Validation of normal reference ranges in cardiac magnetic resonance imaging: The Multi-Ethnic Study of Atherosclerosis.

Background: Normal reference ranges in cardiovascular imaging studies are typically established as the mean value plus and minus twice the standard deviation (SD) of a healthy reference cohort ("2 SD-method"). Although widely used for cardiac magnetic resonance (CMR), this approach has not been previously validated. The purpose of this study was to use longitudinal cohort data to assess the clinical predictive validity of normal reference values for cardiac CMR.

Methods: Normal reference ranges for left- and right ventricular (LV and RV) CMR parameters were derived from baseline exam data of 1518 participants (age 45-84 years) in the Multi-Ethnic Study of Atherosclerosis (MESA) study without known CV disease and without established CV risk factors. Cut-off values at 1 and 2 SDs were obtained for the following LV and RV parameters indexed to body surface area: end-diastolic volume (LVEDVi, RVEDVi), end-systolic volume (LVESVi, RVESVi), mass (LVMi, RVMi), as well as for LVED diameter (LVEDD), LVED wall thickness and ejection fraction (LVEF, RVEF). The relationship of reference values to CV events was then evaluated in the entire MESA cohort with CMR data (n=4915), including individuals with CV risk factors at the baseline exam. Cox proportional hazard models were calculated for major adverse and all CV events (MACE and ACE, respectively) at 5 and 10 years of follow-up.

Results: At 5 years of follow-up, LVEDVi, LVESVi and LVEF beyond the 2SD-threshold of the mean reference values were predictors of MACE and ACE in men and women (HR 2.1-4.3; P <.001-.029). In men, LVMi and LVED wall thickness above the 1 SD-threshold were associated with CV events (HR 1.6-2.1; P <.001-.002). For women, LVED wall thickness above the 1 SD-threshold significantly increased risk of adverse events (HR 1.6-2.3; P.034-.002) while LVMi was associated with events only for values above the 2SD-threshold (HR 2.7-4.1; P <.001). Notably, LVEDD, RVMi, RVESVi and RVEF were not associated with CV events in men or women. CV events over 10 years showed similar trends.

Conclusions: Our results support the clinical relevance of CMR normal reference ranges for LV parameters. Most LV CMR parameters beyond the normal reference range (2SD-threshold) were associated with elevated CV risk at 5 and 10 years. Elevated LVEDDi, RVMi, RVESVi and RVEF however were not associated with CV events.