This study showed that TTE-derived estimates of RV-PA coupling including FAC/PASP, and TAPSE/PASP and SVI/PASP were associated with PE-related adverse events in 820 normotensive patients with PE. The TAPSE/PASP and SVI/PASP had incremental value to the Bova score and CTPA RV/LV ratio, and subjective assessment of TTE-derived RVD in discriminating PE-related adverse events. These findings provide important insights into the importance of RV-PA coupling in the pathophysiology of hemodynamic decompensation in PE. Additionally, it underscores the challenges in identifying a universal TTE-derived prognostic marker to risk stratify normotensive patients, who represent a significant proportion of patients with PE. Lastly
This is the first study to assess the association of multiple parameters of RV-PA coupling with PE-related adverse events in the same cohort of patients and directly compare its utility against other markers RVD and risk stratification tools. Importantly, this study showed that in multivariate analysis with CTPA-derived RV/LV, the Bova score and subjective TTE assessment of RVD, SVI/PASP and TAPSE/PASP were both independently associated with PE-related adverse events. This suggests that RV-PA coupling has additive prognostic value beyond RVD identified by CTPA or clinical risk prediction scores, and it underscores the importance of quantitative assessment of RVD over subjective assessment alone. We also demonstrated that the conventional definition of RVD used in the PEITHO trial was not associated with adverse PE-related events in our population, while quantitative TTE measures including RV-PA coupling indices were strongly associated. Conventional definitions of RVD are ubiquitous in this population being present in 37% of patients with normotensive PE emphasizing the importance of more specific tools for identifying patients at heightened risk of adverse events [2]. This may be one reason that the PEITHO trial was unable to show a net benefit from systemic thrombolysis [4]. It suggests that future trials of thrombolysis or invasive catheter directed therapies may need to use a different definition for TTE-derived RVD that is more strongly associated with adverse events.
Ciurzyński et al. was the first to evaluate an RV-PA coupling parameter in PE using a stepwise approach to risk stratification with tricuspid annular plane systolic excursion (TAPSE) < 20mm followed by the ratio of tricuspid regurgitation peak gradient divided by TAPSE [7]. More recently, studies by Kamran et al. evaluated pulmonary artery systolic pressure (PASP) divided by left ventricular stroke volume and Lyhne et al. and Falsetti et al. evaluated TAPSE/PASP showing that these markers were associated with adverse outcomes in PE [8–10]. Kamran et al. concluded that PASP/left ventricular stroke volume was superior to the velocity time integral (VTI) although this was done comparing continuous odds ratios with different units [9]. However, Falsetti et al. found no difference in the association with adverse outcomes between TAPSE/PASP and VTI when comparing categorical odds ratios. Echocardiographic markers of RV-PA coupling and stroke volume all seem to have competitive risk stratification potential. However, it is unlikely that identifying an incrementally superior single TTE-derived markers of RVD will dramatically change outcomes of risk stratification. Instead, current guidelines appropriately promote a multimodality approach using clinical, biochemical, and radiologic markers of risk [6]. We did not directly compare markers of RV-PA coupling directly with other quantitative measures of RVD due to lack of statistical power for meaningful comparisons and because most of the quantitative measures of RVD in this study are components of the RV-PA parameters.
As pulmonary vascular resistance increases, there is an inverse nonlinear relationship in the compliance [27]. In turn, this results in an exaggerated RV pulsatile load, RV ejection pressure, and increased RV stroke work, all of which contribute to RV failure [28, 29]. The cardiovascular system operates in dynamic state whereby ventricular contractility is coupled with arterial afterload, otherwise known as ventricular-arterial coupling. Accordingly, in response to increased pulmonary artery pressures, the RV undergoes adaptive changes to increase contractility and preserve RV-PA coupling. RV-PA decoupling occurs when the RV contractility fails to match arterial afterload resulting in RV failure and hemodynamic decompensation thereafter. In the case of PE, this may result from excessive arterial elastance, direct impairment of RV contractility by cardiac ischemia, and the harmful RV-LV interaction whereby abnormal septal motion impairs left ventricular filling and resulting left sided stroke volume [14]. The fact that TAPSE/PASP, FAC/PASP, and SVI/PASP were all strongly associated with PE-related adverse events strengthens the finding that RV-PA decoupling is implicated in the pathophysiology of hemodynamic decompensation. SVI uniquely measures the most downstream hemodynamic effect of a PE, which not only decreases during RV-PA decoupling but also when left ventricular filling is impaired due to abnormal septal movement towards the left ventricle.
Indices of RV-PA coupling including SVI/PASP, FAC/PASP, and TAPSE/PASP were strongly associated with adverse in-hospital PE-related events in patients with normotensive PE. Stroke volume index, TAPSE and PASP are simple measurements that are easily obtainable during standard TTE. While FAC/PASP was associated with adverse PE-related events, FAC requires accurate RV endocardial contouring in both systole and diastole which may be difficult to perform reliably in clinical practice. The RV can be particularly challenging to accurately image due to its asymmetric shape and is prone to off axis imaging which may falsely estimate its function. The utility of direct assessment of RV size and function may be more limited due to these factors. Another challenge can be in obtaining a complete doppler signal to calculate the PASP. In this study, PASP could be determined in only 603 patients, FAC was only possible in 632 patients compared to TAPSE that was measurable in 763 patients and SVI that was measurable in 795 patients. These RV-PA coupling parameters represent multiple potential measurements that can be obtained during a standard TTE to identify normotensive patients at higher risk of PE-related mortality or hemodynamic decompensation. These parameters could have the potential to enrich future clinical trials of invasive therapies (i.e. thrombolytic therapy or catheter directed therapies) with truly intermediate-high risk patients. Future prospective prognostic studies are required to determine the feasibility of performing these measurements and validate these retrospective findings.
This study has several limitations. Our cohort had only 26 adverse PE-related events (3.2%). This is in part due to the more stringent definition of PE-related mortality rather than all-cause mortality. In our study, markers of RV-PA coupling were less associated with all-cause mortality than PE-related mortality. This is because all-cause mortality is less related to the underlying pathophysiologic mechanism of mortality in PE and is therefore likely of less suitable outcome than PE-related mortality when evaluating echocardiographic measurements. However, our event rates are similar to other unselected PE populations assessing RV-PA coupling such as Ciurzyński et al. where 8/400 (2%) PE-related death or hemodynamic decompensation [7] and Falsetti et al. where 10/256 (3.9%) had in-hospital mortality [10]. Data collection was retrospective and some TTE parameters were unavailable as they were not recorded routinely but at the discretion of the echocardiography technologist. At least one of FAC/PASP, TAPSE/PASP, or SVI/PASP was only possible in 599/820 (73%) of patients. This means that in 27% of patients another simpler marker of TTE-derived RVD must be used. This seems consistent with Kamran et al. who reported that only 215/343 (63%) patients that met inclusion had complete data for analysis, and Falsetti et al. who reported that only 270/326 (83%) patients had complete data [9, 10]. Lastly, because performing a TTE was at the discretion of the attending physician, there have been some selection bias in this cohort (only 820/2067 patients had a TTE within 48 hours of diagnosis). Despite this, we saw similar event rates compared to other contemporary studies assessing RV-PA coupling parameters.