Abstract
Introduction: To date, there is no specific evidence or criteria for the selection of patients with PH and severe tricuspid insufficiency that can be initiated into correction of tricuspid valvulopathy. Tricuspid regurgitation is a risk marker independent of mortality in patients with pulmonary hypertension. The critical factor for the procedure’s success is to find the parameters to select patients so that they do not become just a futile act. Method: From the initial group of 271 patients, a final group of 123 patients were selected, all diagnosed with precapillary PH confirmed by catheterization and with tricuspid regurgitation by echocardiography. Patients were in groups 1 and 2 according to the 2022 Pulmonary Hypertension Guidelines. Patients with right to left shunt were not excluded. Results: In patients with severe precapillary PH, the sPAP/PAAT ratio was close to 1 (0.89 ± 0.43), while in patients with mild precapillary PH or in the postcapillary group, the sPAP/PAAT ratio was considerably lower (0.47 ± 0.20, p < 0.001). The average sPAP/PAAT of deceased patients was 0.76. Among the 68 deceased patients, 42 (61.70%) had severe tricuspid regurgitation. Conclusion: In our study, the average sPAP/PAAT ratio of the deceased patients with severe FTR was 0.76 mm Hg/ms; nevertheless, this knowledge could have a potential use but is not sufficient for full-informed qualification or disqualification for valve intervention, which requires specific TTVR-related data.
Introduction
In pulmonary hypertension (PH), right ventricular dilatation and right ventricular failure are signs of disease progression [1, 2]. Both pulmonary pressure values and degree of heart failure expressed through NYHA functional class and/or result of the 6MWT are independently related to clinical worsening [3, 4]. The role of functional tricuspid valve regurgitation (FTR) is still unclear and may add additional information regarding the right ventricle remodeling as a consequence of volume overload. Although the noninvasive estimation of systolic pulmonary artery pressure (sPAP) by Doppler echocardiography has been well established [5‒9], it does not measure right ventricular (RV)-arterial coupling and pulmonary vascular resistance (PVR) [10‒12]. On the other hand, the pulmonary artery acceleration time (PAAT) offers an indirect measure of PVR [13]. Despite the limitations, there is a wide consensus to consider echocardiography as the most immediate and simple approach to obtaining reliable markers of the right ventricle systolic function in cardiopulmonary disorders. Among the echocardiographic variables used for the evaluation of the systolic function of the RV, the tricuspid annular plane systolic excursion (TAPSE) is easy to obtain but weakly predictive of outcome in patients with PH [10, 11]. Assessment of PAAT and sPAP would provide more physiological information. Consequently, we hypothesized that the relationship between PAAT (time) and sPAP (developed pressure) could be useful for the stratification of PH patients according to their prognosis and after further studies helpful in the choice of the tailored treatment focused on PVR lowering or including TTVR.
Materials and Methods
Our study analyzed data extracted from the medical records of patients followed since 2012 at the Pulmonary Hypertension Center of Cardiology of the University Hospital of Parma, Italy, with a diagnosis of PH and presence at the transthoracic echocardiogram (TTE) of a tricuspid regurgitation of moderate-to-severe degree (Fig. 1). Patients were in groups 1 and 2 according to the 2022 Pulmonary Hypertension Guidelines. Patients with right to left shunt were not excluded.
From a group of 271 patients, 63 patients were excluded for various reasons (e.g., they were not submitted to the right catheterization procedures for confirmation of the diagnosis and characterization of the disease or their vital status data could not be determined at the end of the follow-up). From the remaining group of 208 patients, 85 were excluded at the right catheterization procedures because they presented a borderline value of PH and/or were affected by postcapillary PH. This selection resulted in a final sample group of 123 patients, all diagnosed with isolated precapillary or combined PH confirmed by RHC and with tricuspid insufficiency at TTE (Fig. 2).
