Prognostic Role of Right Ventricular-Pulmonary Artery Coupling Assessed by TAPSE/PASP Ratio in Patients With Acute Heart Failure

Study population

We included all consecutive patients with AHF who were admitted to Chungnam National University Hospital in Daejeon, Korea, between January 2009 and December 2016. AHF was diagnosed based on symptoms, elevated levels of N-terminal pro-B-type natriuretic peptide, and evidence of either pulmonary edema or objective findings of structural heart disease. Patients with severe valvular disease requiring surgery or those with acute coronary syndrome were excluded from the study. The study protocol received approval from the Institutional Review Board (IRB) of the hospital (IRB No. 2017-04-005). Due to the retrospective nature of the study, the IRB waived the requirement for informed consent from the participants. The research was conducted in accordance with the principles outlined in the Helsinki Declaration.

Study variables and definitions

Baseline demographic data and past medical history were extracted from the patients’ medical records. Body mass index (BMI) was calculated using the recorded height and weight measurements. We used the blood test results on the day of admission. Hypertension was defined as the use of antihypertensive medication for a duration of more than 6 months. Additionally, patients who had a diagnosis of hypertension and were solely on lifestyle modification treatment were also classified as hypertensive.

Patients with diabetes mellitus (DM) were identified as those who were actively receiving treatment with oral hypoglycemic agents or insulin. Furthermore, individuals with an abnormal fasting glucose level (≥ 126 mg/dL) or an abnormal 2-hour postprandial glucose level (≥ 200 mg/dL) who were being treated with dietary modification only were also diagnosed with DM. The presence of atrial fibrillation (AF) was determined by documentation of AF on electrocardiograms or by a previous diagnosis of AF using the International Classification of Diseases 10th Revision (ICD-10) code I48. Ischemic heart disease (IHD) was ascertained if patients had a history of coronary artery intervention and a corresponding diagnosis of IHD using the ICD-10 codes I20, I21, and I25. Based on the left ventricular ejection fraction (LVEF) derived from echocardiographic findings during AHF admission, patients were categorized into 3 groups: heart failure with reduced ejection fraction (HFrEF) if LVEF was ≤ 40%, heart failure with mildly reduced ejection fraction (HFmrEF) if 40% < LVEF < 50%, and heart failure with preserved ejection fraction (HFpEF) if LVEF was ≥ 50%.

Echocardiographic measurement

All echocardiographic examinations were performed with echocardiographic machines and a 2.5 MHz probe using standard echocardiographic techniques, including M-mode, 2-dimensional, and Doppler modalities, as recommended by the American Society of Echocardiography.10) We selected the most recent echocardiogram if there were multiple echocardiograms during admission, and the mean time between the admission and the echocardiographic examination was 2.5 ± 4.9 days.

LV end-diastolic and end-systolic volumes were calculated from the apical 4- and 2-chamber views using the 2-dimensional Simpson’s method, and LVEF was calculated from these values. Mitral inflow velocities (mitral E and A velocities, E/A ratio, deceleration time) were measured by pulsed-wave Doppler at the point of mitral valve coaptation, and mitral annular velocities (mitral annular E′ velocity) were estimated by the tissue Doppler of the mitral annular septum. Anteroposterior LA diameter was measured from the parasternal long-axis view. PASP was estimated from the peak tricuspid regurgitation jet velocity (TR Vmax) derived from continuous wave Doppler, and right atrial (RA) pressure was estimated from the size and collapsibility of the inferior vena cava. Right ventricular fractional area change (RVFAC), one of the global parameters of RV systolic function, was calculated from the areas of RV with RV-focused apical 4-chamber view. TAPSE was measured as the length between the end-diastolic and peak systolic points of the lateral tricuspid annulus.

We measured left atrial (LA) strain from the stored echocardiographic images using TomTec-Arena version 4.6 (TomTec, Munich, Germany), a vendor-independent strain measurement software.11) The software automatically tracked speckles along the endocardial border and myocardium throughout the cardiac cycle after manually tracing the endocardial border on the end-systolic frame in the selected image. The left atrial global longitudinal strain (LAGLS) was defined as the first peak of positive deflection demonstrating LA reservoir function, using the R-R gating as the zero reference point. The LAGLS was calculated as the mean of the four segments of each apical view, averaged from the global longitudinal strain values obtained from the apical 4- and 2-chamber views. Due to poor delineation and contamination of the pulmonary veins, the roof of the LA was not analyzed. All LAGLS values were measured on a single cardiac cycle and all LAGLS values were calculated independently by an echocardiography specialist who was blinded to the clinical data.

Statistical analyses

Continuous variables are presented as means ± standard deviations, categorical variables as frequencies. For comparisons between groups, we used the Student’s t-test for continuous variables and the χ² test for categorical variables. Pearson’s correlation coefficient was used to calculate the correlation between TAPSE/PASP and other echocardiographic variables. We used multivariate Cox proportional hazards analysis to determine the independent predictors of all-cause death and included all significant variables in the univariate analysis as covariates in the multivariate analysis because we had a sufficient number of death events in our study. However, in the multivariate analysis, we excluded variables that had multicollinearity with other variables. SPSS version 25 (IBM Corp., Armonk, NY, USA) was used for data analysis. A 2-tailed p-value of < 0.05 was considered statistically significant.

