The review, conducted by researchers at Universiti Teknologi MARA in Malaysia and registered prospectively on PROSPERO, systematically searched PubMed, Scopus and Web of Science for studies that combined metabolomic profiling with genetic characterisation of hypertrophic cardiomyopathy cohorts. From an initial pool of 985 records, the team distilled 14 eligible studies comprising 1511 participants aged 23 to 71, published between 2015 and 2026. To qualify, studies had to perform spectroscopic or spectrometric metabolomics, lipidomics or multi-omics on human biospecimens, report genotype information at the individual or cohort level, and exclude phenocopies such as Fabry disease, cardiac amyloidosis and secondary hypertrophy from hypertension or aortic stenosis. The aim was to isolate genuine sarcomeric disease biology and ask three questions: which metabolic pathways are consistently dysregulated, whether specific gene variants carry distinct metabolic signatures, and whether any of the identified metabolites could serve as diagnostic or prognostic biomarkers.

Methodologically, the field has converged on liquid chromatography-mass spectrometry as the dominant platform, typically coupling UPLC systems to high-resolution Orbitrap or QTOF instruments for untargeted profiling, with triple quadrupole systems reserved for targeted quantification of acyl carnitines and eicosanoids. Plasma was the most frequently analysed specimen, followed by left ventricular or septal myocardial tissue obtained during surgery, serum, whole blood and combined plasma-plus-tissue designs. More exotic approaches also appeared, including direct-infusion high-resolution mass spectrometry for rapid screening and, in one 2026 study, spatial metabolomics using desorption electrospray ionisation imaging mass spectrometry to map metabolites directly within myocardial tissue sections. Most studies employed untargeted designs, though a minority integrated lipidomics, proteomics and transcriptomics into broader multi-omics workflows.

Across this heterogeneous literature, a strikingly consistent pattern of metabolic remodelling emerged. The adult heart normally derives most of its ATP from mitochondrial fatty acid oxidation, but hypertrophied myocardium in these studies showed reduced long-chain acyl carnitines, depleted high-energy phosphates including ATP, ADP and phosphocreatine, diminished acetyl-CoA, and reduced tricarboxylic acid cycle intermediates such as citrate, malate and succinate. Tissue analyses revealed damaged mitochondrial cristae, disordered architecture and reduced NAD(H)-linked respiratory capacity. In parallel, the diseased heart appeared to shift toward less efficient alternative substrates: elevated beta-hydroxybutyrate signalled increased ketone utilisation, while lactate accumulation pointed to heightened glycolytic flux. Circulating metabolites told a complementary story, with elevated long-chain acyl carnitines in more severe disease, interpreted as incomplete fatty acid oxidation and systemic metabolic spillover rather than enhanced fat burning.

Amino acid metabolism emerged as a second recurring theme. Branched-chain amino acids, leucine, isoleucine and valine, were elevated in both plasma and myocardial tissue and tracked with greater hypertrophic severity. Because these amino acids are catabolised primarily through the mitochondrial branched-chain alpha-keto acid dehydrogenase complex, their accumulation is consistent with impaired mitochondrial oxidative capacity, though they may also modulate hypertrophic signalling through mTOR. Other amino acid-related metabolites, including aminoadipic acid, 3-methylhistidine and dimethylglycine, were associated with more severe phenotypes in MYBPC3-confirmed cohorts. Lipid disturbances extended beyond acyl carnitines to reductions in polyunsaturated fatty acids, lysophosphatidylcholines and glycerophospholipids in plasma, alongside increased ceramides and sphingomyelins in tissue, suggesting broad disruption of membrane remodelling and lipid signalling.

The review’s central and arguably most provocative finding concerns genotype. Despite the explicit focus on genetically characterised cohorts, no distinct genotype-specific metabolic signature could be identified. Several studies reported no significant metabolomic differences between genotype-positive and genotype-negative patients, and in principal component analyses the two groups did not cluster separately. Even directly comparing the two major sarcomere genes, MYH7 and MYBPC3 carriers displayed nearly identical metabolic signatures, and circulating eicosanoid profiles were reduced across a variety of mutations including FLNC, MYBPC3, MYH7, TNNI3 and TNNT2. In founder-variant populations enriched for specific MYBPC3 mutations, metabolic signatures aligned more strongly with disease phenotype than with genotype. The authors interpret this convergence as evidence that metabolic remodelling represents a final common pathway: diverse sarcomeric mutations impair cross-bridge cycling, increase ATP consumption and reduce contractile efficiency, driving a shared energetic deficit whose severity, rather than the causal variant, shapes the metabolome.