These patients were monitored for a median follow-up period of 1,255 days (incidence rate 691–2,402 days), with clinical reevaluations and periodic echocardiography. Imaging was performed using a Philips EPIC 6 and a 5.2 MHz transducer (Philips Medical Systems, Andover, MA), using through views specifically designed to optimize the RV imaging. The echocardiographic data were collected by an experienced and dedicated operator following the most up-to-date recommendations of the American Society of Echocardiography endorsed by the European Association of Echocardiography [14]. In particular, the quantification of the degree of mitral and tricuspid regurgitation was performed using both semiquantitative and quantitative multiparametric analysis, the mediated calculation of maximum regurgitation rate, vena contracta, effective regurgitant orifice area, proximal isovelocity surface area, and regurgitating volume [15]. The apical four-chamber view was used to obtain the TAPSE, and an M-mode cursor was placed through the lateral tricuspid annulus in real time. The TAPSE was measured as the peak excursion of the tricuspid annulus (mm) from the end of diastole to the end of systole. The PAAT was measured by pulsed-wave-Doppler through the pulmonary valve jet from the short axis view as the time interval between the onset of ejection and the peak flow velocity (Figure 3). RV systolic filling pressure was determined from the TR jet velocity using Bernoulli’s simplified equation and combining this value with an estimate of the right atrial pressure by the diameter and collapsibility of the inferior vena cava, which was then added to the calculated gradient for the sPAP. All measurements were performed by two senior researchers blinded to patients’ clinical diagnosis. Subjects with hypertrophic or dilated cardiomyopathy, pericardial diseases, poor acoustic windows, and unstable ischemic heart disease were excluded from the study.
The patients underwent femoral right heart catheterization (RHC) using a 7F catheter thermodilution within 2 weeks from the last echocardiographic exam to evaluate the systolic, mean, and capillary pulmonary pressure and calculate the transpulmonary gradient (= PAPm–PCWPm), cardiac output, and PVR (dynes/s/cm−5 = transpulmonary gradient/cardiac output × 80) [15, 16]. PH was defined as a mean PAP >25 mm Hg and a pulmonary capillary wedge pressure <15 mm Hg [2]. Although new values have been proposed, and a new hemodynamic definition and an updated clinical classification of PH have emerged from the 2022 ESC/ERS Guidelines of PH [1], the authors chose not to consider the new guidelines as they have not been yet published after this study. The data of the right catheterization were obtained with a standardized data acquisition protocol with vasoreactivity test indicated only in selected cases of PH, and saved on the company server for subsequent postprocedural analysis.
Statistical Analysis
The primary objective of the study was to assess the range of sPAP/PAAT ratio in patients with different levels of FTR and PH severity. The secondary objective was to correlate the sPAP/PAAT ratio and the hemodynamic parameters (mPAP, PVR) for the RHC. Data are expressed as mean values ± SD unless otherwise stated. Pearson’s correlation coefficient and Bland-Altman analysis were used to compare PAP, PAAT, sPAP/PAAT ratio, FTR grade, and TAPSE with PAP, PVR, and New York Heart Association (NYHA) class. Stepwise forward multiple regression analysis allowed the weighting of the independent effects of the potential determinants on an independent variable. The null hypothesis was rejected when the p value was <0.05. Two sonographers blinded to the clinical data measured the sPAP/PAAT ratio to assess the interobserver variability. The area under the receiver-operating characteristic curve was used to plot the true-positive rate (i.e., sensitivity) as a function of the false-positive rate (specificity) for different cutoff scores of sPAP (mm/Hg).
Results
At TTE, the overall systolic function of the left ventricle was substantially preserved in the test population, with mean left ventricular ejection fraction estimated at 56 ± 7%, while the average basal diameter of the right ventricle was at the upper limits of normal values (40 ± 6). All patients had moderate-to-severe or severe FTR (effective regurgitant orifice area >0.30 cm2). The average TAPSE value was 19 ± 3 mm, and the PAAT value tended to be lower than in subjects not suffering from PH (mean value 93 ± 22 ms).
At RHC, the mean pulmonary blood pressure was 38 mm Hg, and PVR was 9 ± 6 HRU. Thirty-seven percent of patients (45/123) had a mild precapillary PH; 23% of them (29/123) had a moderate precapillary PH; and 40% (49/123) had a severe precapillary PH. The univariate analysis revealed a statistically significant correlation between patients death and different clinical parameters, in particular, age at the time of diagnosis (HR: 1.04, CI: 1.03–1.08, p = 0.023), presence of chronic obstructive pulmonary disease (HR: 3.21, CI: 1.01–9.47, p = 0.035), and functional class NYHA class (HR: 2.30, CI: 1.38–3.83, p = 0.001).