Patients characteristics

After screening all patients with AHF admitted to our hospital, we analyzed a total of 1,147 patients (575 men, aged 70.81 ± 13.56 years) after excluding patients with exclusion criteria. Baseline characteristics are summarized in Table 1. Hypertension was the most common associated cardiovascular risk factor (56.5%), and 385 patients (33.6%) had DM. The mean LVEF was 39.0 ± 15.4%, and 638 (55.6%), 175 (15.3%) and 334 (29%) patients were classified as having HFrEF, HFmrEF and HFpEF, respectively. The mean value of TAPSE was 14.8 ± 4.7 mm, PASP was 42.3 ± 13.3 mmHg, and TAPSE/PASP ratio was 0.37 ± 0.17. TAPSE/PASP ratio showed significant correlations with LVEF (r = 0.243, p < 0.001), LA diameter (r = −0.320, p < 0.001), LAGLS (r = 0.496, p < 0.001), mitral E/E′ ratio (r = −0.337, p < 0.001), and RVFAC (r = 0.496, p < 0.001).

Table 1
Baseline characteristics according to tricuspid annular plane systolic excursion/pulmonary artery systolic pressure ratio (> 0.33)

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Patients with a decreased TAPSE/PASP ratio (< 0.33) exhibited several notable differences compared to those with a preserved TAPSE/PASP ratio (Table 1). Specifically, the decreased TAPSE/PASP ratio group had a significantly lower BMI, lower systolic blood pressure, and higher heart rate. AF was also more frequently observed in patients with a decreased TAPSE/PASP ratio. Furthermore, the decreased TAPSE/PASP ratio group demonstrated significantly higher LV dimensions and volumes, lower LVEF, increased LA diameter, and decreased LAGLS. PASP was notably elevated in the decreased TAPSE/PASP ratio group. Moreover, HFrEF was more prevalent in the decreased TAPSE/PASP ratio group.

All-cause death and its determinants

A total of 387 patients (33.7%) died during the median follow-up of 29.0 months. The comparison of variables by death is shown in Supplementary Table 1. Patients who died were older (76.4 ± 10.6 years old vs. 68.0 ± 14.0 years old, p < 0.001), had a lower BMI (21.9 ± 3.6 kg/m² vs. 23.8 ± 4.4 kg/m², p < 0.001), and a higher proportion of patients with severe symptoms of New York Heart Association (NYHA) functional class IV (12.7% vs. 5.6%, p < 0.001). The incidence of hypertension (61.2% vs. 54.1%, p = 0.023), DM (38.8% vs. 30.9%, p = 0.008), and IHD (39.3% vs. 32.0%, p = 0.015) was higher in the deceased group than in the survivors. Blood tests also showed higher BUN (28.6 ± 16.5 mg/dL vs. 21.8 ± 12.6 mg/dL, p < 0.001) and creatinine (1.58 ± 1.28 mg/dL vs. 1.24 ± 1.49 mg/dL, p < 0.001) in the death group. Total cholesterol was significantly lower in the deceased group (145.4 ± 42.5 mg/dL vs. 154.3 ± 44.8 mg/dL, p = 0.001).

Echocardiography showed that LV volumes were significantly lower in the death group, but LVEF did not differ between the two groups (39.5 ± 15.2% vs. 38.7 ± 15.5%, p = 0.415). In terms of LV diastolic parameters, LA diameter (44.6 ± 10.1 mm vs. 43.2 ± 7.9 mm, p = 0.022) and mitral E/E′ ratio (19.6 ± 9.3 vs. 17.9 ± 9.3, p = 0.030) were higher in the death group. While RV systolic function as assessed by TAPSE and RVFAC was similar in both groups, PASP was significantly higher in the death group (44.9 ± 13.7 mmHg vs. 41.0 ± 12.9 mmHg, p < 0.001). Thus, TAPSE/PASP ratio was significantly lower in the death group (0.33 ± 0.16 vs. 0.37 ± 0.17, p < 0.001).

In univariate analysis in the prediction of all-cause death (Table 2), TAPSE/PASP ratio (hazard ratio [HR], 0.219; p < 0.001) was a significant variable. Other variables included age, BMI, diastolic blood pressure, NYHA functional class IV, hypertension, DM, IHD, creatinine, total cholesterol, LV end-diastolic dimension, LA diameter, mitral E/E′ ratio, PASP, LAGLS, TAPSE, and use of renin-angiotensin system (RAS)-blockers and beta-blockers.

Table 2
Univariate analysis in the prediction of all-cause death within 5 years

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The results of the multivariate analysis, including the variables that were significant in the univariate analysis, were presented in Table 3. TAPSE/PASP ratio was a statistically significant parameter of all-cause mortality (HR, 0.450; p = 0.037) after the adjustment of significant variables in the univariate analysis including age, BMI, NYHA functional class, hypertension, DM, serum creatinine, total cholesterol, LV end-diastolic dimension, LA diameter, and use of RAS-inhibitor and beta-blocker. In the receiver operating curve analysis, the best cut-off level for predicting all-cause death is 0.33 (area under the curve = 0.576, p < 0.001), with a sensitivity of 65% and a specificity of 47%. TAPSE/PASP ratio < 0.33 was associated with increased all-cause mortality after adjustment of other variables (HR, 1.306; p = 0.025; Figure 1) after the multivariate analysis.

Table 3
Multivariate analysis in the prediction of all-cause death within 5 years

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Figure 1
Survival curve according to tricuspid annular plane systolic excursion/pulmonary arterial systolic pressure (TAPSE/PASP ratio). Patients with TAPSE/PASP ratio ≥ 0.33 have better survival.
CI: confidence interval, HR: hazard ratio, PASP: pulmonary artery systolic pressure, TAPSE: tricuspid annular plane systolic excursion.

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