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