Heart failure (HF), a condition associated with high mortality and morbidity, constitutes a major and growing worldwide public health problem (1–4), resulting in a requirement for the development of effective management. To this end, cardiac resynchronization therapy (CRT) implantation has proved useful as a therapeutic strategy for managing HF (5, 6). However, 30% of such treated patients fail to show beneficial outcomes (7) or even show further deterioration in cardiac mechanics and function with CRT implantation (8–10). CRT likely addresses the association of HF with mechanical dyssynchrony (MD) or disparities in wall contraction timing (8). This may therefore reflect the importance of variations in the contributory factors for HF in individual patients. These include delayed electrical conduction or electromechanical coupling, or altered regional myocardial properties following ischemic damage or myocardial infarction (8). Previous experimental reports had positively correlated durations of canine ventricular depolarization and repolarization intervals with wall thickness and cardiac size. The latter potentially alter in HF (11) causing both pro-arrhythmic effects (12, 13) and mechanical dyssynchrony. However, contributions of electromechanical coupling are less well understood.

Nevertheless, left ventricular mechanical delays (LVMDs), assessed using ultrasound methods (14) are useful prognosticators in both ischemic (15) and nonischemic dilated cardiomyopathy (16), acute myocardial infarction (17) and coronary artery disease (18). They may also be of prognostic importance following CRT implantation (7).

However, to this end, little is known about patterns of either normal or abnormal ventricular mechanical synchronization. This applies to both the right or left ventricle, whether to systolic or diastolic function, or to disparities between them, between different species of large mammals, or between healthy and diseased human hearts. Previous studies using M-mode, pulse-wave Doppler and tissue Doppler imaging have been confined to human studies of systolic as opposed to diastolic, and left ventricular asynchrony in HF patients (19–23). In particular, few studies to date have explored their diastolic ventricular asynchrony.

The present study therefore extends these previous studies in the following respects for the first time. We examine diastolic in addition to systolic ventricular synchrony. We also provide simultaneous readouts from the right in addition to the left ventricle. Such measures are surveyed and compared in exemplars of large mammalian canine and nonhuman primate species, of potential value in future experimental studies, in addition to human hearts. Finally the analyses are extended to HF patients. We thus characterize and compare left and right ventricular, systolic and diastolic mechanical sequences in canine, primate, and normal and failing human hearts for the first time.

We accordingly applied clinically accepted diagnostic electrocardiographic and echocardiographic methods to obtain and compare: (a) As systolic indicators: right and left ventricular pre-ejection periods (RVPEP and LVPEP) and (b) As diastolic indicators: mitral and tricuspid diastolic opening times (Q-MVE and Q-TVE). Corresponding values from these measurements were also compared between the right and left ventricles, between normal hearts in the species examined and in failing human hearts. This additionally provided incidences of the situations where there were relative right or left ventricular delays as well as the resulting interventricular, systolic or diastolic delays.

We have demonstrated for the first time that (a) normal animal and human hearts show greater left than right delay times and therefore positive systolic (IVMDs) and diastolic IVMD delays (IVMDd). (b) In contrast, a greater proportion of individual HF patients show reversals in both these IVMDs and IVMDd trends.

Our demonstration of such left/right mechanical differences and variations in patterns of both systolic and diastolic function between individual hearts thus have potential implications for clinical therapeutic techniques based on correcting mechanical activation times such as cardiac resynchronization therapy. Thus, the findings suggest that systolic and diastolic ventricular mechanical sequence assessment by echocardiography should be performed before and after CRT, in individual patients as a guide for the optimization of pacing indices. Furthermore, effectiveness of the therapeutic response may be optimized with the aid of determinations of ventricular mechanical sequence in individual patients and monitored by echocardiographic examinations.

We performed comparative echocardiographic analyses of ventricular mechanical activation sequences bearing on the synchrony of left and right ventricular systole and diastole in experimental animals, normal human subjects and HF patients. We report a predominance of left ventricular mechanical delay in systole (LVMDs) (76.9, 55.9, and 74.0% respectively) and highly consistent diastolic filling patterns (LVMDd) (93.3, 98.3, and 81.0% respectively) on the basis of paired comparisons of LV and RV parameters in each subject, in normal canine, primate and human hearts. Previous reports (21, 22) had not detected deviations from synchronous or slightly earlier LV relative to RV mechanical activation on the basis of their unpaired comparisons of mean LV and RV ejection time through entire experimental groups. The later LV repolarization times observed here may reflect the thicker LV walls resulting in prolonged LV repolarization times. Previous animal studies have positively correlated such repolarization times with wall thickness (25, 26). Our present observation of significantly reduced LVMDd to 41.1% in HF patients, could then reflect changes in LV wall anatomy and electrical conduction. This would be consistent with our findings that the negative value of IVMDd was positively associated with the reduction in LVEF (Figure 5). IVMDd may thus have potential prognostic significance in HF.

