Ratiology and a Complementary Class of Metrics for Cardiovascular Investigations.

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 Pythagorean theorem reveals the inherent companion of cardiac ejection fraction.

BACKGROUND: Quantification of ventricular performance requires a comprehensive metric which is manageable for patient care and clinical trials. Ejection fraction (EF) has been embraced as an attractive candidate. However, being a dimensionless ratio, EF has serious limitations. METHODS: We aim to identify what information is not recognized when limiting the volume-related analysis by exclusively relying on EF. This investigation applies the volume domain concept, relating end-systolic volume (ESV) to end-diastolic volume (EDV). This approach allows graphical identification of the information not covered by EF. Implications for atria, left ventricle (LV) and right ventricle (RV) are investigated in healthy individuals, and cardiac patient groups using various imaging modalities. RESULTS: The Pythagorean theorem indicates that the hypotenuse which relates any {EDV, ESV} combination to EF corresponds with the information not covered by the single metric EF. The impact of the recovered EF companion (EFC) is illustrated in healthy adults (N = 410, LV 2D echocardiography), heart transplant patients (N = 101, LV CT), individuals with heart failure (N = 197, biplane angiocardiography), for the RV with corrected Fallot (N = 124, MRI), diameters for left atrium (N = 49, MRI) and area for right atrium (N = 51, MRI). For any limited EF range we find a spectrum of EFC values, showing that the two metrics contain (partly) independent information, and emphasizing that the sole use of EF only partially conveys the full information available. CONCLUSIONS: The EFC is a neglected companion, containing information which is additive to EF. Analysis based on ESV and EDV is preferred over the use of EF.

Heart Function Analysis in Cardiac Patients with Focus on Sex-Specific Aspects.

Cardiac function is best described by investigating the pressure-volume relationships. This information permits description in terms of the ventricular volume regulation graph (VRG), estimation of systolic elastance, evaluation of lusitropic properties, and assessment of ventriculo-arterial coupling. Current techniques yield noninvasive determination of cardiac compartmental volumes, along with systolic/diastolic arterial pressure, while ventricular end-diastolic pressure can be inferred from an echocardiography-based surrogate measure. Ventricular volume is known to vary with age, as well as to be affected by intrinsic cardiac disease and abnormalities of the vascular system. Moreover, 35 years ago it has been shown in healthy adults that left ventricular volume is significantly smaller in women compared to men. This important observation has serious implications for several metrics which are routinely used in clinical practice, e.g., ejection fraction. The remarkable difference between ventricular size in men and women is also a powerful starting point for the study of aging and the investigation of interventions such as exercise. In this review we evaluate sex-specific characteristics of the VRG and the implications for various cardiac patient populations, during basal conditions and intervention such as exercise.

Sex- and Age-Related Reference Values in Cardiology, with Annotations and Guidelines for Interpretation.

The definition of "abnormal" in clinical sciences is often based on so-called reference values which point to a range that experts by some sort of consensus consider as normal when looking at biological variables. Such a level is commonly calculated by taking (twice) the standard deviation from the mean, or considering certain percentiles. The suspicion or even confirmation of a disease is then established by demonstrating that the value measured exceeds the upper or lower reference value. As is often the case, the measurement accuracy may depend on the conditions and specific method employed to collect and analyze data. This implies that, for example, data assessed by 2D echocardiography possibly differ from those obtained by MRI and therefore require modality-specific reference values. In this review we summarize reference values for the electrocardiogram, cardiac compartmental volumes, and arterial vessel size in males and females for various age groups. These values may further depend on other variables such as body size, physical training status, and ethnicity. Additional variables relevant for cardiology such as those referring to the microcirculation and biomarkers are only mentioned with reference to the pertinent literature. In general, the sex- and age-specific differences observed are often remarkable and warrant consideration in clinical practice and basic biomedical sciences.

Ejection fraction as related to basic components in the left and right ventricular volume domains.

BACKGROUND: Ejection fraction (EF) is commonly applied as a clinically relevant metric to assess ventricular function. The numerical value of EF depends on the interplay between end-systolic volume (ESV) and end-diastolic volume (EDV). Remarkably, the relative impact of the two constitutive components on EF received little attention. METHODS: Three patient groups not using beta-blockers were analyzed for a robust investigation into the relative contribution of ESV and EDV when assessing EF: cardiac patients (N=155) with left ventricular (LV) data obtained by biplane ventriculography, near-normals (N=276) by gated SPECT investigation, and an MRI-based post Fallot repair study including right ventricular (RV) data (N=124), besides LV. We compared various routes to evaluate EF via linear and several types of nonlinear regression with ESV as independent variable. Advanced statistics was applied to evaluate sex-specific differences. RESULTS: In all cases ESV emerges as the dominant component of EF, with less (P<0.0001) impact of EDV. The relationship for EF versus ESV is nonlinear (P<0.0001), and similar for both sexes. A linear approach may be inadequate and generate erroneous statistical outcomes when comparing subgroups of patients. CONCLUSIONS: Values for EF primarily depend on ESV, both for LV and RV. This relationship is essentially nonlinear, and similar for both sexes. A logarithmic approximation is convenient and often acceptable. However, application of linear regression for EF vs ESV may lead to incorrect conclusions, particularly when comparing males and females.

