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Aims: Cardiac resynchronization therapy (CRT) may exert its beneficial haemodynamic effect by improving ventricular synchrony and improving atrioventricular (AV) timing. The aim of this study was to establish the relative importance of the mechanisms through which CRT improves cardiac function and explore the potential for additional improvements with improved ventricular resynchronization., Methods and Results: We performed simulations using the CircAdapt haemodynamic model and performed haemodynamic measurements while adjusting AV delay, at low and high heart rates, in 87 patients with CRT devices. We assessed QRS duration, presence of fusion, and haemodynamic response. The simulations suggest that intrinsic PR interval and the magnitude of reduction in ventricular activation determine the relative importance of the mechanisms of benefit. For example, if PR interval is 201 ms and LV activation time is reduced by 25 ms (typical for current CRT methods), then AV delay optimization is responsible for 69% of overall improvement. Reducing LV activation time by an additional 25 ms produced an additional 2.6 mmHg increase in blood pressure (30% of effect size observed with current CRT). In the clinical population, ventricular fusion significantly shortened QRS duration (Δ-27 ± 23 ms, P < 0.001) and improved systolic blood pressure (mean 2.5 mmHg increase). Ventricular fusion was present in 69% of patients, yet in 40% of patients with fusion, shortening AV delay (to a delay where fusion was not present) produced the optimal haemodynamic response., Conclusions: Improving LV preloading by shortening AV delay is an important mechanism through which cardiac function is improved with CRT. There is substantial scope for further improvement if methods for delivering more efficient ventricular resynchronization can be developed., Clinical Trial Registration: Our clinical data were obtained from a subpopulation of the British Randomised Controlled Trial of AV and VV Optimisation (BRAVO), which is a registered clinical trial with unique identifier: NCT01258829, https://clinicaltrials.gov., (© The Author 2016. Published by Oxford University Press on behalf of the European Society of Cardiology.)

Aims: Cardiac resynchronization therapy (CRT) produces clinical benefits in chronic heart failure patients with left bundle-branch block (LBBB). The position of the pacing site on the left ventricle (LV) is considered an important determinant of CRT response, but the mechanism how the LV pacing site determines CRT response is not completely understood. The objective of this study is to investigate the relation between LV pacing site during biventricular (BiV) pacing and cardiac function., Methods and Results: We used a finite element model of BiV electromechanics. Cardiac function, assessed as LV dp/dt max and stroke work, was evaluated during normal electrical activation, typical LBBB, fascicular blocks and BiV pacing with different LV pacing sites. The model replicated clinical observations such as increase of LV dp/dt max and stroke work, and the disappearance of a septal flash during BiV pacing. The largest hemodynamic response was achieved when BiV pacing led to best resynchronization of LV electrical activation but this did not coincide with reduction in total BiV activation time (∼ QRS duration). Maximum response was achieved when pacing the mid-basal lateral wall and this was close to the latest activated region during intrinsic activation in the typical LBBB, but not in the fascicular block simulations., Conclusions: In these model simulations, the best cardiac function was obtained when pacing the mid-basal LV lateral wall, because of fastest recruitment of LV activation. This study illustrates how computer modeling can shed new light on optimizing pacing therapies for CRT. The results from this study may help to design new clinical studies to further investigate the importance of the pacing site for CRT response., (Published on behalf of the European Society of Cardiology. All rights reserved. © The Author 2016. For Permissions, please email: journals.permissions@oup.com.)

Mathematical or computer models have become increasingly popular in biomedical science. Although they are a simplification of reality, computer models are able to link a multitude of processes to each other. In the fields of cardiac physiology and cardiology, models can be used to describe the combined activity of all ion channels (electrical models) or contraction-related processes (mechanical models) in potentially millions of cardiac cells. Electromechanical models go one step further by coupling electrical and mechanical processes and incorporating mechano-electrical feedback. The field of cardiac computer modelling is making rapid progress due to advances in research and the ever-increasing calculation power of computers. Computer models have helped to provide better understanding of disease mechanisms and treatment. The ultimate goal will be to create patient-specific models using diagnostic measurements from the individual patient. This paper gives a brief overview of computer models in the field of cardiology and mentions some scientific achievements and clinical applications, especially in relation to cardiac resynchronisation therapy (CRT).