A similar correlation was also found for several hemodynamic parameters, such as mPAP (HR: 1.04, CI: 1.02–1.07, p < 0.001), right atrial pressure (HR: 1.09), RVP (HR: 1.04, CI: 1.03–1.09, p = 0.03), and venous oxygen saturation (SvO2) (HR: 0.96, CI: 0.93–0.99, p = 0.035) and also for echocardiographic parameter such as TAPSE (HR: 0.80, CI: 0.72–0.89, p < 0.001), basal right ventricle diameter (HR: 0.96, CI: 0.93–0.99, p = 0.035), PAAT (HR: 0.980, CI: 0.96–0.99, p = 0.023), and VD-AD gradient (HR: 1.02, CI: 1.02–1.04, p = 0.006).
The fact that univariate analysis revealed a greater correlation with mortality in subjects with precapillary PH was related to the degree of tricuspid regurgitation (HR: 4.56, CI: 2.69–7.73, p < 0.001); this observation was supported by the multivariate analysis, where FTR was confirmed as the most relevant predictor of mortality (HR: 5.40, CI: 2.90–10.06, p < 0.0001), followed by the functional NYHA class (HR: 1.85, CI: 1.02–1.35, p = 0.042), and the value of mPAP (HR: 1.04, CI: 0.86–1.09, p = 0.006) (Table 1). We performed a subanalysis and divided the population according to the severity of pulmonary (Table 2). This shows that patients with severe PH were predominantly males and had an mPAP of 53 mm/Hg; SVO2 averaged 65%; IC 2.7; PVR 12.5 HRU. In patients with severe FTR and precapillary PH, the sPAP/PAAT ratio tended to a value close to 1 (0.9 ± 0.4 mm Hg/ms), while in patients with mild precapillary PH or in the combined group, it was much considerably lower (0.47 ± 0.2 mm Hg/ms) (p < 0.001). The mean value of sPAP/PAAT ratio in patients who survived was 0.41 ± 0.1 mm Hg/ms. The average sPAP/PAAT of deceased patients was 0.76 mm Hg/ms, and of these, 62% (42/68) had severe FTR.
. | Univariate analyses . | Multivariate analyses . | ||
---|---|---|---|---|
HR (95% CI) . | p value . | HR (95% CI) . | p value . | |
Age | 1.04 (1.01–1.08) | 0.023* | ||
Gender | 1.51 (0.75–3.03) | 0.248 | ||
BSA | 0.78 (0.16–3.75) | 0.756 | ||
BMI | 1.01 (0.95–1.07) | 0.779 | ||
CAD | 0.62 (0.19–2.04) | 0.428 | ||
COPD | 3.21 (1.01–9.47) | 0.035* | ||
AF | 0.55 (0.13–2.31) | 0.412 | ||
NYHA class | 2.30 (1.38–3.83) | 0.001* | 1.85 (1.02–3.35) | 0.042 |
IT degree | 4.56 (2.69–7.73) | <0.001* | 5.40 (2.90–10.06) | <0.001 |
mPAP | 1.04 (1.02–1.07) | <0.001* | 1.04 (1.02–1.07) | 0.002 |
Right atrium P | 1.09 (1.04–1.15) | <0.001* | ||
Right ventricle P | 1.04 (1.03–1.09) | 0.032* | ||
PVR | 1.07 (1.02–1.11) | 0.003* | ||
CI | 0.87 (0.61–1.25) | 0.456 | ||
SvO2 | 0.96 (0.93–0.99) | 0.035* | ||
LVEF | 0.98 (0.93–1.02) | 0.230 | ||
