Joost Lumens

Right heart adaptation to pulmonary arterial hypertension: physiology and pathobiology.

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 underlying 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.

Three-Wall Segment (TriSeg) Model Describing Mechanics and Hemodynamics of Ventricular Interaction

A mathematical model (TriSeg model) of ventricular mechanics incorporating mechanical interaction of the left and right ventricular free walls and the interventricular septum is presented. Global left and right ventricular pump mechanics were related to representative myofiber mechanics in the three ventricular walls, satisfying the principle of conservation of energy. The walls were mechanically coupled satisfying tensile force equilibrium in the junction. Wall sizes and masses were rendered by adaptation to normalize mechanical myofiber load to physiological standard levels. The TriSeg model was implemented in the previously published lumped closed-loop CircAdapt model of heart and circulation. Simulation results of cardiac mechanics and hemodynamics during normal ventricular loading, acute pulmonary hypertension, and chronic pulmonary hypertension (including load adaptation) agreed with clinical data as obtained in healthy volunteers and pulmonary hypertension patients. In chronic pulmonary hypertension, the model predicted right ventricular free wall hypertrophy, increased systolic pulmonary flow acceleration, and increased right ventricular isovolumic contraction and relaxation times. Furthermore, septal curvature decreased linearly with its transmural pressure difference. In conclusion, the TriSeg model enables realistic simulation of ventricular mechanics including interaction between left and right ventricular pump mechanics, dynamics of septal geometry, and myofiber mechanics in the three ventricular walls.

Septal Deformation Patterns Delineate Mechanical Dyssynchrony and Regional Differences in Contractility: Analysis of Patient Data Using a Computer Model

Background— Response to cardiac resynchronization therapy depends both on dyssynchrony and (regional) contractility. We hypothesized that septal deformation can be used to infer integrated information on dyssynchrony and regional contractility, and thereby predict cardiac resynchronization therapy response. Methods and Results— In 132 cardiac resynchronization therapy candidates with left bundle branch block (LBBB)-like electrocardiogram morphology (left ventricular ejection fraction 19±6%; QRS width 170±23 ms), longitudinal septal strain was assessed by speckle tracking echocardiography. To investigate the effects of dyssynchronous activation and differences in septal and left ventricular free wall contractility on septal deformation pattern, we used the CircAdapt computer model of the human heart and circulation. In the patients, 3 characteristic septal deformation patterns were identified: LBBB-1=double-peaked systolic shortening (n=28); LBBB-2=early systolic shortening followed by prominent systolic stretching (n=34); and LBBB-3=pseudonormal shortening with less pronounced late systolic stretch (n=70). LBBB-3 revealed more scar (2 [2–5] segments) compared with LBBB-1 and LBBB-2 (both 0 [0–1], P<0.05). In the model, imposing a time difference of activation between septum and left ventricular free wall resulted in pattern LBBB-1. This transformed into pattern LBBB-2 by additionally simulating septal hypocontractility, and into pattern LBBB-3 by imposing additional left ventricular free wall or global left ventricular hypocontractility. Improvement of left ventricular ejection fraction and reduction of left ventricular volumes after cardiac resynchronization therapy were most pronounced in LBBB-1 and worst in LBBB-3 patients. Conclusions— A double-peaked systolic septal deformation pattern is characteristic for LBBB and results from intraventricular dyssynchrony. Abnormal contractility modifies this pattern. A computer model can be helpful in understanding septal deformation and predicting cardiac resynchronization therapy response.

Cardiac resynchronization: Insight from experimental and computational models

Cardiac resynchronization therapy (CRT) is a promising therapy for heart failure patients with a conduction disturbance, such as left bundle branch block. The aim of CRT is to resynchronize contraction between and within ventricles. However, about 30% of patients do not respond to this therapy. Therefore, a better understanding is needed for the relation between electrical and mechanical activation. In this paper, we focus on to what extent animal experiments and mathematical models can help in order to understand the pathophysiology of asynchrony to further improve CRT.