The present echocardiographic ventricular mechanical sequence findings have potential implications for therapeutic cardiac resynchronization therapy (CRT), with applicability to assessment and optimization of CRT. First, current bi-ventricular pacing in CRT typically sets the LV pacing time to be simultaneous with or slightly later than that of the RV. However, we here report differing ventricular mechanical sequences between individuals which could then confound the effectiveness of CRT. Furthermore, HF patients showed altered RV and LV mechanical sequences with potential implications for CRT optimization. Such differences in RV and LV systolic and diastolic sequences may require transthoracic echocardiographic determination for optimization and monitoring of CRT.

Secondly, prolonged QRS duration is currently used to measure ventricular mechanical dyssynchrony as an indication for CRT in HF. However, electrical dyssynchrony may not exactly parallel mechanical dyssynchrony. Thus, Yu et al. (27) reported that LV systolic and diastolic mechanical asynchrony are common in HF patients with normal QRS durations. Significant systolic asynchrony was thus observed in >40% of patients with narrow QRS complexes. Conversely, ~36% of HF patients with wide QRS complexes (>120 ms) did not have obvious intraventricular asynchrony. Furthermore, there was no correlation between the degree of LV asynchrony and QRS duration. Gabe B et al. reported a similar result (28). Furthermore, baseline QRS duration was not a good predictor for a better response to CRT in HF patients. Neither baseline nor shortening of QRS duration were good predictors for hemodynamic, clinical or echocardiographic improvement. However, the baseline severity of ventricular dyssynchrony assessed by echocardiography proved of predictive value (29, 30).

Thirdly, assessment of interventricular dyssynchrony may be critical for optimizing interventricular delays (V-V delays) in CRT. Their optimal timing improves ventricular filling capacity and stroke volume, reducing mitral regurgitation and reversing LV remodeling with subsequent reductions in short-term morbidity and mortality. Admittedly, there is evidence for intraventricular but not interventricular synchrony as an independent prognostic indicator in CRT patients. However, previous work had assessed IVMDs as a predictor without considering the interventricular mechanical sequence with V-V delays, setting LV timing simultaneously with or slightly earlier than RV. This contrasts with the LVMDs patterns we report here.

By using Pulse-wave Doppler echocardiographic approaches, we have explored and characterized the cardiac mechanical sequence in LV and RV and their relationships in three large species. Significant variations in LV and RV systolic and diastolic mechanical sequences are demonstrated between healthy subjects and HF patients. Systolic and diastolic ventricular mechanical sequence assessment by echocardiography should be done before and after CRT, as a guide for the optimization of pacing indices. To gain a highly effective therapeutic response, ventricular mechanical sequence should be considered for individual patients and recorded in routine echocardiographic examination.

The original data upon which this article is based is available from the corresponding author upon reasonable request.

The studies involving human participants were reviewed and approved by the Peking University People's Hospital following approval by the local Ethics Committee. The patients/participants provided their written informed consent to participate in this study. All studies involving animal procedures were approved by the Animal Care and Use Committee of Peking University (IACUC approval numbers: 2011–0010 for canine and IMM-ZhangXQ-1 for primate studies) and complied with the principles of laboratory animal care of the National Academy of Sciences/National Research Council of the People's Republic of China.

TZ was responsible for overall study design. ML supervised the canine. XZ supervised the primate experiments. RZ, YZ, WZ, and YL performed the animal experiments. WJ, CY, DL, XQ, LK, and SL recruited and studied the healthy human subjects and heart failure patients. ZW performed data analysis and figure preparation. CH performed data statistical analysis and writing of this article. All authors contributed to the article and approved the submitted version.

This study was funded by a National Key Research and Development (R&D) Program of China grant (2018YFA0801405), the Beijing Science and Technology Project (81670090) and the National Natural Science Funding of China (91646202, 81471063, 31221002, and 31871181).

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

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