Right ventricle BD | 1.06 (1.01–1.12) | 0.017* | 1.03 (0.86–1.09) | 0.09 |
TAPSE | 0.80 (0.72–0.89) | <0.001* | ||
PAAT | 0.98 (0.96–0.99) | 0.023* | ||
RV-RA gradient | 1.02 (1.01–1.04) | 0.006* | ||
HTP-TP | 0.90 (0.44–1.85) | 0.779 |
. | Univariate analyses . | Multivariate analyses . | ||
---|---|---|---|---|
HR (95% CI) . | p value . | HR (95% CI) . | p value . | |
Age | 1.04 (1.01–1.08) | 0.023* | ||
Gender | 1.51 (0.75–3.03) | 0.248 | ||
BSA | 0.78 (0.16–3.75) | 0.756 | ||
BMI | 1.01 (0.95–1.07) | 0.779 | ||
CAD | 0.62 (0.19–2.04) | 0.428 | ||
COPD | 3.21 (1.01–9.47) | 0.035* | ||
AF | 0.55 (0.13–2.31) | 0.412 | ||
NYHA class | 2.30 (1.38–3.83) | 0.001* | 1.85 (1.02–3.35) | 0.042 |
IT degree | 4.56 (2.69–7.73) | <0.001* | 5.40 (2.90–10.06) | <0.001 |
mPAP | 1.04 (1.02–1.07) | <0.001* | 1.04 (1.02–1.07) | 0.002 |
Right atrium P | 1.09 (1.04–1.15) | <0.001* | ||
Right ventricle P | 1.04 (1.03–1.09) | 0.032* | ||
PVR | 1.07 (1.02–1.11) | 0.003* | ||
CI | 0.87 (0.61–1.25) | 0.456 | ||
SvO2 | 0.96 (0.93–0.99) | 0.035* | ||
LVEF | 0.98 (0.93–1.02) | 0.230 | ||
Right ventricle BD | 1.06 (1.01–1.12) | 0.017* | 1.03 (0.86–1.09) | 0.09 |
TAPSE | 0.80 (0.72–0.89) | <0.001* | ||
PAAT | 0.98 (0.96–0.99) | 0.023* | ||
RV-RA gradient | 1.02 (1.01–1.04) | 0.006* | ||
HTP-TP | 0.90 (0.44–1.85) | 0.779 |
LVEF, left ventricular ejection fraction; COPD, chronic obstructive pulmonary disease.
. | Mild PHT . | Moderate PHT . | Severe PHT . | p value . |
---|---|---|---|---|
AGE, years | 65.0±15.67 | 68.51±10.85 | 65.18±11.64 | NS |
Male, % | 24.44% | 41.37 | 53.06 | - |
Female, % | 75.56% | 58.63 | 46.94 | - |
BSA, m2 | 1.76±0.23 | 1.81±0.20 | 1.80±0.27 | NS |
BMI, kg/m2 | 26.01±5.33 | 27.42±5.22 | 27.69±6.56 | NS |
HTA, % | 40 | 51.72 | 48.97 | - |
Dyslipidemia, % | 24.44 | 24.13 | 28.57 | - |
Smoke habit, % | 15.55 | 20.68 | 24.48 | - |
DM, % | 6.67 | 6.89 | 8.16 | - |
PAPm, mm Hg | 23.66±2.16 | 33.43±3.39 | 53.22±10.13 | 0.002 |
PWP, mm Hg | 10.62±3.31 | 12.06±2.6 | 12.44±2.41 | NS |
PR, HRU | 7.37±4.27 | 6.86±2.65 | 13.47±7.36 | 0.001 |
CI, L/m2 | 2.89±0.81 | 3.22±1.30 | 2.7±1.1 | NS |
Spo2c, % | 70.80±7.83 | 69.79±9.48 | 65.51±9.75 | 0.005 |
EDD, mm | 47.28±7.74 | 48.51±6.25 | 46.04±5.70 | NS |
ESD, mm | 28.55±7.40 | 28.65±7.67 | 26.85±5.79 | NS |
EDV, mL | 91.82±28.34 | 95.27±21.58 | 90.87±23.37 | NS |
ESV, mL | 41.82±10.01 | 41.24±9.45 | 40.14±9.29 | NS |
IVSd, mm | 10.28±1.51 | 11.17±2.17 | 10.93±1.90 | NS |
PWd, mm | 9.37±1.62 | 9.34±1.60 | 9.65±1.69 | NS |
RWT, % | 42.40±7.95 | 42.71±6.90 | 45.46±9.61 | 0.006 |
FEVS, % | 55.82±6.85 | 56.45±7.51 | 55.90±7.49 | NS |
