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The mechanisms by which cardiac mechanics effect coronary perfusion (cardiac-to-coronary coupling) remain incompletely understood. Several coronary models have been proposed to deepen our understanding of coronary hemodynamics, but possibilities for in-depth studies on cardiac-to-coronary coupling are limited as mechanical properties like myocardial stress and strain are most often neglected. To overcome this limitation, a mathematical model of coronary mechanics and hemodynamics was implemented in the previously published multi-scale CircAdapt model of the closed-loop cardiovascular system. The coronary model consisted of a relatively simple one-dimensional network of the major conduit arteries and veins as well as a lumped parameter model with three transmural layers for the microcirculation. Intramyocardial pressure was assumed to arise from transmission of ventricular cavity pressure into the myocardial wall as well as myocardial stiffness, based on global pump mechanics and local myofiber mechanics. Model-predicted waveforms of global epicardial flow velocity, as well as of intramyocardial flow and diameter were qualitatively and quantitatively compared with reported data. Versatility of the model was demonstrated in a case study of aortic valve stenosis. The reference simulation correctly described the phasic pattern of coronary flow velocity, arterial flow impediment, and intramyocardial differences in coronary flow and diameter. Predicted retrograde flow during early systole in aortic valve stenosis was in agreement with measurements obtained in patients. In conclusion, we presented a powerful multi-scale modeling framework that enables realistic simulation of coronary mechanics and hemodynamics. This modeling framework can be used as a research platform for in-depth studies of cardiac-to-coronary coupling, enabling study of the effect of abnormal myocardial tissue properties on coronary hemodynamics.

The tight coupling between myocardial oxygen demand and supply has been recognized for decades, but it remains controversial whether this coupling persists under asynchronous activation, such as during left bundle branch block (LBBB). Furthermore, it is unclear whether the amount of local cardiac wall growth, following longer lasting asynchronous activation, can explain differences in myocardial perfusion distribution between subjects. For better understanding of these matters, we built upon our existing modeling framework for cardiac mechanics-to-perfusion coupling by incorporating coronary autoregulation. Regional coronary flow was regulated with a vasodilator signal based on regional demand, as estimated from regional fiber stress-strain area. Volume of left ventricular wall segments was adapted with chronic asynchronous activation towards a homogeneous distribution of myocardial oxygen demand per tissue weight. Modeling results show that: (1) both myocardial oxygen demand and supply are decreased in early-activated regions and increased in late-activated regions; (2) but that regional hyperemic flow remains unaffected; while (3) regional myocardial flow reserve (the ratio of hyperemic to resting myocardial flow) decreases with increases in absolute regional myocardial oxygen demand as well as with decreases in wall thickness. These findings suggest that septal hypoperfusion in LBBB represents an autoregulatory response to reduced myocardial oxygen demand. Furthermore, oxygen demand-driven remodeling of wall mass can explain asymmetric hypertrophy and the related homogenization of myocardial perfusion and flow reserve. Finally, the inconsistent observations of myocardial perfusion distribution can primarily be explained by the degree of dyssynchrony, the degree of asymmetric hypertrophy, as well as the imaging modality used.

Funding Acknowledgements Type of funding sources: Public grant(s) – National budget only. Main funding source(s): The Dutch Research Council (NWO) Background Left bundle branch area pacing (LBBAP) has been introduced as an alternative, more physiological pacing strategy to biventricular pacing (BiVP). LBBAP can result in selective LBB pacing (sLBBP), non-selective LBB pacing (nsLBBP), or LV septal pacing (LVSP). Direct comparison between the different pacing strategies is challenging due to the practical implications of performing multiple pacing procedures within the same patients, as well as the large heterogeneity of underlying disease in patients. Computational models can be used to perform controlled in silico experiments and to compare all possible pacing modalities under the same conditions. Aim To investigate the effects of LBBAP strategies versus BiVP on cardiac mechanics and hemodynamics in a set of well-defined virtual heart failure patients. Methods An electrophysiological model was used to calculate biventricular electrical activation maps during LBBB and the different pacing strategies. The resulting regional activation times were imposed to the well-validated CircAdapt model of the human four-chamber heart and circulation. A set of virtual patients at different stages of heart failure are then defined within the CircAdapt framework, which is achieved by decreasing the contractility of the LV myocardium, such that LVEF≤35%. The CircAdapt model is then used to compute regional ventricular strain patterns and myocardial work as well as global ventricular pump function during LBBB, BiVP and the different LBBAP modalities. Results Selective LBBP is best at restoring mechanical homogeneity in LV contraction as evidenced by simulated wall strains waveforms (Fig 1, Left). NsLBBP increases septal dyssynchrony and introduces small pre-stretch in the LVfw (1.3±0.3%). This effect is more pronounced in LVSP (2.4±1.4%). In BiVP, pre-stretch occurs only in a single LV free wall (LVfw) segment, but all septal segments display a distinct oscillatory pattern. Work load homogeneity (Fig 1, Center) was best restored in sLBBP (4.9±1.1 kPa). NsLBBP lead to reduced homogeneity (4.9±1.8 kPa). LVSP reduced this further (4.8±2.6kPa), while BiVP performed similarly (4.6±2.6kPa) to LVSP. All modalities vastly improved on the baseline LBBB (4.06±5.6 kPa). Hemodynamically (Fig 1, Right), sLBBP showed greatest improvement in LV function (LVESV:-8.1%; LVEF:+6.8%; MLAP:-16.4%; LVdp/dtmax:+12.8%), followed by nsLBBP (LVESV:-7.2%; LVEF:+6.0%; MLAP:-14.5%; LVdp/dtmax:+12.5%), LVSP (LVESV:-5.6%; LVEF:+4.6%; MLAP:-11.7%; LVdp/dtmax:+12.358%) and finally BiVP (LVESV: -4.6%; LVEF:+3.8%; MLAP:-9.3%; LVdp/dtmax:+9.8%) Conclusion We were able to simulate LBBB and subsequent pacing strategies in virtual heart failure patients. This approach allowed direct comparison of mechanical and hemodynamic effects of BiVP and LBBAP modalities without confounding variables. Our results indicate that all LBBAP modalities perform at least similar to bi-ventricular pacing regardless of mechanical viability.