cardiac health. Depletion of tetralinoleoyl CL (TLCL), the signature CL species, is implicated in human and animal models of heart failure. We investigated whether pathological CL remodeling by lysocardiolipin acyltransferase-1 (ALCAT1) promotes the progression of left ventricular (LV) hypertrophy induced by pressure overload by depleting TLCL in the heart and underlying molecular mechanisms.
    METHODS AND RESULTS: We identified a remarkable causative role of ALCAT1 in promoting the development of pressure overload hypertrophy in a mouse model of heart failure by transverse aortic constriction (TAC). We show that ALCAT1 expression in the heart is dramatically upregulated by TAC. Consequently, deletion or inhibition of ALCAT1 through targeted genetic manipulation or pharmacological intervention with Dafaglitapin (Dafa), a highly potent and specific small molecular inhibitor, effectively mitigates pressure overload hypertrophy and its related pathogenesis, including cardiomyopathy, cardiac dysfunction, inflammation, and fibrosis by preventing mitochondrial dysfunction in the heart. Furthermore, ablation or inhibition of ALCAT1 not only restores TLCL level, but also mitochondrial function and the related signal transduction pathways underlying these disorders, including mTORC1 signaling, oxidative stress, inflammation, and apoptosis in the heart of TAC mice.
    CONCLUSIONS: In summary, these findings identified ALCAT1 not only as a key mediator of mitochondrial etiology of pressure overload-induced heart failure, but also a novel drug target for hypertensive heart failure and Dafa as a potential treatment for the disorder.
    Keywords:  Cardiolipin remodeling; Hypertrophy; TLCL; Transverse aortic constriction
    DOI:  https://doi.org/10.1093/cvr/cvag091
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