BRIEF ARTICLE

Pulmonary hypertension (PH) is a multifactorial en­tity due to multiple causes and is defined as a complex hemodynamic condition characterized by a mean pul­monary arterial pressure (mPAP) > 20 mm Hg. Re­gardless of the underlying cause (such as left heart disease, respiratory disease, or pulmonary vascular disease), PH is always associated with high morbidity and mortality, and its occurrence always worsens the clinical course of patients.

Its prognosis is determined by the ability of the right ventricle (RV) to adapt to the progressive exces­sive pressure load of the pulmonary circulation (RV-pulmonary artery coupling). In this sense, several hemodynamic parameters have been proposed to bet­ter characterize this issue. The 2022 European Guide­lines for the Diagnosis and Treatment of Pulmonary Hypertension identify several prognostic hemody­namic parameters in patients with pulmonary arterial hypertension, including right atrial pressure (RAP), cardiac index (CI), central venous oxygen saturation (SvO2), and stroke volume index (SVI). (1, 2) These pa­rameters have been validated during follow-up, espe­cially CI and SvO2. (3,4)

There are other hemodynamic parameters of right ventricular function and RV-pulmonary artery cou­pling that can be measured during right heart cath­eterization (RHC). These include pulmonary vascular resistance (PVR), pulmonary arterial compliance, RV systolic work index (RVSWI) (5,6) or pulmonary artery pulsatility index (PAPI). (7,8) Although PVR is widely used as a hemodynamic parameter in pul­monary arterial hypertension (PAH) and even as a clinical endpoint in most current clinical trials, recent European recommendations do not consider it a prog­nostic marker. The REVEAL registry only uses a cut-off value of 5 Wood units (WU) with little hierarchy within the score based on baseline characteristics. (9) This may be due to the fact that some studies have failed to demonstrate its prognostic value. (10,11)

However, we lack information on the prognostic value of the different measurements of right ven­tricular function and pulmonary circulation that can be obtained in the catheterization laboratory. In this context, the aim of this study was to determine the predictive ability of various hemodynamic parameters that can be calculated during RHC to predict serious events such as death or hospitalization due to worsen­ing pulmonary hypertension.

The Pulmonary Hypertension Working Group consists of a multidisciplinary team working in 5 centers in the Autono­mous City of Buenos Aires and the Greater Buenos Aires Area (Sanatorio de la Trinidad Quilmes, Centro Gallego de Buenos Aires, Sanatorio Dupuytren, Sanatorio Trinidad Ramos Mejía and Sanatorio Mater Dei). We performed a retrospective cohort analysis of our registry which included consecutive patients recorded in the work group database who underwent RHC between January 2011 and May 2023. All the patients signed an informed consent form to undergo RHC and authorized the anonymous use of the result of the test for research purposes. All patients with PH, defined as mPAP > 20 mmHg at rest, were included in the analysis. Patients were classified into PH groups 1 to 5 according to international recommendations. Group 1 patients with PAH were subdivided into idiopathic PAH, associated with con­nective tissue diseases, congenital heart disease, human immunodeficiency virus (HIV) infection or drugs, and por­topulmonary hypertension, following the same recommen­dations.

The values of the hemodynamic variables were defined as high or low risk as stated by the 2022 ESC (European So­ciety of Cardiology) recommendations. Low risk was defined as CI > 2.5 L/min/m2 and SVI > 38 mL/m2. For variables not defined by the guidelines, we used the mean or median val­ues of our population, according to their distribution. Quan­titative variables with normal distribution are expressed as mean ± standard deviation (SD) and those with non-nor­mal distribution are expressed as median and interquartile range (IQR). The incidence of events (death, hospitalization due to worsening PH, or need for dose escalation of a specific therapy) was assessed and compared in the high-risk and low-risk groups for each variable using the chi square test and logistic regression analysis with calculation of odds of the occurrence of events (odds ratio).

A total of 324 patients with PH documented by RHC were prospectively included in the registry. Mean age was 61.5 ± 17.6 years and 69.0% were men. Median (IQR) follow-up was 23 (14-44) months. The patients were classified as follows: 62.1% in Group 1, 8. 7% in Group 2, 19.2% in Group 3, 7.7% in Group 4, and 2.1% in Group 5. In group 1, the etiologies were idiopathic PAH in 57.1%, associated with connective tissue dis­eases in 26.1%, associated with congenital heart dis­ease in 12.8%, portopulmonary hypertension in 1.9%, associated with HIV in 1.4%, and associated with drugs in 0.4%. The event rate (death or hospitalization for heart failure) was 60.6% and all-cause mortality was 24.5%. The mean ± SD values or median (IQR) values of the hemodynamic variables of the sample were: CI 2.72 ± 0.72 L/min/m2, SVI 33.1 ± 12.4 mL/m2, PVR 6 (3.7-9.8) WU, PAPI 3.76 (2.5-5.8), RVSWI 11.6 (8.6- 16.5) g.m/m2, and pulmonary arterial compliance 1.84 (1.09-3.03) mL/mm Hg. Tables 1 and 2 show the event rates for each hemodynamic variable in the low-risk and high-risk groups. The rate of combined events was higher in high-risk patients, although statistically significant only in patients with PVR > 6 WU (OR 1.99, 95% CI 1.17-3.38, p = 0.006). Mortality was also higher in the high-risk groups, with statistical signifi­cance for the variables CI (OR 1.8, 95% CI 1.38-3.31, p = 0.038), SVI (OR 3.46, 95% CI 1.51-8.92, p = 0.001), PVR (OR 2.75, 95% CI 1.45-5.34, p < 0.001) and com­pliance (OR 5.95, 95% CI 2.17-18.86, p < 0.001).