Aims: It is unclear how the position of the left ventricular (LV) lead relative to a scar affects the haemodynamic response in patients with dyssynchronous heart failure receiving cardiac resynchronization therapy. We investigated this complex interaction using a computational model., Methods and Results: The CircAdapt computational cardiovascular system model was used to simulate heart failure with left bundle branch block (LBBB). Myocardial scar was induced in four different regions of the LV free wall (LVFW). We then simulated biventricular pacing (BVP) in each heart, in which LV lead position was varied. The LV lead position leading to maximal acute change in LV stroke volume (SV) was defined as optimal lead position. In LBBB without scar, SV increase was maximal when pacing the LVFW region most distant from the septum. With a scar adjacent to the septum, maximal response was achieved when pacing remote from both the septum and the scar. When the scar was located further from the septum, the BVP-induced increase of SV was small. For all hearts, pacing from the optimal LV lead position resulted in the most homogeneous distribution of local ventricular myofibre work and the largest increase in summed left and right ventricular pump work., Conclusions: These computer simulations suggest that, in hearts with LBBB and scar, the optimal LV lead position is a compromise between a position distant from the scar and from the septum. In infarcted hearts, the best haemodynamic effect is achieved when electromechanical resynchronization of the remaining viable myocardium is most effective., (Published on behalf of the European Society of Cardiology. All rights reserved. © The Author 2014. For permissions please email: journals.permissions@oup.com.)

Survival in patients with pulmonary arterial hypertension (PAH) is closely related to right ventricular (RV) function. Although pulmonary load is an important determinant of RV systolic function in PAH, there remains a significant variability in RV adaptation to pulmonary hypertension. In this report, the authors discuss the emerging concepts of right heart pathobiology in PAH. More specifically, the discussion focuses on the following questions. 1) How is right heart failure syndrome best defined? 2) What are the uderlying molecular mechanisms of the failing right ventricle in PAH? 3) How are RV contractility and function and their prognostic implications best assessed? 4) What is the role of targeted RV therapy? Throughout the report, the authors highlight differences between right and left heart failure and outline key areas of future investigation. (J Am Coll Cardiol 2013;62:D22-33) a 2013 by the American College of Cardiology Foundation).

At present, it is unknown why patients suffering from severe pulmonary hypertension (PH) benefit from atrial septostomy (AS). Suggested mechanisms include enhanced filling of the left ventricle, reduction of right ventricular preload, increased oxygen availability in the peripheral tissue, or a combination. A multiscale computational model of the cardiovascular system was used to assess the effects of AS in PH. Our model simulates beat-to-beat dynamics of the four cardiac chambers with valves and the systemic and pulmonary circulations, including an atrial septal defect (ASD). Oxygen saturation was computed for each model compartment. The acute effect of AS on systemic flow and oxygen delivery in PH was assessed by a series of simulations with combinations of different ASD diameters, pulmonary flows, and degrees of PH. In addition, blood pressures at rest and during exercise were compared between circulations with PH before and after AS. If PH did not result in a right atrial pressure exceeding the left one, AS caused a left-to-right shunt flow that resulted in decreased oxygenation and a further increase of right ventricular pump load. Only in the case of severe PH a right-to-left shunt flow occurred during exercise, which improved left ventricular preload reserve and maintained blood pressure but did not improve oxygenation. AS only improves symptoms of right heart failure in patients with severe PH if net right-to-left shunt flow occurs during exercise. This flow enhances left ventricular filling, allows blood pressure maintenance, but does not increase oxygen availability in the peripheral tissue.

