Finding concordance in discord: the value of discordant invasive and echocardiographic pulmonary artery pressure measurements with severe tricuspid regurgitation

This editorial refers to ‘Clinical characteristics, diagnosis, and risk stratification of pulmonary hypertension in severe tricuspid regurgitation and implications for transcatheter tricuspid valve repair’†, by P. Lurz et al., on page 2785. Transcatheter tricuspid valve repair (TTVR) for the treatment of tricuspid regurgitation (TR) has been embraced in the setting of the suboptimal results with open surgical therapy. Isolated tricuspid valve (TV) surgery is associated with high in-hospital mortality1 and a lack of mortality benefit.2 The rapid ascent of structural heart interventions presents an interesting dilemma for this disease: the deployment of transcatheter treatment options before a complete understanding of the complex pathophysiology of functional TR. The intimate relationship of the TV to right ventricular (RV) size and function, and the known sensitivity of the right ventricle to increases in afterload,3 has led many TTVR trials to exclude patients with ‘severe’ pulmonary hypertension (PHT). Whether this approach to trial design is warranted, is currently unknown. Echocardiography has been a cornerstone of non-invasive evaluation of PHT. The 2015 ESC/ERS Guidelines for the diagnosis and treatment of PHT state that conclusions derived from an echocardiographic examination should aim to assign a level of probability of PHT by using multiple echocardiographic variables.4 These parameters include not only an estimate of systolic pulmonary artery pressure (sPAP), and pulmonary vascular resistance, but also right atrial (RA) size and pressure, and RV size and function. Although the correlation between echocardiographic and invasive measures of sPAP may be high in the general population (r = 0.87, P < 0.0001),5 both underestimation5 and overestimation6 of invasive measurements have been reported in the setting of severe TR, frequently related to the inaccurate estimation of RA pressure. Because TR velocity reflects the pressure gradient between the RV and RA pressures in systole, high RA pressure and reduced RV contractility could also reduce this pressure gradient, despite high PAP. Rapid equilibration of the RV and RA pressures occurs with greater severity of TR and a high V-wave,7 higher resting RA pressures, and reduced RV function. In the setting of very severe TR with laminar flow, the estimation of PAP using the modified Bernoulli equation may also be invalid.8 , 9 The normal right heart ejects a stroke volume equivalent to that of the left heart while using 25% of the stroke work and against a closed mitral valve; thus cardiac output is dependent upon normal pulmonary arterial and venous compliance.3 Instead of evaluating the right heart and pulmonary vasculature as separate entities, evaluating the RV contractility response to increased afterload (RV–PA coupling) has become the focus of a number of studies.10 Although the most objective measure of this relationship is the ratio between ventricular elastance and arterial elastance, a number of non-invasive surrogates appear to correlate with outcomes.3 The relationship between non-invasive measures of RV function and sPAP is an important independent predictor of incident heart failure or death.11 The study by Lurz et al. in this issue of the European Heart Journal 12 evaluates the role of PHT and RV–PA coupling in outcomes in a cohort of 243 patients undergoing TTVR with the edge-to-edge (ETE) device. The authors measured PAP both invasively (iPAP) and echocardiographically (ePAP) and identify patients with (+) or without (–) PHT. In this mixed population, 50% (n = 122) had an iPHT ≥50 mmHg, 46% of patients had concomitant mitral regurgitation (MR) requiring ETE repair (TMTVR), and discordance between the two measurement methods (iPHT+/ePHT–) occurred in 55%, with echo underestimating invasive measurements. In addition, they determine tricuspid annular plane systolic excursion (TAPSE)/iPAP (combined echocardiographic and invasive measurements) as a measure of RV–PA coupling. The primary endpoint was a composite of all-cause mortality, need for repeat hospitalization for heart failure, and reintervention during follow-up Patients with iPHT+ had a higher risk score, more heart failure hospitalizations, more severe symptoms, higher NT-proBNP, more renal impairment, a higher rate of chronic lung disease, and more impaired functional capacity. TAPSE/iPAP