The present study represents the analysis of hemody­namic variables with the largest number of patients carried out by a PH working group in our country and confirms the importance of measuring and cal­culating hemodynamic parameters to determine the patients' prognosis. We decided to include the hemo­dynamic variables with the best correlation to RV-pulmonary artery coupling and RV work, namely CI and SVI, as SvO2 is a surrogate of CI and RAP is also influenced by the volume overload present in these patients. This study confirms that estimates of CI and SVI are strongly associated with mortal­ity at follow-up. These findings support the concept that RV function and RV-pulmonary artery coupling have a significant impact on patients' survival. How­ever, our analysis questions the need for including other variables in determining prognosis. Beyond the known association of IVS with prognosis, PVR and pulmonary arterial compliance demonstrated an ex­cellent association with the event rate, even greater than the variables suggested by international recom­mendations. Although the cause of this finding has not been established, a possible hypothesis is that both compliance and PVR continuously worsen from the onset of the disease to the later stages. (12,13) In contrast, cardiac output and stroke volume remain normal due to compensatory mechanisms, only to worsen in advanced stages of PH. (14) In this sense, the absence of association between PAPI and RVSWI and the incidence of events can be explained because both variables not only do not decrease in the initial stages, but also tend to increase during these stages, only to decrease in the final stages of PH. This makes their behavior unpredictable and poorly related to the severity of the disease. (15)

Table 1. Baseline characteristics

6MWT: 6-minute walking test; CI: cardiac index; CO: cardiac output; HIV: human immunodeficiency virus; mPAP: mean pulmonary arterial pressure; NYHA FC: New York Heart Association functional class; PAWP: pulmonary arterial wedge pressure; PDE5: phosphodiesterase 5; PVR: pulmonary vascular resistance; RAP: right atrial pressure; WU: Wood Units Quantitative variables are presented as mean ±SD or median (IQR) according to their distribution.

These parameters can be very useful in the assess­ment of the prognosis of PH in entities other than those in group 1. The European guidelines support this assertion by establishing specific medical treat­ment for PAH in patients with left heart failure or pulmonary parenchymal disease (groups 2 and 3), as long as PVR is > 5 WU. This implies that there is an underlying acknowledgment of the correlation be­tween elevated PVR and the severity of the disease. In addition, in recent years, several clinical trials in PAH have included PVR as a pathophysiologic end­point to determine the presence or absence of clini­cal benefit from treatment without considering other hemodynamic variables. (16-18) Both situations, in addition to the findings of not only our study but also others that suggest similar conclusions, underscore the prognostic significance of PVR and compliance as hemodynamic markers. This explains their useful­ness both for diagnosis and during follow-up. In fact, an analysis of the REVEAL registry shows that pa­tients with PVR < 5 WU have a 5-year survival rate >70%, while those with higher PVR have a survival rate < 60%. (19)

Table 2. Event rates for each hemodynamic variable

PAPI: pulmonary artery pulsatility index; PVR: pulmonary vascular resistance; RVSWI:right ventricular systolic work index; SVI: stroke volume index.

Table 3. Mortality for each hemodynamic variable

PAPI: pulmonary artery pulsatility index; PVR: pulmonary vascular resistance; RVSWI: right ventricular systolic work index; SVI: stroke volume index.

Our study has some limitations. First, most pa­tients had idiopathic PAH or PAH associated with connective tissue disease, with few patients associ­ated with congenital heart disease, less than in other registries, who usually present with hemodynamic pa­rameters different from the general population with PAH. Second, the hemodynamic variables used as risk parameters are recommended for patients with group 1 pulmonary hypertension, whereas our registry in­cluded patients from all groups. This is because most of these risk parameters have been defined based on expert recommendations with little scientific evi­dence to support them, and are suggested mainly for patients with idiopathic or heritable PAH or associ­ated with drugs. Additionally, they are commonly used for all the groups in clinical practice worldwide, since groups 2 to 5 lack their own risk parameters.

Finally, we did not analyze whether the improve­ment of worsening of the hemodynamic parameters during follow-up affected the event rate, as indicated by the risk variables recommended by the guidelines. Further follow-up of patients will be required to dem­onstrate this question.

CONCLUSIONS

Conflicts of interest

None declared.
(See conflicts of interest forms on the website).

https://creativecommons.org/licenses/by-nc-sa/4.0/

©Revista Argentina de Cardiología

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