Mechanistically, this model fits with earlier work showing reduced phosphocreatine-to-ATP ratios even in mutation carriers without overt hypertrophy, indicating that energy deficiency precedes structural remodelling. Sarcomeric mutations destabilise energy-conserving states of myosin, promoting hypercontractility and impaired relaxation. The resulting energetic imbalance is compounded by mitochondrial dysfunction, impaired calcium handling, oxidative stress and coronary microvascular dysfunction that limits oxygen delivery, forming a self-reinforcing cycle that downstream signalling through AMPK, mTOR and PPAR pathways may amplify. Notably, some of this remodelling appears reversible: longitudinal plasma sampling around surgical myectomy showed postoperative declines in beta-hydroxybutyrate, bilirubin, biliverdin and various lipid species, consistent with improved organ perfusion after relief of left ventricular outflow tract obstruction, and suggesting that systemic metabolic abnormalities in the disease are dynamic rather than fixed.

On the translational front, several multi-metabolite panels showed impressive diagnostic performance. A plasma-based random forest model using just five metabolites, 8:0-carnitine, hypoxanthine, creatine, phenylalanine and tryptophan, discriminated hypertrophic cardiomyopathy from controls with an area under the curve of 0.976. A targeted eicosanoid panel combining 12-HETE and EPA achieved an AUC of 0.884, while serum signatures distinguished preclinical from obstructive disease carriers with accuracy comparable to imaging-derived energetic parameters. Metabolomic clustering also identified patient subgroups with differing outcomes, where poorer prognosis was linked to increased purine metabolism and reduced carnitines, and better survival to preserved tricarboxylic acid intermediates such as isocitrate and fumarate. Circulating acyl carnitines correlated with ventricular wall thickness and ejection fraction in MYBPC3-positive cohorts, hinting at a role in severity stratification.

The authors are careful to temper enthusiasm. Most included studies were single-centre, modestly sized case-control designs with cross-sectional data that cannot establish temporal relationships. Confounders such as diabetes, renal function, BMI and medication use were inconsistently accounted for, and most reported metabolites were annotated only at Metabolomics Standards Initiative Level 2, meaning putative identification by spectral matching rather than confirmation with authentic reference standards. Platform differences in sensitivity, chromatographic separation and library coverage further complicate cross-study comparison, and fasting status and sample handling varied widely. Critically, because every comparator group consisted of healthy controls or genotype-negative relatives, the review cannot establish whether any candidate metabolite panel can distinguish sarcomeric disease from other causes of left ventricular hypertrophy, a prerequisite for clinical differential diagnosis. Genetic testing also leaves roughly 40 percent of cases without a pathogenic variant, a gap metabolomics might eventually help address but has not yet closed.

The review concludes that metabolomics should currently be regarded as a hypothesis-generating tool rather than an established clinical modality, but one whose mechanistic signal is coherent and therapeutically suggestive. If hypertrophic cardiomyopathy is fundamentally a bioenergetic disorder, then interventions targeting myocardial energetics, from metabolic modulators to cardiac myosin inhibitors such as mavacamten that reduce ATP consumption at the sarcomere, address the primary driver the metabolomes reveal. The priority now, the authors argue, is prospective longitudinal cohorts following genotype-positive individuals from the pre-hypertrophic stage, with serial sampling integrated into family screening programmes, standardised collection protocols, Level 1 metabolite identification and independent external validation. Only then will the metabolic signature of the failing heart translate from an intriguing research signal into a tool that predicts disease progression and guides precision treatment for this heterogeneous and sometimes deadly condition.