Comparative Electromechanical and Hemodynamic Effects of Left Ventricular and Biventricular Pacing in Dyssynchronous Heart Failure: Electrical Resynchronization Versus Left–Right Ventricular Interaction

OBJECTIVES The purpose of this study was to enhance understanding of the working mechanism of cardiac resynchronization therapy by comparing animal experimental, clinical, and computational data on the hemodynamic and electromechanical consequences of left ventricular pacing (LVP) and biventricular pacing (BiVP). BACKGROUND It is unclear why LVP and BiVP have comparative positive effects on hemodynamic function of patients with dyssynchronous heart failure. METHODS Hemodynamic response to LVP and BiVP (% change in maximal rate of left ventricular pressure rise [LVdP/dtmax]) was measured in 6 dogs and 24 patients with heart failure and left bundle branch block followed by computer simulations of local myofiber mechanics during LVP and BiVP in the failing heart with left bundle branch block. Pacing-induced changes of electrical activation were measured in dogs using contact mapping and in patients using a noninvasive multielectrode electrocardiographic mapping technique. RESULTS LVP and BiVP similarly increased LVdP/dtmax in dogs and in patients, but only BiVP significantly decreased electrical dyssynchrony. In the simulations, LVP and BiVP increased total ventricular myofiber work to the same extent. While the LVP-induced increase was entirely due to enhanced right ventricular (RV) myofiber work, the BiVP-induced increase was due to enhanced myofiber work of both the left ventricle (LV) and RV. Overall, LVdP/dtmax correlated better with total ventricular myofiber work than with LV or RV myofiber work alone. CONCLUSIONS Animal experimental, clinical, and computational data support the similarity of hemodynamic response to LVP and BiVP, despite differences in electrical dyssynchrony. The simulations provide the novel insight that, through ventricular interaction, the RV myocardium importantly contributes to the improvement in LV pump function induced by cardiac resynchronization therapy.

Septal Deformation Patterns Delineate Mechanical Dyssynchrony and Regional Differences in ContractilityClinical Perspective

Background— Response to cardiac resynchronization therapy depends both on dyssynchrony and (regional) contractility. We hypothesized that septal deformation can be used to infer integrated information on dyssynchrony and regional contractility, and thereby predict cardiac resynchronization therapy response. Methods and Results— In 132 cardiac resynchronization therapy candidates with left bundle branch block (LBBB)-like electrocardiogram morphology (left ventricular ejection fraction 19±6%; QRS width 170±23 ms), longitudinal septal strain was assessed by speckle tracking echocardiography. To investigate the effects of dyssynchronous activation and differences in septal and left ventricular free wall contractility on septal deformation pattern, we used the CircAdapt computer model of the human heart and circulation. In the patients, 3 characteristic septal deformation patterns were identified: LBBB-1=double-peaked systolic shortening (n=28); LBBB-2=early systolic shortening followed by prominent systolic stretching (n=34); and LBBB-3=pseudonormal shortening with less pronounced late systolic stretch (n=70). LBBB-3 revealed more scar (2 [2–5] segments) compared with LBBB-1 and LBBB-2 (both 0 [0–1], P<0.05). In the model, imposing a time difference of activation between septum and left ventricular free wall resulted in pattern LBBB-1. This transformed into pattern LBBB-2 by additionally simulating septal hypocontractility, and into pattern LBBB-3 by imposing additional left ventricular free wall or global left ventricular hypocontractility. Improvement of left ventricular ejection fraction and reduction of left ventricular volumes after cardiac resynchronization therapy were most pronounced in LBBB-1 and worst in LBBB-3 patients. Conclusions— A double-peaked systolic septal deformation pattern is characteristic for LBBB and results from intraventricular dyssynchrony. Abnormal contractility modifies this pattern. A computer model can be helpful in understanding septal deformation and predicting cardiac resynchronization therapy response.

