Comprehensive Interpretation of Reference Values for Cardiac Volume-Related Metrics: When is Normal Truly Normal?

Reference values for measurement devices or methods serve to define the normal range. Cardiac imaging modalities often apply paired determinations, referring to a maximum and a minimum value for the phasic pattern of a (patho)physiological process. For example, it is common to measure end-systolic ventricular (residual) volume in combination with end-diastolic (filling) volume. Apart from these primary variables, clinicians often consider derived metrics, mostly based on the ratio or difference of the primary data. Remarkably, for these derived metrics, reference values are defined that are not fully compatible with those established for the primary variables. This conflict has rarely been recognized. Generally, the single criterion based on the ejection fraction ratio includes numerous data points that fall outside the reference ranges as established for volumes, leading to serious conflicts. Matters are further complicated when employing sex-specific cut-off values. These inconsistencies are insufficiently documented in studies reporting reference values. We propose a graphical representation that depicts all relevant metrics within a single insightful diagram. This approach allows estimation of potential conflicts regarding subgroups when cut-offs associated with different metrics are applied to address the same problem. The graph clearly shows that indiscriminate application of combined cut-offs may result in conflicting outcomes. The discordance that we describe here may partly explain the variability encountered when comparing published studies using distinct criteria. Particularly, our study documents that current guidelines for phenotyping heart failure are flawed, and should be replaced by sex-specific criteria based on ventricular volumes, thus conforming to established principles known from physiology.