Beyond Traditional Risk Factors: The MAINER Approach to Atherosclerotic Cardiovascular Disease

Recent studies have increasingly shown that cardiovascular risk cannot be adequately explained by isolated biomarkers alone. Among emerging metabolic markers, the triglyceride-glucose (TyG) index and its anthropometric derivatives have demonstrated promising associations with coronary slow flow phenomenon, highlighting the importance of metabolic dysfunction in cardiovascular disease.¹ Atherosclerotic cardiovascular disease results from the interaction of insulin resistance, central adiposity, systemic inflammation, endocrine dysfunction, and nutritional status rather than from isolated metabolic abnormalities.^{2, 3} This complexity has stimulated the development of composite indices that integrate biomarkers from different biological domains, although most currently focus on only a limited number of pathways. Furthermore, the TyG index has recently been shown to independently predict major adverse cardiovascular and cerebrovascular events in a large prospective cohort of nondiabetic individuals, reinforcing its role as a clinically relevant metabolic risk marker.⁴ Similarly, in our study of patients with decompensated heart failure admitted to the coronary intensive care unit, the C-reactive protein (CRP)-TyG index (CTI) was identified as a predictor of in-hospital mortality.⁵ These findings suggest that a single biochemical or clinical index may not adequately capture the complexity of cardiovascular disease.

In addition to these parameters, incorporating body shape-related characteristics may further improve patient evaluation. Composite indices that simultaneously assess inflammatory burden, metabolic status, anthropometric characteristics, and endocrine balance may provide a more comprehensive assessment. In particular, the body roundness index (BRI) has emerged as a promising anthropometric parameter that better reflects central obesity and visceral adiposity than body mass index.⁶ Recent studies have shown that BRI predicts cardiometabolic risk more accurately than traditional anthropometric measurements. Furthermore, indices derived by combining BRI with metabolic markers have demonstrated significantly improved prognostic performance. For example, the combination of the TyG index and BRI has been shown to predict cardiovascular events more effectively than either parameter alone.⁷  Similarly, the BRI/thyroid-stimulating hormone (TSH) ratio (BRITSH), which integrates anthropometric and endocrine components, has been identified as a strong and independent predictor of coronary artery disease in patients with hypothyroidism.⁸ In addition, a recent study demonstrated that geriatric nutritional risk index and systemic inflammatory response index, together with dietary metabolic factors, were independently associated with stroke risk in older adults, further emphasizing the importance of integrating nutritional and inflammatory pathways into cardiovascular risk assessment.⁹

These findings suggest that cardiovascular risk assessment should not rely on isolated nutritional or metabolic parameters but should instead consider multiple biological pathways. Therefore, prognostic nutritional index (PNI) alone may have limited utility in assessing complex pathophysiological processes such as ISR. Instead, evaluating PNI within composite indices that incorporate BRI, TyG, TSH, and inflammatory markers such as CRP may better reflect the balance among metabolic, anthropometric, inflammatory, nutritional, and endocrine risk factors.¹⁰

We propose the metabolic-anthropometric-inflammatory-nutritional-endocrine risk integration (MAINER) approach as a conceptual framework for understanding cardiometabolic risk (Figure 1). Unlike existing composite indices, which generally combine a limited number of biomarkers for specific clinical settings, the MAINER approach integrates five complementary biological domains into a single framework for cardiovascular risk assessment. These domains were selected because they represent key mechanisms involved in the development and progression of atherosclerotic cardiovascular disease, including insulin resistance and metabolic dysfunction, central and visceral adiposity, chronic inflammation, nutritional reserve, and endocrine regulation. Composite indices such as TyG-BRI, BRITSH, CTI, and PNI may be regarded as practical examples that reflect different components of the MAINER framework. However, MAINER should currently be considered a conceptual model, and prospective studies are needed to determine its incremental value, identify its optimal components, and establish its clinical applicability before it can be incorporated into routine cardiovascular risk assessment.

Figure 1.

The parameters of MAINER approach.

MAINER, metabolic-anthropometric-inflammatory-nutritional-endocrine risk.

TyG, triglyceride-glucose; BRI, body roundness index; CTI, C-reactive protein-triglyceride-glucose index; BRITSH, body roundness index/thyroid-stimulating hormone ratio; PNI, prognostic nutritional index; CRP, C-reactive protein; TSH, thyroid-stimulating hormone.