Table 1.

Summary selection of human studies on metabolomics and cardiovascular disease endpoints among older adults

a Human studies, publication year	Study population	Results	Inferences	Details/limitations
Rizza et al., 2014 111	N = 67 Mean age 85 ± 3 years High rate of prior CVD (85%)	Medium‐chain and long‐chain acylcarnitines were associated with major adverse cardiac events (MACE)	Ageing mitochondrial dysfunction associated with MACE	Small sample size; high‐risk cohort
Ganna et al., 2014 115	N = 1028 Average age 70 years	Lipid‐related metabolites lysophosphatidylcholine, monoglyceride, and sphingomyelin were associated with incident coronary heart disease over 3.9 to 10 years of median follow‐up	Potential causal role in coronary heart disease development	Population‐based, longitudinal cohorts; integrated genetic and metabolomic analyses
Cheng et al., 2015 116	N = 515 Average age 55 to 64 years across groups	Metabolite panel consisting of methylarginine/arginine ratio, butyrylcarnitine, spermidine, total essential amino acids, and prognosticated endpoints of death or heart failure‐related hospitalization over 6 and 12 months	Metabolite panel provided better prognostic value over B‐type natriuretic peptide	Targeted metabolomics; participants were in heart failure stages A, B, and C
Zordoky et al., 2015 19	Total N = 82 Heart failure with preserved ejection fraction (N = 24) Heart failure with reduced ejection fraction (N = 20) Age‐matched controls (N = 38) Average age 61 to 67 years across groups	Short‐chain acylcarnitines were higher in both HFpEF and HFrEF than in controls Medium‐chain and long‐chain acylcarnitines were higher in HFpEF than both HFrEF and controls	Metabolomics fingerprint of HFpEF is distinct from that of HFrEF and controls	Small sample size; 181 metabolites; other heterogeneous factors involved such as background coronary artery disease and medication usage
Hunter et al., 2016 16	CATHGEN study of sequential patients who underwent cardiac catheterization Comparison between HFpEF cases (N = 282) and HFrEF (N = 279) and controls (N = 191) Average age 55 to 66 years across groups	Long‐chain acylcarnitines were higher in HFrEF than HFpEF, increasing linearly with declining ejection fraction	Possible shared mechanism in HF regardless of ejection fraction	Replication cohort data unavailable; cardiac catheterization cohort could have over‐represented ischaemic phenotypes; clinically obtained data; targeted metabolite profiling
Ahmad et al., 2016 15	N = 453 chronic systolic heart failure patients (HF‐ACTION cohort) Median age 59 years	Long‐chain acylcarnitines were associated with increased risk of all‐cause mortality, all‐cause hospitalization, cardiovascular death, and cardiovascular hospitalization	Greater circulating levels of long‐chain acylcarnitines predicted functional status and mortality in patients with chronic systolic HF	Subset study from HF‐ACTION cohort
Bedi Jr et al., 2016 117	N = 15 patients with chronic dilated nonischaemic cardiomyopathy N = 20 controls Transmural sampling of the left ventricular myocardium obtained during left ventricular assist device implantation or heart transplantation	Increased abundance of ketogenic β‐hydroxybutyryl‐CoA, decreased levels of myocardial β‐OH‐butyrate, increased circulating levels of ketones	Increased ketone utilization in the end‐stage failing heart	End‐stage heart failure; male gender predominance in the failing heart group
Wang et al., 2017 118	PREDIMED trial N = 230 incident CVD cases N = 787 random participants Patients were randomized to Mediterranean diets or control diet Average age 67 to 69 years across groups	Plasma ceramide concentrations associated with elevated risk of composite CVD outcome (acute myocardial infarction, stroke, and cardiovascular death)	Mediterranean diet may have the potential to mitigate detrimental effect associated with elevated baseline plasma ceramide concentrations on CVD risk	Participants were European Caucasians, limits generalizability to other populations; high CVD risk profiles
Menni et al., 2018 119	N = 617 middle‐aged women Average age 61 years TwinsUK cohort	Pulse wave velocity correlated negatively with gut microbiome alpha diversity, adjusted for levels of gut‐derived metabolites (indolepropionate, trimethylamine oxide, and phenylacetylglutamine)	Gut microbiome diversity is inversely associated with arterial stiffness in women, only minimally mediated by metabolic syndrome	Analyses limited to middle‐aged white female twins; faecal sampling not necessarily taken at time of arterial stiffness assessment

CVD, cardiovascular disease; HF, heart failure; HFpEF, heart failure with preserved ejection fraction; HFrEF, heart failure with reduced ejection fraction.

^aStudies selected based on human studies, older age groups, and cardiovascular endpoints/surrogate endpoints.