VDx-Db, mm | 37.1±4.57 | 38.82±4.75 | 43.22±6.41 | 0.003 |
TAPSE, mm | 20.72±2.78 | 21.62±3.07 | 18.32±2.92 | 0.001 |
VD-AD, mm Hg | 41.66±14.28 | 43.03±16.22 | 56.87±19.77 | <0.001 |
sPAP-PAAT ratio, mm Hg/ms | 0.47±0.20 | 0.62±0.15 | 0.89±0.42 | <0.001 |
Severe IT, % | 6.89 | 17.24 | 32.65 | - |
Deaths, % | 13.33 | 17.24 | 42.85 |
. | Mild PHT . | Moderate PHT . | Severe PHT . | p value . |
---|---|---|---|---|
AGE, years | 65.0±15.67 | 68.51±10.85 | 65.18±11.64 | NS |
Male, % | 24.44% | 41.37 | 53.06 | - |
Female, % | 75.56% | 58.63 | 46.94 | - |
BSA, m2 | 1.76±0.23 | 1.81±0.20 | 1.80±0.27 | NS |
BMI, kg/m2 | 26.01±5.33 | 27.42±5.22 | 27.69±6.56 | NS |
HTA, % | 40 | 51.72 | 48.97 | - |
Dyslipidemia, % | 24.44 | 24.13 | 28.57 | - |
Smoke habit, % | 15.55 | 20.68 | 24.48 | - |
DM, % | 6.67 | 6.89 | 8.16 | - |
PAPm, mm Hg | 23.66±2.16 | 33.43±3.39 | 53.22±10.13 | 0.002 |
PWP, mm Hg | 10.62±3.31 | 12.06±2.6 | 12.44±2.41 | NS |
PR, HRU | 7.37±4.27 | 6.86±2.65 | 13.47±7.36 | 0.001 |
CI, L/m2 | 2.89±0.81 | 3.22±1.30 | 2.7±1.1 | NS |
Spo2c, % | 70.80±7.83 | 69.79±9.48 | 65.51±9.75 | 0.005 |
EDD, mm | 47.28±7.74 | 48.51±6.25 | 46.04±5.70 | NS |
ESD, mm | 28.55±7.40 | 28.65±7.67 | 26.85±5.79 | NS |
EDV, mL | 91.82±28.34 | 95.27±21.58 | 90.87±23.37 | NS |
ESV, mL | 41.82±10.01 | 41.24±9.45 | 40.14±9.29 | NS |
IVSd, mm | 10.28±1.51 | 11.17±2.17 | 10.93±1.90 | NS |
PWd, mm | 9.37±1.62 | 9.34±1.60 | 9.65±1.69 | NS |
RWT, % | 42.40±7.95 | 42.71±6.90 | 45.46±9.61 | 0.006 |
FEVS, % | 55.82±6.85 | 56.45±7.51 | 55.90±7.49 | NS |
VDx-Db, mm | 37.1±4.57 | 38.82±4.75 | 43.22±6.41 | 0.003 |
TAPSE, mm | 20.72±2.78 | 21.62±3.07 | 18.32±2.92 | 0.001 |
VD-AD, mm Hg | 41.66±14.28 | 43.03±16.22 | 56.87±19.77 | <0.001 |
sPAP-PAAT ratio, mm Hg/ms | 0.47±0.20 | 0.62±0.15 | 0.89±0.42 | <0.001 |
Severe IT, % | 6.89 | 17.24 | 32.65 | - |
Deaths, % | 13.33 | 17.24 | 42.85 |
Discussion
FTR has for a long time been considered as directly dependent on the form of secondary PH in left heart disease. Therefore, it has not been considered worthy of treatment during valve surgery because it was thought to improve after the correction of the causative valvulopathy. However, in daily clinical practice, it is quite common to observe the persistence, if not even the worsening, of tricuspid regurgitation after treatment of basal heart disease, and in recent years, increasing evidence has emerged, suggesting that FTR adversely affects the outcome in patients with both pre- and postcapillary pulmonary PH, regardless of the severity and characteristics of any concurrent left heart disease [17‒19].
