Comparison of Left Ventricular Function Derived from Subject-Specific Inverse Finite Element Modeling Based on 3D ECHO and Magnetic Resonance Images.

Three-dimensional echocardiography (3D ECHO) and magnetic resonance (MR) imaging are frequently used in patients and animals to evaluate heart functions. Inverse finite element (FE) modeling is increasingly applied to MR images to quantify left ventricular (LV) function and estimate myocardial contractility and other cardiac biomarkers. It remains unclear, however, as to whether myocardial contractility derived from the inverse FE model based on 3D ECHO images is comparable to that derived from MR images. To address this issue, we developed a subject-specific inverse FE model based on 3D ECHO and MR images acquired from seven healthy swine models to investigate if there are differences in myocardial contractility and LV geometrical features derived using these two imaging modalities. We showed that end-systolic and end-diastolic volumes derived from 3D ECHO images are comparable to those derived from MR images (R2=0.805 and 0.969, respectively). As a result, ejection fraction from 3D ECHO and MR images are linearly correlated (R2=0.977) with the limit of agreement (LOA) ranging from -17.95% to 45.89%. Using an inverse FE modeling to fit pressure and volume waveforms in subject-specific LV geometry reconstructed from 3D ECHO and MR images, we found that myocardial contractility derived from these two imaging modalities are linearly correlated with an R2 value of 0.989, a gradient of 0.895, and LOA ranging from -6.11% to 36.66%. This finding supports using 3D ECHO images in image-based inverse FE modeling to estimate myocardial contractility.

Preconditioning with selective autoretroperfusion: In vivo and in silico evidence of washout hypothesis.

Introduction: Prompt reperfusion of coronary artery after acute myocardial infarction (AMI) is crucial for minimizing heart injury. The myocardium, however, may experience additional injury due to the flow restoration itself (reperfusion injury, RI). The purpose of this study was to demonstrate that short preconditioning (10 min) with selective autoretroperfusion (SARP) ameliorates RI, based on a washout hypothesis. Methods: AMI was induced in 23 pigs (3 groups) by occluding the left anterior descending (LAD) artery. In SARP-b (SARP balloon inflated) and SARP-nb (SARP balloon deflated) groups, arterial blood was retroperfused for 10 min via the great cardiac vein before releasing the arterial occlusion. A mathematical model of coronary circulation was used to simulate the SARP process and evaluate the potential washout effect. Results: SARP restored left ventricular function during LAD occlusion. Ejection fraction in the SARP-b group returned to baseline levels, compared to SARP-nb and control groups. Infarct area was significantly larger in the control group than in the SARP-b and SARP-nb groups. End-systolic wall thickness was preserved in the SARP-b compared to the SARP-nb and control groups. Analyte values (pH, lactate, glucose, and others), measured every 2 min during retroperfusion, suggest a "washout" effect as one important mechanism of action of SARP in reducing infarct size. With SARP, the values progressively approached baseline levels. The mathematical model also confirmed a possible washout effect of tracers. Discussion: RI can be ameliorated by delaying restoration of arterial flow for a brief period of time while pretreating the infarction with SARP to restore homeostasis via a washout mechanism.

Mechanisms of coronary sinus reducer for treatment of myocardial ischemia: in silico study.