Chronic thromboembolic pulmonary hypertension (CTEPH) is associated with abnormal left ventricular (LV) filling hemodynamics [mitral early passive filling wave velocity/late active filling wave velocity (E/A) < 1]. Pulmonary endarterectomy (PEA) acutely reduces pulmonary vascular resistance, resulting in an increase of mitral E/A. The abolishment of leftward septal bulging and an increase in right ventricular (RV) output are thought to be responsible for the increase of mitral E/A. In this study, we quantified the separate effects of leftward septal bulging and RV output on LV hemodynamics. In 39 CTEPH patients who underwent PEA, transmitral flow velocities and RV hemodynamic data were obtained pre- and postoperatively. A mathematical model describing the mechanics of ventricular interaction was fitted to the preoperative average values of cardiac output (CO; 4.4 l/min), mean pulmonary artery pressure (mPAP; 50 mmHg), mitral E/A (0.74), and mean left atrial pressure (mLAP; 9.8 mmHg). Starting from this preoperative reference state with leftward septal bulging, PEA was simulated by changing mPAP and CO to average postoperative values (28 mmHg and 5.7 l/min, respectively). Simulated and postoperatively measured data on E/A (1.27 vs. 1.48), mLAP (12.6 vs. 11.5 mmHg), and septal curvature (both rightward) were consistent. When an exclusive decrease of mPAP was simulated, mitral E/A increased 26%, mLAP decreased 16%, and septal curvature became rightward. When an exclusive increase of CO was simulated, mitral E/A increased 53% and mLAP increased 62%, whereas leftward septal bulging persisted. Thus, our simulations suggest that the increase of mitral E/A with PEA is caused two-thirds by an increase of RV output and one-third by the abolishment of leftward septal bulging.

In pulmonary arterial hypertension (PAH), duration of myofiber shortening is prolonged in the right ventricular (RV) free wall (RVfw) compared with that in the interventricular septum and left ventricular free wall. This interventricular mechanical asynchrony eventually leads to right heart failure. We investigated by computer simulation whether, in PAH, early RVfw pacing may improve interventricular mechanical synchrony and, hence, cardiac pump function. A mathematical model of the human heart and circulation was used to simulate left ventricular and RV pump mechanics and myofiber mechanics. First, we simulated cardiovascular mechanics of a healthy adult at rest. Size and mass of heart and blood vessels were adapted so that mechanical tissue load was normalized. Second, compensated PAH was simulated by increasing mean pulmonary artery pressure to 32 mmHg while applying load adaptation. Third, decompensated PAH was simulated by increasing mean pulmonary artery pressure further to 79 mmHg without further adaptation. Finally, early RVfw pacing was simulated in severely decompensated PAH. Time courses of circumferential strain in the ventricular walls as simulated were similar to the ones measured in healthy subjects (uniform strain patterns) and in PAH patients (prolonged RVfw shortening). When simulating pacing in decompensated PAH, RV pump function was best upon 40-ms RVfw preexcitation, as evidenced by maximal decrease of RV end-diastolic volume, reduced RVfw myofiber work, and most homogeneous distribution of workload over the ventricular walls. Thus our simulations indicate that, in decompensated PAH, RVfw pacing may improve RV pump function and may homogenize workload over the ventricular walls.

Direct ventricular interaction via the interventricular septum plays an important role in ventricular hemodynamics and mechanics. A large amount of experimental data demonstrates that left and right ventricular pump mechanics influence each other and that septal geometry and motion depend on transmural pressure. We present a lumped model of ventricular mechanics consisting of three wall segments that are coupled on the basis of balance laws stating mechanical equilibrium at the intersection of the three walls. The input consists of left and right ventricular volumes and an estimate of septal wall geometry. Wall segment geometry is expressed as area and curvature and is related to sarcomere extension. With constitutive equations of the sarcomere, myofiber stress is calculated. The force exerted by each wall segment on the intersection, as a result of wall tension, is derived from myofiber stress. Finally, septal geometry and ventricular pressures are solved by achieving balance of forces. We implemented this ventricular module in a lumped model of the closed-loop cardiovascular system (CircAdapt model) The resulting multiscale model enables dynamic simulation of myofiber mechanics, ventricular cavity mechanics, and cardiovascular system hemodynamics. The model was tested by performing simulations with synchronous and asynchronous mechanical activation of the wall segments. The simulated results of ventricular mechanics and hemodynamics were compared with experimental data obtained before and after acute induction of left bundle branch block (LBBB) in dogs. The changes in simulated ventricular mechanics and septal motion as a result of the introduction of mechanical asynchrony were very similar to those measured in the animal experiments. In conclusion, the module presented describes ventricular mechanics including direct ventricular interaction realistically and thereby extends the physiological application range of the CircAdapt model.