Although increased pulmonary pressure is the defining characteristic of PH, it presents only the modest prognostic significance. Rather, it is the functional reserve of the RV to perform under increased volume and pressure load that determines survival and functionality. The prognostic value of FTR has been recently analyzed by Essayagh and colleagues [20]. At the follow-up of their study, with an average duration of 6.8 years, the presence of at least moderate degree tricuspid regurgitation (18% in the test group) was significantly associated with a worse clinical evolution, with more episodes of decompensation, less stroke volume, and worse kidney function. From a pathophysiological point of view, this phenomenon can be partly justified by a condition of “relative” volumetric overload that develops in the presence of moderate or severe tricuspid regurgitation. This right volumetric overload can lead to an unfavorable remodeling not only of the RV but also of the pulmonary circulation, with intimal hyperplasia at the level of the pulmonary arterioles, with a consequent increase in PVR, similar to what happens in some forms of precapillary PH caused by left-to-right shunt.
It is well known that FTR itself can predispose to a worsening of PH, resulting in a volumetric and pressure overload on the pulmonary circulation, which in turn triggers a condition of “stress failure,” described for the first time by West and Mathieu-Costello [21], and characterized by endothelial dysfunction with alterations of permeability and overexpression of endothelin receptors, as well as by a reduction of biological activity linked to nitric oxide pathways and prostanoids [22].
In our study, between patients with severe IT and precapillary PH, the sPAP/PAAT ratio tended to have a value close to 1 (0.89 ± 0.43 mm Hg/ms), indicative of advanced right ventricular dysfunction and loss of right ventricle-pulmonary artery coupling, so these patients should be excluded from TTVR. Patients with severe IP were predominantly males and had an mPAP of 53 mm/Hg 53 mm/Hg; SVO2 averaged 65%; IC 2.7; PVR 12.5 HRU. Furthermore, the average sPAP/PAAT ratio of deceased patients with severe tricuspid regurgitation was 0.76 mm Hg/ms. The average SVO2 of the subjects is relatively low, but there are several mechanisms attributed to low SVO2 in patients with precapillary pH, e.g., a chronic pulmonary disease with severe thoracic restriction in lung function test or presence of pulmonary thrombus. Currently, there is little specific evidence or criteria for the selection of patients with precapillary PH and severe FTR which could be referred to as correction of tricuspid valvulopathy [19], but this approach could allow earlier detection of patients with a reduction of RV functional reserve, and the sPAP/PAAT ratio could have potential use as a marker of pulmonary vascular load and pulmonary arterial ventricle interaction.
Conclusion
In our study, average sPAP/PAAT ratio of the deceased patients with severe FTR was 0.76 mm Hg/ms; nevertheless, this knowledge could have a potential use but is not sufficient for full-informed qualification or disqualification for valve intervention, which requires specific TTVR-related data.
Limitations
Our study was a single center and relatively small study. Moreover, echocardiographic examinations and RHC were not performed simultaneously, which may have affected the results. Finally, the assessment of sPAP/PAAT ratio was slightly limited by the availability of pulmonary Doppler signals.
Statement of Ethics
This study was conducted by good clinical practices and the current version of the revised Declaration of Helsinki. This study protocol was reviewed and approved by Ethical Committee of University Hospital of Parma, Approval No. 12751, March 21, 2023. Prior to the study, written and informed consent of participants was obtained.
Conflict of Interest Statement
The authors have no conflicts of interest to declare.
Funding Sources
The authors have not received any financial support.
Author Contributions
Walter Serra designed, wrote the article, and produced the additional material (Figures, Tables, etc.). Andrea Botti produced the additional material. Luigi Vignali produced hemodynamic data. Alfredo Chetta reviewed the article and the statistics data.
Data Availability Statement
The data that support the findings of this study are not publicly available due to their containing information that could compromise the privacy of research participants, but are available from the corresponding author (W.S.; wserra@libero.it), upon reasonable request.