Mechanistic Evaluation of Echocardiographic Dyssynchrony Indices Patient Data Combined With Multiscale Computer Simulations

Background— The power of echocardiographic dyssynchrony indices to predict response to cardiac resynchronization therapy (CRT) appears to vary between indices and between studies. We investigated whether the variability of predictive power between the dyssynchrony indices can be explained by differences in their operational definitions. Methods and Results— In 132 CRT-candidates (left ventricular [LV] ejection fraction, 19 ± 6%; QRS width, 170 ± 22 ms), 4 mechanical dyssynchrony indices (septal systolic rebound stretch [SRSsept], interventricular mechanical dyssynchrony [IVMD], septal-to-lateral peak shortening delay [Strain-SL], and septal-to-posterior wall motion delay [SPWMD]) were quantified at baseline. CRT response was quantified as 6-month percent change of LV end-systolic volume. Multiscale computer simulations of cardiac mechanics and hemodynamics were used to assess the relationships between dyssynchrony indices and CRT response within wide ranges of dyssynchrony of LV activation and reduced contractility. In patients, SRSsept showed best correlation with CRT response followed by IVMD, Strain-SL, and SPWMD (R=−0.56, −0.50, −0.48, and −0.39, respectively; all P<0.01). In patients and simulations, SRSsept and IVMD showed a continuous linear relationship with CRT response, whereas Strain-SL and SPWMD showed discontinuous relationships characterized by data clusters. Model simulations revealed that this data clustering originated from the complex multipeak pattern of septal strain and motion. In patients and simulations with (simulated) LV scar, SRSsept and IVMD retained their linear relationship with CRT response, whereas Strain-SL and SPWMD did not. Conclusions— The power to predict CRT response differs between indices of mechanical dyssynchrony. SRSsept and IVMD better represent LV dyssynchrony amenable to CRT and better predict CRT response than the indices assessing time-to-peak deformation or motion.Background— The power of echocardiographic dyssynchrony indices to predict response to cardiac resynchronization therapy (CRT) appears to vary between indices and between studies. We investigated whether the variability of predictive power between the dyssynchrony indices can be explained by differences in their operational definitions. Methods and Results— In 132 CRT-candidates (left ventricular [LV] ejection fraction, 19 ± 6%; QRS width, 170 ± 22 ms), 4 mechanical dyssynchrony indices (septal systolic rebound stretch [SRSsept], interventricular mechanical dyssynchrony [IVMD], septal-to-lateral peak shortening delay [Strain-SL], and septal-to-posterior wall motion delay [SPWMD]) were quantified at baseline. CRT response was quantified as 6-month percent change of LV end-systolic volume. Multiscale computer simulations of cardiac mechanics and hemodynamics were used to assess the relationships between dyssynchrony indices and CRT response within wide ranges of dyssynchrony of LV activation and reduced contractility. In patients, SRSsept showed best correlation with CRT response followed by IVMD, Strain-SL, and SPWMD ( R =−0.56, −0.50, −0.48, and −0.39, respectively; all P <0.01). In patients and simulations, SRSsept and IVMD showed a continuous linear relationship with CRT response, whereas Strain-SL and SPWMD showed discontinuous relationships characterized by data clusters. Model simulations revealed that this data clustering originated from the complex multipeak pattern of septal strain and motion. In patients and simulations with (simulated) LV scar, SRSsept and IVMD retained their linear relationship with CRT response, whereas Strain-SL and SPWMD did not. Conclusions— The power to predict CRT response differs between indices of mechanical dyssynchrony. SRSsept and IVMD better represent LV dyssynchrony amenable to CRT and better predict CRT response than the indices assessing time-to-peak deformation or motion.

Differentiating Electromechanical From Non-Electrical Substrates of Mechanical Discoordination to Identify Responders to Cardiac Resynchronization Therapy.

