Two Distinct Classes of Heart Failure with Preserved Ejection Fraction Emerge from Analysis of Standard Clinical Measures using Mechanistic Models of the Cardiovascular System

Abstract

Diagnosis and treatment of heart failure are determined through the analysis of echocardiography (EC) and right heart catheterization (RHC) measures made in the clinic. To uncover the underlying causes of heart failure with reduced ejection fraction (HFrEF, ejection fraction < 50%) and heart failure with preserved ejection fraction (HFpEF, ejection fraction > 50%), thirty‐one patient records (ten HFrEF, twenty‐one HFpEF) have been obtained from the Cardiovascular Health Improvement Project (CHIP) database at the University of Michigan. Using these patient specific EC and RHC measures, we identify key parameters representing mechanical and hemodynamic function including systemic arterial stiffness, contractility of the right and left ventricle, diastolic relaxation as well as ventricular filling in a closed loop model of the cardiovascular system. Model simulations were tuned to match RHC and EC measures of systolic and diastolic pressures in the right ventricle, pulmonary artery, and aorta, along with cardiac output, pulmonary capillary wedge pressure, and left ventricular volumes in each patient with average error between data and model of 6.0 ± 2.3%. The underlying physiological parameters of these thirty‐one tuned models were then plotted against model‐based norms (blue dotted line in Figure 1 below) and compared between the HFrEF and HFpEF groups. Our results confirm that the main parameter driving HFrEF is reduced left ventricular contractility, while for HFpEF there is an evident increase in systemic arterial stiffness and left ventricle elastance, and a reduced relaxation during diastolic filling. Conducting a Principal Component Analysis (PCA) of both clinical measures and optimized model parameters shows a distinct group of HFpEF patients sharing strong patterns with our HFrEF cohort. However, only the analysis of our optimized parameters give us an understanding of the mechanistic differences between the two HFpEF groups. The optimized parameter PCA indicates significant differences (p‐value<. 05) in left ventricular active contractility, left ventricular relaxation, right ventricular relaxation and systemic arterial stiffness when comparing our classical HFpEF patients to those grouped as similar to HFrEF. These results as well as the wide range of parameter values in HFpEF supports the observed clinical heterogeneity and suggests that cardiovascular system modeling of standard clinical data is able to phenotype and group HFpEF as different sub diagnoses, elucidating patient specific treatment strategies for these patients.Support or Funding InformationThis work is supported by grants from the National Institute of Health HL139813, R01 HL139813, U01 HL122199, T32GM008322, F31HL149214Normalized model parameters from analysis of clinical measures. A: Ejection fraction from patient data records. Panels B, C and D: Left ventricular active contractility, systemic arterial stiffness and left ventricular passive stiffness, respectively. Model parameters are normalized to a value representing normal cardiovascular function. Gray dashed line is average, light dotted is standard deviation and the grey box contains the middle 50% of the parameter values.Figure 1