The coronary sinus reducer (CSR) is an emerging medical device for treating patients with refractory angina, often associated with myocardial ischemia. Patients implanted with CSR have shown positive outcomes, but the underlying mechanisms are unclear. This study sought to understand the mechanisms of CSR by investigating its effects on coronary microcirculation hemodynamics that may help explain the therapy's efficacy. We applied a validated computer model of the coronary microcirculation to investigate how CSR affects hemodynamics under different degrees of coronary artery stenosis. With moderate coronary stenosis, an increase in capillary transit time (CTT) [up to 69% with near-complete coronary sinus (CS) occlusion] is the key change associated with CSR. Because capillaries in the microcirculation can still receive oxygenated blood from the upstream artery with moderate stenosis, the increase in CTT allows more time for the exchange of gases and nutrients, aiding tissue oxygenation. With severe coronary stenosis; however, the redistribution of blood draining from the nonischemic region to the ischemic region (up to 96% with near-complete CS occlusion) and the reduction in capillary flow heterogeneity are the key changes associated with CSR. Because blood draining from the nonischemic region is not completely devoid of O2, the redistribution of blood to the capillaries in the ischemic region by CSR is beneficial especially when little or no oxygenated blood reaches these capillaries. This simulation study provides insights into the mechanisms of CSR in improving clinical symptoms. The mechanisms differ with the severity of the upstream stenosis.NEW & NOTEWORTHY Emerging coronary venous retroperfusion treatments, particularly coronary sinus reducer (CSR) for refractory angina linked to myocardial ischemia, show promise; however, their mechanisms of action are not well understood. We find that CSR's effectiveness varies with the severity of coronary stenosis. In moderate stenosis, CSR improves tissue oxygenation by increasing capillary transit time, whereas in severe stenosis, it redistributes blood from nonischemic to ischemic regions and reduces capillary flow heterogeneity.

Simulation of coronary capillary transit time based on full vascular model of the heart.

Capillary transit time (CTT) is a fundamental determinant of gas exchange between blood and tissues in the heart and other organs. Despite advances in experimental techniques, it remains difficult to measure coronary CTT in vivo. Here, we developed a novel computational framework that couples coronary microcirculation with cardiac mechanics in a closed-loop system that enables prediction of hemodynamics in the entire coronary network, including arteries, veins, and capillaries. We also developed a novel "particle-tracking" approach for computing CTT where "virtual tracers" are individually tracked as they traverse the capillary network. Model predictions compare well with blood pressure and flow rate distributions in the arterial network reported in previous studies. Model predictions of transit times in the capillaries (1.21 ± 1.5 s) and entire coronary network (11.8 ± 1.8 s) also agree with measurements. We show that, with increasing coronary artery stenosis (as quantified by fractional flow reserve, FFR), intravascular pressure and flow rate downstream are reduced but remain non-stationary even at 100 % stenosis because some flow (∼3 %) is redistributed from the non-occluded to the occluded territories. Importantly, the model predicts that occlusion of a large artery results in higher CTT. For moderate stenosis (FFR > 0.6), the increase in CTT (from 1.21 s without stenosis to 2.23 s at FFR=0.6) is caused by a decrease in capillary flow rate. In severe stenosis (FFR = 0.1), the increase in CTT to 14.2 s is due to both a decrease in flow rate and an increase in path length taken by "virtual tracers" in the capillary network.

Pre-arterialization of coronary veins prior to retroperfusion of ischemic myocardium: percutaneous closure device.

Background: Chronic coronary retroperfusion to treat myocardial ischemia has previously failed due to edema and hemorrhage of coronary veins suddenly exposed to arterial pressures. The objective of this study was to selectively adapt the coronary veins to become arterialized prior to coronary venous retroperfusion to avoid vascular edema and hemorrhage. Methods and results: In 32 animals (Group I = 19 and Group II = 13), the left anterior descending (LAD) artery was occluded using an ameroid occlusion model. In Group I, the great cardiac vein was blocked with suture ligation (Group IA = 11) or with occlusion device (Group IB = 8) to arterialize the venous system within 2 weeks at intermediate pressure (between arterial and venous levels) before a coronary venous bypass graft (CVBG) was implemented through a left internal mammary artery (LIMA) anastomosis. Group II only received the LAD artery occlusion and served as control. Serial echocardiograms showed recovery of left ventricular (LV) function with this adaptation-arterialization approach, with an increase in ejection fraction (EF) in Group I from 38% ± 5% after coronary occlusion to 53% ± 7% eight weeks after CVBG, whereas in Group II the EF never recovered (41% ± 2%-33% ± 7%). The remodeling of the venous system not only allowed restoration of myocardial function when CVBG was implemented but possibly promoted a novel form of "collateralization" between the native arterioles and the newly arterialized venules, which revascularized the ischemic myocardium. Conclusions: These findings form a potential rationale for a venous arterialization-revascularization treatment for the refractory angina and the "no-option" patients using a hybrid percutaneous (closure device for arterialization)/surgical approach (CVBG) to revascularize the myocardium.