was significantly lower in the PHT+ group compared with PHT– patients. In the total cohort, PHT+ did not predict freedom from the composite endpoint but was however a strong predictor of outcomes in the TTVR only cohort. The discordant (iPHT+/ePHT–) cohort had a number of significant differences in both baseline clinical and echocardiographic parameters. Discordant patients presented with significantly higher NYHA class, worse functional capacity, higher invasive RA pressure, worse LV function, the lowest ePAP measurements, and more severe TR. Echocardiographic predictors of discordance included LVEF <50%, TAPSE <17 mm, V-wave cut-off sign (triangular spectral profile), and TR grade >3. These findings make sense given the above discussion of the determinants of discordant measurements of PAP (i.e. high RA pressure and reduced RV function, laminar flow with worse TR severity) and the LV and RV interdependence linking LV and RV function.12 Thus iPHT/ePHT discordance is a marker for more advanced valvular and ventricular disease and logically might predict the lower procedural success and freedom from the composite endpoint found by Lurz et al. Importantly, there is no difference in outcomes between the PHT– and iPHT+/ePHT+ (concordant) groups (P = 0.48), whereas a discordant diagnosis (iPHT+/ePHT–) had the highest risk for the combined endpoint [hazard ratio (HR) 3.76, 95% confidence interval (CI) 2.25–6.37, P <0.01 for TMTVR and TTVR cohorts]. The TMTVR group deserves mention. PHT+ and TAPSE/iPAP were independent predictors for the combined endpoint in the TTVR cohort and not in the combined cohort, whereas discordant PAP measurements predicted outcomes for both the overall and TTVR cohort. In the TMTVR population, ETE repair is an effective therapy for PHT related to significant MR and parameters using baseline PAP measurements, and thus might not be predictive of outcomes. Discordant measurements, however, define a high-risk patient population with worse TR, ventricular dysfunction, and heart failure, with or without concomitant MR. The study by Lurz and colleagues not only is an important advancement in understanding the possible pathophysiology of the complex patient population presenting with severe symptomatic TR, but also identifies a powerful predictor of poor outcomes in this mixed population (Figure 1). There are a number of take-home messages. First, given the high frequency of discordant iPAP and ePAP measures, invasive measurements should be performed in patients with severe TR. Secondly, iPAP measurements alone cannot fully risk-stratify patients; invasive and echocardiographic discordance results in the worst outcomes. Thirdly, patients with discordant measures, particularly in the absence of concomitant MR, may not benefit from ETE repair. The pivotal Triluminate trial (ClinicalTrials.gov Identifier: NCT03904147) should be able to validate these findings. In this trial, patients with severe, symptomatic TR (without significant MR) will be randomized to ETE repair with optimal medical therapy vs. optimal medical therapy alone. An invasive right heart catheterization is required for enrolment to exclude an sPAP >70 mmHg or fixed pre-capillary PHT and will allow an assessment of invasive vs. non-invasive PAP measurements in the two treatment cohorts. The results of this trial should allow us to risk-stratify patients with varying degrees of PHT and provide insight into the appropriate treatment algorithm. Take home message from Lurz et al. ePHT, echocardiographically measured PHT; HR, hazard ratio; iPAP, invasive pulmonary artery pressure; iPHT, invasively measured PHT; PHT, pulmonary hypertension; TAPSE, tricuspid annular plane systolic excursion; TMTVR, transcatheter mitral and tricuspid valve repair; TTVR, transcatheter tricuspid valve repair; +, presence of; -, absence of. Conflict of interest: R.T.H. reports speaker fees from Boston Scientific Corporation, Baylis Medical, Edwards Lifescience, and Medtronic; consulting fees for Abbott Structural, Edwards Lifesciences, Gore & Associates, Medtronic, Navigate, and Philips Healthcare; non-financial support from 3mensio; equity with Navigate; and is the Chief Scientific Officer for the Echocardiography Core Laboratory at the Cardiovascular Research Foundation for multiple industry-sponsored trials, for which she receives no direct industry compensation. The opinions expressed in this article are not necessarily those of the Editors of the European Heart Journal or of the European Society of Cardiology.