Peter R. Huntjens

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.

Influence of left ventricular lead position relative to scar location on response to cardiac resynchronization therapy: a model study.

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.

Septal flash and septal rebound stretch have different underlying mechanisms

Abnormal left-right motion of the interventricular septum in early systole, known as septal flash (SF), is frequently observed in patients with left bundle branch block (LBBB). Transseptal pressure gradient and early active septal contraction have been proposed as explanations for SF. Similarities in timing (early systole) and location (septum) suggest that SF may be related to septal systolic rebound stretch (SRSsept). We aimed to clarify the mechanisms generating SF and SRSsept. The CircAdapt computer model was used to isolate the effects of timing of activation of the left ventricular free wall (LVFW), right ventricular free wall (RVFW), and septum on SF and SRSsept. LVFW and septal activation times were varied by ±80 ms relative to RVFW activation time. M-mode-derived wall motions and septal strains were computed and used to quantify SF and SRSsept, respectively. SF depended on early activation of the RVFW relative to the LVFW. SF and SRSsept occurred in LBBB-like simulations and against a rising transseptal pressure gradient. When the septum was activated before both LVFW and RVFW, no SF occurred despite the presence of SRSsept. Computer simulations therefore indicate that SF and SRSsept have different underlying mechanisms, even though both can occur in LBBB. The mechanism of leftward motion during SF is early RVFW contraction pulling on and straightening the septum when unopposed by the LVFW. SRSsept is caused by late LVFW contraction following early contraction of the septum. Changes in transseptal pressure gradient are not the main cause of SF in LBBB.

Cardiovascular magnetic resonance features of mechanical dyssynchrony in patients with left bundle branch block

Patients with left bundle branch block (LBBB) can exhibit mechanical dyssynchrony which may contribute to heart failure; such patients may benefit from cardiac resynchronization treatment (CRT). While cardiac magnetic resonance imaging (CMR) has become a common part of heart failure work-up, CMR features of mechanical dyssynchrony in patients with LBBB have not been well characterized. This study aims to investigate the potential of CMR to characterize mechanical features of LBBB. CMR examinations from 43 patients with LBBB on their electrocardiogram, but without significant focal structural abnormalities, and from 43 age- and gender-matched normal controls were retrospectively reviewed. The following mechanical features of LBBB were evaluated: septal flash (SF), apical rocking (AR), delayed aortic valve opening measured relative to both end-diastole (AVOED) and pulmonic valve opening (AVOPVO), delayed left-ventricular (LV) free-wall contraction, and curvatures of the septum and LV free-wall. Septal displacement curves were also generated, using feature-tracking techniques. The echocardiographic findings of LBBB were also reviewed in those subjects for whom they were available. LBBB was significantly associated with the presence of SF and AR; within the LBBB group, 79 % had SF and 65 % had AR. Delayed AVOED, AVOPVO, and delayed LV free-wall contraction were significantly associated with LBBB. AVOED and AVOPVO positively correlated with QRS duration and negatively correlated with ejection fraction. Hearts with electrocardiographic evidence of LBBB showed lower septal-to-LV free-wall curvature ratios at end-diastole compared to normal controls. CMR can be used to identify and evaluate mechanical dyssynchrony in patients with LBBB. None of the normal controls showed the mechanical features associated with LBBB. Moreover, not all patients with LBBB showed the same degree of mechanical dyssynchrony, which could have implications for CRT.

Assessment of Septal Motion Abnormalities in Left Bundle Branch Block Patients Using Computer Simulations

Septal Flash (SF) is a rapid leftward – rightward motion of the septal wall during the isovolumic contraction phase that is frequently but not always observed in heart failure patients with left bundle branch block (LBBB). The goal of the present study is to evaluate the feasibility of detecting SF by assessing septal curvature both in patients with LBBB using MRI and in simulations using the CircAdapt model of the heart and circulation. In both patients and simulations, SF was characterized by a decrease of septal wall curvature and septum to lateral wall distance, followed by a rapid increase prior to aortic valve opening. Additionally, computer simulations revealed that SF can be explained by an intra-left ventricular (septal-to-lateral wall) activation delay. Reducing contractility in the left ventricular free wall abolished the rightward SF motion in LBBB. This finding suggests that lack of SF may indicate co-morbidities that can result in non-response to cardiac resynchronization therapy.

