Hypertension is a significant causative factor of cardiovascular diseases and affects approximately 1.13 billion individuals globally [1,2]. Hypertensive heart disease results from prolonged pressure overload, leading to structural and functional alterations in the heart, and its incidence has been increasing [3]. Cardiac hypertrophy, an adaptive response of the heart to stress, may lead to heart failure (HF) eventually and increases the morbidity and mortality of cardiovascular disorders. Early identification and timely treatment of cardiac hypertrophy can greatly delay the progression of HF [4].

Recent investigations have demonstrated the relationship between amino acid metabolism, particularly the metabolism of branched-chain amino acids (BCAAs), including leucine, isoleucine, and valine, and cardiovascular diseases [[5], [6], [7], [8]]. Currently, more and more studies have shown that it is expected to become a biological marker and potential therapeutic target [9]. At the same time, it is confirmed that the level of BCAAs is closely related to hypertension. In 2019, a prospective study conducted by Flores-Guerrero et al. showed that high plasma BCAAs were associated with an increased risk of new-onset hypertension, and the association persisted after adjusting for age, sex, body mass index, and lipid profile [10]. In 2024, a meta-analysis combined with Mendelian randomization showed that increased BCAA levels were significantly associated with increased risk of hypertension, and sensitivity analyses also showed stable results. In the corresponding subgroup analysis of categorical variables, isoleucine, leucine and valine levels all increased the risk of hypertension. Its the OR values were 1.55 (95 % CI, 1.25 1.93), 1.55 (95 %, 1.32 1.82) and 1.63 (95 % CI, 1.39 1.91) [11]. At the same time, some studies have found that increased dietary BCAA intake is associated with increased risk of hypertension [12].

Additionally, impairment of BCAA metabolism has been confirmed to play significant roles in the development and progression of various cardiac metabolic disorders [13,14]. As essential amino acids, BCAAs cannot be synthesized endogenously and are obtained from food. BCAAs are transported to mitochondria by amino acid transporters and are then converted to branched-chain keto acids by branched-chain aminotransferase (Bcat) in conjunction with α-ketoglutarate/glutamine. These branched-chain keto acids are then converted to acetyl-CoA and succinyl-CoA by branched-chain alpha-ketoacid dehydrogenase (Bckdh). These intermediates enter the tricarboxylic acid cycle and generate adenosine triphosphate (ATP) via the respiratory chain in mitochondria [15,16].

Elevated BCAA levels have been observed in the hypertrophic heart, both in mice subjected to transverse aortic constriction (TAC) and spontaneously hypertensive rats (SHRs) [[17], [18], [19]]. Recent studies have increasingly focused on the different effects of 3 types of BCAAs on molecular signaling, metabolism and biological processes [20]. Several clinical studies have revealed that the levels of these three types of BCAAs are obviously altered in cardiovascular diseases, sometimes exhibiting opposite changes [21]. Moreover, it has been reported that BCAAs can activate downstream molecular pathways but that different BCAAs have different targets and mechanisms of action. Consequently, further investigation of the specific amino acid that plays a pivotal role in hypertension rather than the roles of BCAAs as a whole may provide novel insights for the development of treatments to alleviate cardiac hypertrophy and delay HF.

Mitochondria are highly abundant in cardiomyocytes. Theyplay a crucial role in ATP production, which is essential for the metabolic needs of cardiomyocytes. Impairment of the energy-generating capacity of mitochondria can disrupt the excitation‒contraction coupling process in the heart, leading to dysfunctional myocardial contraction and promoting the development of HF. An increasing number of studies have confirmed that bioenergetic processes in myocardial mitochondria are impaired in HF [22,23]. Mitochondrial quality control (MQC) mechanisms, including mitochondrial fission, mitochondrial fusion and mitophagy, are responsible for maintaining mitochondrial function and bioenergetics, which are critical for cardiac homeostasis [24]. Since MQC plays an important role in cardiac hypertrophy and HF, the regulation of MQC is essential. It has been reported that impaired BCAA metabolism can be directly responsible for cardiac mitochondrial dysfunction, reactive oxygen species (ROS) generation, and aberrant myocardial metabolism [12,25,26]. This suggests that the relationship between BCAAs and MQC in cardiomyocytes may be a crucial factor in cardiac remodeling.

The present study aimed to explore the role of BCAA metabolism in the progression of cardiac remodeling during chronic pressure overload in SHRs. Targeted amino acid metabolomics analysis and transcriptomics were combined to identify novel biomarkers associated with cardiac hypertrophy and elucidate the underlying mechanisms by which valine accumulation accelerates HF progression.