Heart failure (HF) may be accompanied by considerable alterations of left ventricular (LV) volume, depending on the particular phenotype. Two major types of HF have been identified, although heterogeneity within each category may be considerable. All variants of HF show substantially elevated LV filling pressures, which tend to induce changes in LV size and shape. Yet, one type of HF is characterized by near-normal values for LV end-diastolic volume (EDV) and even a smaller end-systolic volume (ESV) than in matched groups of persons without cardiac disease. Furthermore, accumulating evidence indicates that, both in terms of shape and size, in men and women, the heart reacts differently to adaptive stimuli as well as to certain pharmacological interventions. Adjustments of ESV and EDV such as in HF patients are associated with (reverse) remodeling mechanisms. Therefore, it is logical to analyze HF subtypes in a graphical representation that relates ESV to EDV. Following this route, one may expect that the two major phenotypes of HF are identified as distinct entities localized in different areas of the LV volume domain. The precise coordinates of this position imply unique characteristics in terms of the actual operating point for LV volume regulation. Evidently, ejection fraction (EF; equal to 1 minus the ratio of ESV and EDV) carries little information within the LV volume representation. Thus far, classification of HF is based on information regarding EF combined with EDV. Our analysis shows that ESV in the two HF groups follows different patterns in dependency of EDV. This observation suggests that a superior HF classification system should primarily be founded on information embodied by ESV.

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Cardiovascular investigations often involve ratio-based metrics or differences: ejection fraction, arterial pressure augmentation index, coronary fractional flow reserve, pulse pressure. Focusing on a single number (ratio or difference) implies that information is lost. The lost companions constitute a well-defined but thus far unrecognized class, having additive value, a physical dimension, and often a physiological meaning. Physiologists should play a prominent role in exploring these complementary avenues and also define alternatives.

The heart is often regarded as a compression pump. Therefore, determination of pressure and volume is essential for cardiac function analysis. Traditionally, ventricular performance was described in terms of the Starling curve, i.e., output related to input. This view is based on two variables (namely, stroke volume and end-diastolic volume), often studied in the isolated (i.e., denervated) heart, and has dominated the interpretation of cardiac mechanics over the last century. The ratio of the prevailing coordinates within that paradigm is termed ejection fraction (EF), which is the popular metric routinely used in the clinic. Here we present an insightful alternative approach while describing volume regulation by relating end-systolic volume (ESV) to end-diastolic volume. This route obviates the undesired use of metrics derived from differences or ratios, as employed in previous models. We illustrate basic principles concerning ventricular volume regulation by data obtained from intact animal experiments and collected in healthy humans. Special attention is given to sex-specific differences. The method can be applied to the dynamics of a single heart and to an ensemble of individuals. Group analysis allows for stratification regarding sex, age, medication, and additional clinically relevant covariates. A straightforward procedure derives the relationship between EF and ESV and describes myocardial oxygen consumption in terms of ESV. This representation enhances insight and reduces the impact of the metric EF, in favor of the end-systolic elastance concept advanced 4 decades ago.

The increase in pulse pressure (PP) that occurs with advancing age is predominantly due to reduced arterial distensibility leading to decreased aortic compliance, particularly in the elderly, in whom high blood pressure mainly manifests as isolated systolic hypertension. Since age-related changes in stroke volume are minimal compared with changes in PP, PP is often considered a surrogate measure of arterial stiffness. However, since PP is determined by both cardiac and arterial function, a more precise and reliable means of assessment of arterial stiffness is arterial pulse wave velocity (PWV), a parameter that is only dependent on arterial properties. Arterial stiffness as measured by PWV has been found to be a powerful pressure-related indicator for cardiovascular morbidity and mortality. We analyzed PP and PWV in men and women of various age groups in healthy volunteers as well as cardiac patients with different types of diseases. The findings identified several striking sex-specific differences which demand consideration in guidelines for diagnostic procedures, for epidemiological analysis, and in evaluation of therapeutic interventions.