Subject of Research: Metabolomic biomarkers and metabolic remodelling in genetically characterised hypertrophic cardiomyopathy

Article Title: Metabolomic biomarkers and metabolic remodelling in genetically characterised hypertrophic cardiomyopathy: a systematic review

Article References: Ahmad Razmy, A. H., Abd Latip, N., Ab-Rahim, S., & Sheikh Abdul Kadir, S. H. (2026). Metabolomic biomarkers and metabolic remodelling in genetically characterised hypertrophic cardiomyopathy: a systematic review. Metabolomics, 22(5), Article 164. https://doi.org/10.1007/s11306-026-02526-1

Image Credits: AI Generated

DOI: 10.1007/s11306-026-02526-1

Keywords: hypertrophic cardiomyopathy, metabolomics, biomarkers, MYBPC3, MYH7, fatty acid oxidation, branched-chain amino acids, mitochondrial dysfunction, acyl carnitines, sarcomeric genes, systematic review, precision medicine

An international team of researchers from Italy and Brazil, led by Gabriele Rocchetti of the Università Cattolica del Sacro Cuore, used an untargeted metabolomic approach based on ultra-high-performance liquid chromatography coupled to high-resolution Orbitrap mass spectrometry. Rather than testing a pre-selected list of compounds, untargeted metabolomics casts a wide analytical net, capturing and tentatively identifying as many small molecules as possible in a biological sample. In this case, the platform putatively annotated 1,412 metabolites in whole blood, cross-referenced against the comprehensive Bovine Metabolome Database. Amino acids, peptides and their analogues dominated the detectable metabolome with 281 compounds, followed by carbohydrates and their conjugates with 90, and fatty acids and conjugates with 63.

The experimental design took advantage of a long-running field study at São Paulo State University’s experimental station in Araçatuba, Brazil. Twenty-five Nellore and 25 Angus young bulls, half-sibs within each breed to minimize genetic variation, were reared under identical conditions. After an adaptation period with access to shade, half of the animals in each breed were exposed to direct sunlight and high temperature-humidity conditions for 56 days during the height of the southern summer, from early December 2015 to early February 2016. Shading was then restored and the animals entered a recovery phase. Blood was drawn from five sun-exposed animals per breed at the peak of heat stress and again in the cooler season, allowing the researchers to compare each animal against its own baseline. Notably, these were the same animals whose DNA methylation patterns the team had characterized in an earlier study, providing an unusual opportunity to link epigenetic regulation with metabolic chemistry.

When the researchers applied supervised statistical modeling to the metabolomic profiles collected during the challenge period, the two breeds separated cleanly, with a prediction ability of Q² = 0.917. Twenty metabolites showed outstanding discriminating power, each achieving a perfect area under the receiver operating characteristic curve. The single most predictive compound was the steroid 4-hydroxyestrone, which accumulated far more in the blood of heat-stressed Angus than in Nellore, with a log2 fold-change of 3.79. Steroid metabolism is known to be highly responsive to environmental stressors, and this finding points to breed-specific endocrine regulation under thermal load. Other top discriminators included lysine, the membrane lipid LysoPC(16:0), and citric acid, all previously implicated in heat-related metabolic adjustments and consistent with the known effects of heat stress on mitochondrial metabolism, substrate use, and membrane lipid turnover.

The most striking results, however, emerged from the longitudinal comparison of each breed between the heat challenge and the recovery period. Because repeated measurements from the same animals can inflate apparent significance, the team used linear mixed models that accounted for individual identity and then applied stringent false discovery rate correction. Under this rigorous framework, the contrast between the breeds was dramatic. Nellore cattle showed 114 metabolites whose phase-dependent changes remained statistically significant, spanning amino acids and peptides, carbohydrates, purine and pyrimidine derivatives, acyl-carnitines, steroids, and tetrapyrrole-related compounds. Angus, by comparison, retained only three significant metabolites: urobilin, deoxycitidine, and D-1-piperideine-2-carboxylic acid.

Interpreting this asymmetry requires care, the authors caution. The scarcity of significant metabolites in Angus does not mean the breed was unaffected by heat. Multivariate modeling still identified 264 metabolites contributing to class discrimination in Angus, but their univariate changes were modest and variable across animals. The researchers suggest two non-exclusive explanations: either Angus responses are more biologically variable between individuals, or the breed lacks the systemic metabolic plasticity that characterizes its zebu cousin. In Nellore, the large and coherent set of regulated metabolites points to a tightly controlled, network-level reprogramming, precisely the kind of coordinated response one would expect from a breed evolutionarily shaped by tropical climates.