Monte Carlo method applied to the evaluation of the relationship between ejection fraction and its constituent components.

Ventricular function is routinely assessed by applying the clinically accepted metric ejection fraction (EF). The numerical value of EF depends on the interplay between end-systolic volume (ESV) and end-diastolic volume (EDV). The relative impact of the two constitutive components has received little attention. Pediatric cardiologists are interested in EF vs ESV when evaluating various congenital abnormalities. Following successful surgical intervention of Fallot tetralogy, many of these patients receive follow-up, not only during childhood, but also when being adults. Cardiologists diagnosing and treating elderly patients often analyze EF vs EDV, notably for phenotyping heart failure patients. Therefore, we study EF vs ESV as well as EF vs EDV in more detail. We explore the fundamentals of EF while analyzing a Fallot patient group. Three routes were followed, namely nonlinear regression, by implementing a Monte Carlo approach to generate EDV on the basis of known ESV values, and by using a theoretical graphical derivation. Our MRI-based post Fallot repair study includes left (LV) and right ventricular (RV) data (N=124). Using a robust approach we employed nonlinear regression with ESV as an independent variable. EDV was also assessed by Monte Carlo generated values for stroke volume within a physiological range. In all cases ESV emerges as the dominant component of EF, with less (P<;0.0001) impact of EDV. Using three independent routes we demonstrate that values for EF primarily depend on the corresponding ESV. This relationship is nonlinear, and correlation is always better with ESV compared to EDV in these patients, and confirmed in random number modeling studies.

Effect of sex, age, and weight on ejection fraction and end-systolic volume reference limits in gated myocardial perfusion SPECT.

BACKGROUND: The left-ventricular ejection fraction (EF) and end-systolic volume (ESV) are strong predictors of prognosis for cardiac death. Gated myocardial perfusion single-photon emission computed tomography (gSPECT) may be used to measure ESV and EF. However, systematic differences may exist between referred populations. Our aim was to derive male and female reference limits for left-ventricular functional parameters, and determine the effect of age, weight, and body surface area (BSA). METHODS AND RESULTS: The ejection fraction and ESV were derived using QGS software for 127 patients with normal gSPECT studies. The lower reference limits of EF were 46.2% and 55.6% for men and women, respectively. The upper reference limits of ESV were 30.4 mL and 21.4 mL, and 15.7 mL/m(2) and 11.1 mL/m(2), when indexed to BSA for men and women, respectively. There was no correlation between EF and age, weight, or BSA (P > .05). There was a small decrease in ESV with age, and an increase with weight and BSA (P < .05). The sex-specific differences remained after adjusting for confounding variables. CONCLUSIONS: We demonstrated a significant sex difference for all functional parameters measured, and we established the influence of patient age and weight. Local reference limits for ESV and EF have been established, and the latter are transferable to other departments operating similar protocols.

The effect of imaging time, radiopharmaceutical, full fat milk and water on interfering extra-cardiac activity in myocardial perfusion single photon emission computed tomography.

BACKGROUND AND AIM: Extra-cardiac activity can interfere with observer interpretation of myocardial perfusion single photon emission computed tomography (SPECT) images. Fatty meals and drinks to reduce interference have been tested; however, a simple study of delayed imaging with (99m)Tc-tetrofosmin and (99m)Tc-sestamibi has not been specifically addressed. The aim was to quantify the effects of imaging time, radiopharmaceutical and oral administration of full fat milk and water on interfering activity. METHODS: Myocardial perfusion SPECT images were acquired using either tetrofosmin or sestamibi. Patients were imaged at 0.5, 1 or 2 h post-injection (tetrofosmin, 59; sestamibi, 72). Additional groups of patients were imaged either with or without milk (tetrofosmin, 54; sestamibi, 45) and with milk and water (sestamibi, 30). A myocardial region was drawn on the anterior projection and a thin adjacent extra-cardiac region was generated automatically. The count density ratio was calculated and validated with a trial of five observers. A decreasing ratio correlated significantly with observer rank of increasing interference with SPECT image interpretation (r=0.95, P=0.001). RESULTS: The ratio improved significantly as the imaging time increased for both tetrofosmin and sestamibi groups (P<0.05). The groups given milk or milk plus water showed no significant improvement against control groups (P > or = 0.2). There was no significant difference between tetrofosmin and sestamibi at any time point (P > or = 0.4). CONCLUSIONS: Image interpretation may be improved by delayed imaging for tetrofosmin and sestamibi. However, in contrast with common practice, the administration of milk or water appears to be of no clinical value compared with delayed imaging, and there is no significant difference between interfering activity from tetrofosmin and sestamibi.