An in silico study of the effects of left ventricular assist device on right ventricular function and inter-ventricular interaction.

BACKGROUND: Left ventricular assist device (LVAD) is associated with a high incidence of right ventricular (RV) failure, which is hypothesized to be caused by the occurring inter-ventricular interactions when the LV is unloaded. Factors contributing to these interactions are unknown. METHODS: We used computer modeling to investigate the impact of the HeartMate 3 LVAD on RV functions. The model was first calibrated against pressure-volume (PV) loops associated with a heart failure (HF) patient and validated against measurements of inter-ventricular interactions in animal experiments. The model was then applied to investigate the effects of LVAD on (1) RV chamber contractility indexed by V 60 derived from its end-systolic PV relationship, and (2) RV diastolic function indexed by V 20 derived from its end-diastolic PV relationship. We also investigated how septal wall thickness and regional contractility affect the impact of LVAD on RV function. RESULTS: The impact of LVAD on RV chamber contractility is small at a pump speed lower than 4k rpm. At a higher pump speed between 4k and 9k rpm, however, RV chamber contractility is reduced (by ~3% at 6k rpm and ~10% at 9k rpm). The reduction of RV chamber contractility is greater with a thinner septal wall or with a lower myocardial contractility at the LV free wall, septum, or RV free wall. CONCLUSION: RV chamber contractility is reduced at a pump speed higher than 4k rpm, and this reduction is greater with a thinner septal wall or lower regional myocardial contractility. Findings here may have clinical implications in identifying LVAD patients who may suffer from RV failure.

Mechanism of exercise intolerance in heart diseases predicted by a computer model of myocardial demand-supply feedback system.

BACKGROUND AND OBJECTIVE: The myocardial demand-supply feedback system plays an important role in augmenting blood supply in response to exercise-induced increased myocardial demand. During this feedback process, the myocardium and coronary blood flow interact bidirectionally at many different levels. METHODS: To investigate these interactions, a novel computational framework that considers the closed myocardial demand-supply feedback system was developed. In the framework coupling the systemic circulation of the left ventricle and coronary perfusion with regulation, myocardial work affects coronary perfusion via flow regulation mechanisms (e.g., metabolic regulation) and myocardial-vessel interactions, whereas coronary perfusion affects myocardial contractility in a closed feedback system. The framework was calibrated based on the measurements from healthy subjects under graded exercise conditions, and then was applied to simulate the effects of graded exercise on myocardial demand-supply under different physiological and pathological conditions. RESULTS: We found that the framework can recapitulate key features found during exercise in clinical and animal studies. We showed that myocardial blood flow is increased but maximum hyperemia is reduced during exercise, which led to a reduction in coronary flow reserve. For coronary stenosis and myocardial inefficiency, the model predicts that an increase in heart rate is necessary to maintain the baseline cardiac output. Correspondingly, the resting coronary flow reserve is exhausted and the range of heart rate before exhaustion of coronary flow reserve is reduced. In the presence of metabolic regulation dysfunction, the model predicts that the metabolic vasodilator signal is higher at rest, saturates faster during exercise, and as a result, causes quicker exhaustion of coronary flow reserve. CONCLUSIONS: Model predictions showed that the coronary flow reserve deteriorates faster during graded exercise, which in turn, suggests a decrease in exercise tolerance for patients with stenosis, myocardial inefficiency and metabolic flow regulation dysfunction. The findings in this study may have clinical implications in diagnosing cardiovascular diseases.

Optimization of cardiac resynchronization therapy based on a cardiac electromechanics-perfusion computational model.