Background—Left ventricular (LV) mechanical discoordination, often referred to as dyssynchrony, is often observed in patients with heart failure regardless of QRS duration. We hypothesized that different myocardial substrates for LV mechanical discoordination exist from (1) electromechanical activation delay, (2) regional differences in contractility, or (3) regional scar and that we could differentiate electromechanical substrates responsive to cardiac resynchronization therapy (CRT) from unresponsive non–electrical substrates. Methods and Results—First, we used computer simulations to characterize mechanical discoordination patterns arising from electromechanical and non–electrical substrates and accordingly devise the novel systolic stretch index (SSI), as the sum of posterolateral systolic prestretch and septal systolic rebound stretch. Second, 191 patients with heart failure (QRS duration ≥120 ms; LV ejection fraction ⩽35%) had baseline SSI quantified by automated echocardiographic radial strain analysis. Patients with SSI≥9.7% had significantly less heart failure hospitalizations or deaths 2 years after CRT (hazard ratio, 0.32; 95% confidence interval, 0.19–0.53; P<0.001) and less deaths, transplants, or LV assist devices (hazard ratio, 0.28; 95% confidence interval, 0.15–0.55; P<0.001). Furthermore, in a subgroup of 113 patients with intermediate electrocardiographic criteria (QRS duration of 120–149 ms or non–left bundle branch block), SSI≥9.7% was independently associated with significantly less heart failure hospitalizations or deaths (hazard ratio, 0.41; 95% confidence interval, 0.23–0.79; P=0.004) and less deaths, transplants, or LV assist devices (hazard ratio, 0.27; 95% confidence interval, 0.12–0.60; P=0.001). Conclusions—Computer simulations differentiated patterns of LV mechanical discoordination caused by electromechanical substrates responsive to CRT from those related to regional hypocontractility or scar unresponsive to CRT. The novel SSI identified patients who benefited more favorably from CRT, including those with intermediate electrocardiographic criteria, where CRT response is less certain by ECG alone.

Right ventricular free wall pacing improves cardiac pump function in severe pulmonary arterial hypertension: a computer simulation analysis

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.

Electrical dyssynchrony induced by biventricular pacing: Implications for patient selection and therapy improvement

BACKGROUND Biventricular pacing (BVP) may not achieve complete electrical resynchronization. OBJECTIVE The purpose of this study was to assess whether the resynchronizing effect of BVP varies among patients depending on the underlying electrical substrate. METHODS High-resolution electrocardiographic mapping with invasive measurement of the maximal rate of systolic left ventricular (LV) pressure rise (LVdP/dtmax) was performed during baseline activation and during BVP in 61 patients with heart failure with various conduction delays: 13 with narrow QRS duration (<120 ms), 22 with nonspecific intraventricular conduction disturbance, and 26 with left bundle branch block. Electrical dyssynchrony, both during baseline activation and BVP, was quantified by total and LV activation times (TAT and LVTAT) and by ventricular electrical uncoupling (VEU = mean LVTAT - mean right ventricular activation time). Response to BVP was defined as a ≥10% increase in LVdP/dtmax. RESULTS The electrical activation pattern during BVP was similar for all patient groups and, hence, not dependent on baseline conduction disturbance. During BVP, TAT, LVTAT, and VEU were similar for all groups and were either not correlated or weakly correlated with the change in LVdP/dtmax. In contrast, changes in electrical dyssynchrony correlated significantly with the change in LVdP/dtmax: r=0.71, 0.69, and 0.69 for ∆TAT, ∆LVTAT, and ∆VEU, respectively (all P < .001). Responders showed higher baseline dyssynchrony levels and BVP-induced dyssynchrony reduction than did nonresponders (all P < .001); in nonresponders, BVP worsened activation times than did baseline activation. CONCLUSION BVP does not eliminate electrical dyssynchrony, but rather brings it to a common level independent of the patients underlying electrical substrate. Therefore, BVP is of benefit to patients with dyssynchrony but not to patients with insufficient electrical dyssynchrony in whom it induces an iatrogenic electropathy.