Within the Nellore response, each chemical class told a coherent physiological story. Amino acids and peptides formed the largest affected category, with 34 significant compounds showing a global reduction, consistent with heat-induced shifts in nitrogen metabolism, increased amino acid catabolism, and the redistribution of substrates toward energy production. Carbohydrate-related metabolites also declined, plausibly reflecting altered glucose utilization and gluconeogenic flux. Purine and pyrimidine derivatives were predominantly reduced during heat exposure, a pattern linked to energy balance, redox homeostasis, and stress signaling. Perhaps most intriguingly, acyl-carnitines, key intermediates in fatty acid transport and mitochondrial beta-oxidation, showed a strong cumulative increase, suggesting that heat-stressed Nellore cattle shift their metabolism toward lipid substrates. Steroids and steroid-conjugated metabolites were broadly reduced, while phenolic compounds of dietary origin, including quercetin and enterolactone, also fell during the challenge period.

The metabolic findings dovetail elegantly with the team’s earlier epigenetic work on the same animals. In the previous DNA methylation study, Nellore cattle exhibited hypo-methylation of stress-responsive genes during heat exposure, including ELOVL5 and FADS1, which govern fatty acid chain elongation and desaturation, and PDE5A, a regulator of vascular function and oxidative stress responses. The convergence of epigenetic loosening of lipid-metabolism genes with the observed remodeling of acyl-carnitines and membrane lipids supports the hypothesis that Nellore cattle possess a multi-layered adaptive framework: gene regulation and metabolite chemistry responding in concert to preserve membrane stability, optimize lipid turnover, and limit oxidative damage. Pathway analysis reinforced this picture, identifying porphyrin, purine, and pyrimidine metabolism as the routes most consistently modulated by heat, particularly in Nellore, with porphyrin metabolism standing out as a shared signature in both breeds.

That shared porphyrin signature is biologically telling. Urobilin, a downstream catabolite of heme breakdown, plummeted during heat exposure in both breeds, with log2 fold-changes of −6.08 in Angus and −5.97 in Nellore, and achieved maximal predictive power in the Angus model. Heme is central to oxygen transport, mitochondrial electron transfer, and cellular redox balance, and thermal stress is known to influence mitochondrial activity, oxygen utilization, and reactive oxygen species generation. The marked drop in urobilin thus suggests that heat stress perturbs heme turnover in both breeds, even as their broader metabolic responses diverge. In Angus, the rise of deoxycitidine hints at increased nucleotide turnover, possibly reflecting DNA and RNA damage and repair under oxidative stress, while the fall of D-1-piperideine-2-carboxylic acid, a lysine degradation intermediate, points to perturbed amino acid catabolism.

The study’s authors are careful to frame their conclusions within its limits. The cohort was small, with five animals per breed providing longitudinal samples, and data acquisition was performed exclusively in positive ionization mode, meaning that metabolites preferentially detected in negative mode, including several classes of organic acids, may be underrepresented. Larger cohorts and targeted validation will be needed to confirm the functional roles of the identified metabolites. Even so, the implications are considerable. If heat tolerance in cattle reflects the capacity for controlled, systemic metabolic reprogramming rather than the magnitude of any single molecular change, then breeding programs may eventually be able to use blood metabolite panels as biomarkers to select thermotolerant animals. In an era when climate change is squeezing livestock systems on every continent, the humble blood sample of a Nellore steer may hold a blueprint for building more resilient herds.

Subject of Research: Breed-specific blood metabolomic responses of Nellore and Angus cattle to heat stress

Article Title: Metabolomic profiling of blood from Nellore and Angus cattle under heat stress

Article References: Metabolomic profiling of blood from Nellore and Angus cattle under heat stress. (n.d.). https://doi.org/10.1007/s44154-026-00303-7

Image Credits: AI Generated

DOI: 10.1007/s44154-026-00303-7

Keywords: heat stress, cattle, metabolomics, Nellore, Angus, thermotolerance, porphyrin metabolism, purine metabolism, pyrimidine metabolism, acyl-carnitines, urobilin, livestock