Cardiac resynchronization therapy (CRT) is an established treatment for left bundle branch block (LBBB) resulting in mechanical dyssynchrony. Approximately 1/3 of patients with CRT, however, are non-responders. To understand factors affecting CRT response, an electromechanics-perfusion computational model based on animal-specific left ventricular (LV) geometry and coronary vascular networks located in the septum and LV free wall is developed. The model considers contractility-flow and preload-activation time relationships, and is calibrated to simultaneously match the experimental measurements in terms of the LV pressure, volume waveforms and total coronary flow in the left anterior descending and left circumflex territories from 2 swine models under right atrium and right ventricular pacing. The model is then applied to investigate the responses of CRT indexed by peak LV pressure and (dP/dt)max at multiple pacing sites with different degrees of perfusion in the LV free wall. Without the presence of ischemia, the model predicts that basal-lateral endocardial region is the optimal pacing site that can best improve (dP/dt)max by 20%, and is associated with the shortest activation time. In the presence of ischemia, a non-ischemic region becomes the optimal pacing site when coronary flow in the ischemic region fell below 30% of its original value. Pacing at the ischemic region produces little response at that perfusion level. The optimal pacing site is associated with one that optimizes the LV activation time. These findings suggest that CRT response is affected by both pacing site and coronary perfusion, which may have clinical implication in improving CRT responder rates.

Transmural Distribution of Coronary Perfusion and Myocardial Work Density Due to Alterations in Ventricular Loading, Geometry and Contractility.

Myocardial supply changes to accommodate the variation of myocardial demand across the heart wall to maintain normal cardiac function. A computational framework that couples the systemic circulation of a left ventricular (LV) finite element model and coronary perfusion in a closed loop is developed to investigate the transmural distribution of the myocardial demand (work density) and supply (perfusion) ratio. Calibrated and validated against measurements of LV mechanics and coronary perfusion, the model is applied to investigate changes in the transmural distribution of passive coronary perfusion, myocardial work density, and their ratio in response to changes in LV contractility, preload, afterload, wall thickness, and cavity volume. The model predicts the following: (1) Total passive coronary flow varies from a minimum value at the endocardium to a maximum value at the epicardium transmurally that is consistent with the transmural distribution of IMP; (2) Total passive coronary flow at different transmural locations is increased with an increase in either contractility, afterload, or preload of the LV, whereas is reduced with an increase in wall thickness or cavity volume; (3) Myocardial work density at different transmural locations is increased transmurally with an increase in either contractility, afterload, preload or cavity volume of the LV, but is reduced with an increase in wall thickness; (4) Myocardial work density-perfusion mismatch ratio at different transmural locations is increased with an increase in contractility, preload, wall thickness or cavity volume of the LV, and the ratio is higher at the endocardium than the epicardium. These results suggest that an increase in either contractility, preload, wall thickness, or cavity volume of the LV can increase the vulnerability of the subendocardial region to ischemia.

Role of coronary flow regulation and cardiac-coronary coupling in mechanical dyssynchrony associated with right ventricular pacing.

Mechanical dyssynchrony (MD) affects left ventricular (LV) mechanics and coronary perfusion. To understand the multifactorial effects of MD, we developed a computational model that bidirectionally couples the systemic circulation with the LV and coronary perfusion with flow regulation. In the model, coronary flow in the left anterior descending (LAD) and left circumflex (LCX) arteries affects the corresponding regional contractility based on a prescribed linear LV contractility-coronary flow relationship. The model is calibrated with experimental measurements of LV pressure and volume, as well as LAD and LCX flow rate waveforms acquired under regulated and fully dilated conditions from a swine under right atrial (RA) pacing. The calibrated model is applied to simulate MD. The model can simultaneously reproduce the reduction in mean LV pressure (39.3%), regulated flow (LAD: 7.9%; LCX: 1.9%), LAD passive flow (21.6%), and increase in LCX passive flow (15.9%). These changes are associated with right ventricular pacing compared with RA pacing measured in the same swine only when LV contractility is affected by flow alterations with a slope of 1.4 mmHg/mL2 in a contractility-flow relationship. In sensitivity analyses, the model predicts that coronary flow reserve (CFR) decreases and increases in the LAD and LCX with increasing delay in LV free wall contraction. These findings suggest that asynchronous activation associated with MD impacts 1) the loading conditions that further affect the coronary flow, which may explain some of the changes in CFR, and 2) the coronary flow that reduces global contractility, which contributes to the reduction in LV pressure.NEW & NOTEWORTHY A computational model that couples the systemic circulation of the left ventricular (LV) and coronary perfusion with flow regulation is developed to study the effects of mechanical dyssynchrony. The delayed contraction in the LV free wall with respect to the septum has a significant effect on LV function and coronary flow reserve.