Electrical Substrates Driving Response to Cardiac Resynchronization Therapy: A Combined Clinical–Computational Evaluation

Background: The predictive value of interventricular versus intraventricular dyssynchrony for response to cardiac resynchronization therapy (CRT) remains unclear. We investigated the relative importance of both ventricular electrical substrate components for left ventricular (LV) hemodynamic function. Methods and Results: First, we used the cardiovascular computational model CircAdapt to characterize the isolated effect of intrinsic interventricular and intraventricular activation on CRT response (&Dgr;LVdP/dtmax). Simulated &Dgr;LVdP/dtmax (range: 1.3%–26.5%) increased considerably with increasing interventricular dyssynchrony. In contrast, the isolated effect of intraventricular dyssynchrony in either the LV or right ventricle was limited (&Dgr;LVdP/dtmax range: 12.3%–18.3% and 14.1%–15.7%, respectively). Effects of activation during biventricular pacing on &Dgr;LVdP/dtmax were small. Second, electrocardiographic imaging–derived activation characteristics of 51 CRT candidates were used to personalize ventricular activation in CircAdapt. The individualized models were subsequently used to assess the accuracy of &Dgr;LVdP/dtmax prediction based on the electrical data. The model-predicted &Dgr;LVdP/dtmax was close to the actual value in patients with left bundle branch block (measured−simulated: 2.7±9.0%) when only intrinsic interventricular dyssynchrony was personalized. Among patients without left bundle branch block, &Dgr;LVdP/dtmax was systematically overpredicted by CircAdapt (measured−simulated: 9.2±7.1%). Adding intraventricular activation to the model did not improve the accuracy of the response prediction. Conclusions: Computer simulations revealed that intrinsic interventricular dyssynchrony is the dominant component of the electrical substrate driving the response to CRT. Intrinsic intraventricular dyssynchrony and any dyssynchrony during biventricular pacing play a minor role in this respect. This may facilitate patient-specific modeling for prediction of CRT response. Clinical Trial Registration: URL: https://www.clinicaltrials.gov. Unique identifier: NCT01270646.

Response to cardiac resynchronization therapy is determined by intrinsic electrical substrate rather than by its modification

BACKGROUND Electrocardiographic mapping (ECM) expresses electrical substrate through magnitude and direction of the activation delay vector (ADV). We investigated to what extent the response to cardiac resynchronization therapy (CRT) is determined by baseline ADV and by ADV modification through CRT and optimization of left ventricular (LV) pacing site. METHODS ECM was performed in 79 heart failure patients (4 RBBB, 12 QRS < 120 ms, 23 non-specific conduction delay [NICD] and 40 left bundle branch block [LBBB]). 67 patients (QRS ≥ 120 ms) underwent CRT implantation and in 26 patients multiple LV pacing site optimization was performed. ADV was calculated from locations/depolarization times of 2000 virtual epicardial electrodes derived from ECM. Acute response was defined as ≥10% LVdP/dtmax increase, chronic response by composite clinical score at 6 months. RESULTS During intrinsic conduction, ADV direction was similar in patients with QRS < 120 ms, NICD and LBBB, pointing towards the LV free wall, while ADV magnitude was larger in LBBB (117 ± 25 ms) than in NICD (70 ± 29 ms, P < 0.05) and QRS < 120 ms (52 ± 14 ms, P < 0.05). Intrinsic ADV accurately predicted the acute (AUC = 0.93) and chronic (AUC = 0.90) response to CRT. ADV change by CRT only moderately predicted response (highest AUC = 0.76). LV pacing site optimization had limited effects: +3 ± 4% LVdP/dtmax when compared to conventional basolateral LV pacing. CONCLUSION The baseline electrical substrate, adequately measured by ADV amplitude, strongly determines acute and chronic CRT response, while the extent of its modification by conventional CRT or by varying LV pacing sites has limited effects.

Virtual patient simulations for cardiology education and research: A CircAdapt perspective

Nowadays cardiac simulations are becoming increasingly sophisticated. This trend, part of the maturing field of computational medicine, has provided medical students and cardiologists alike with a new tool for education and research – their very own virtual “patient”. The CircAdapt biophysical model of the human heart and circulation (www.circad apt.org) allows the creation of a virtual “patient” for the study of the cardiovascular system and circulatory haemodynamics under diverse physiological and pathophysiological conditions in real time. The interactive CircAdapt model with its modular design based on established physical and physiologial principles allows dynamic monitoring of blood flow velocities, pressures and volumes in the heart and blood vessels, and across valves and shunts. As an educational tool, the CircAdapt model enables medical students and residents in cardiology, neonatology and intensive care medicine to analyze complex situations while improving their comprehension of cardiovascular physics and (patho)physiology. Moreover, the CircAdapt model has been successfully utilized as a research tool for cardiac resynchronization therapy as well as for various cardiovascular pathologies (e.g. pulmonary arterial hypertension, LBBB). All in all the CircAdapt perspective is as follows: bridge education and research from classroom to bedside – to foster the future of clinical practice. ‡ ‡ ‡ ‡ ‡