From diastolic dysfunction to exercise intolerance: an in silico simulation study on the phenotypic markers of heart failure with preserved ejection fraction
Authors: Van Loon T , Knackstedt C , Delhaas T , Reesink K.D , Brunner-La Rocca H.P , Van Empel V.P.M , Lumens J 
Published: November 2020

Abstract

Background
Left ventricular (LV) diastolic dysfunction, i.e. impaired LV relaxation function and/or increased LV stiffness, has been hypothesized to be responsible for at least part of the exercise intolerance in heart failure with preserved ejection fraction (HFpEF). Yet the mechanisms remain largely unknown.

Purpose
To determine in silico if and how abnormal LV diastolic function causes reduction in maximum cardiac output (COmax), i.e. exercise intolerance.

Methods
We used a cardiovascular model (CircAdapt) to simulate the effects of impaired LV relaxation and increased LV myocardial stiffness on cardiac hemodynamics. The model was initialized using a reference simulation with hypertension (systolic blood pressure: 150 mmHg) and concentric LV hypertrophy (LV wall mass: +25%). Impaired LV relaxation was introduced by increasing tau from 35 ms to 65 ms. LV stiffness was increased by increasing LV end-diastolic elastance from 0.15 mmHg/ml to 0.60 mmHg/ml and 2.00 mmHg/ml (moderate and severe LV stiffness, respectively). In each simulation, LV ejection fraction (LVEF), E/A ratio and mean left atrial (LA) pressure (mLAP) was assessed. To evaluate the effect on exercise tolerance, COmax was determined by gradually increasing cardiac output and heart rate in a predefined manner until mLAP exceeded 35 mmHg.

Results
In all simulations, LVEF remained unchanged and preserved (i.e. 60%). In rest, impaired LV relaxation decreased E/A ratio from 1.1 to 0.8 (impaired filling pattern) and increased mLAP from 7.2 mmHg to 8.0 mmHg (Figure top: gray vs. orange). Total LV filling time was reduced at rest, reducing diastolic reserve capacity and thereby of COmax, by 15% compared to the reference (Figure bottom: gray vs. orange). Moderate LV stiffness increased E/A ratio to 1.1 (pseudo-normal filling pattern) and mLAP to 15.0 mmHg (Figure top: gray vs. red). COmax was reduced by 40% due to a steep increase of mLAP with exercise intensity. Severe LV stiffness increased E/A ratio to 2.2 (i.e. restrictive filling pattern), but resulted in a non-physiological mLAP of 40 mmHg at rest. However, when combining moderate LV stiffness with LA dysfunction (i.e. reduced LA contractility and increased LA stiffness) also led to restrictive filling pattern (E/A ratio &gt;2.0) with mLAP 19 mmHg (Figure top: red vs. dashed blue). COmax reduced most severely by 53%, emphasizing the importance of LA function in LV diastolic dysfunction (Figure bottom: gray vs. dashed blue).

Conclusions
Through variations in LV and LA function, we linked the progression of LV diastolic dysfunction to LV and LA properties. Increased LV stiffness, more than impaired LV relaxation, is associated with substantially reduced exercise tolerance. The combination of LV and LA dysfunction led to the most severe exercise intolerance. Our unique in silico framework enables future studies to investigate other potential cardiac and vascular mechanisms underlying exercise intolerance in HFpEF.
Figure 1

Funding Acknowledgement
Type of funding source: Public grant(s) – National budget only. Main funding source(s): This work was funded by the Netherlands Organisation for Scientific Research and the Dutch Heart Foundation.