Atrioventricular area difference does not predict outcome in pulmonary arterial hypertension

Background: In pulmonary arterial hypertension (PAH), right ventricular (RV) pressure overload causes increased RV stiffness, prolonged relaxation, and altered RV diastolic function. Concurrently, left ventricular (LV) filling and size are reduced, with altered diastolic mechanics as a result. Thus, diastolic function may be altered on both sides of the heart and is associated with disease severity. Atrioventricular area difference (AVAD) is a novel method to evaluate diastolic function, based on assessing the difference in cross-sectional area between the ventricle and atrium during diastole [1, 2], and has shown promise as a prognostic tool in adults with and without diastolic dysfunction [3]. AVAD and its prognostic ability has so far not been assessed in PAH. Therefore, the aim of this study was to assess the prognostic utility of left- and right-sided AVAD, in terms of predicting transplantation-free survival in patients with PAH.

Methods: Patients with idiopathic/hereditable PAH (IPAH/HPAH) or PAH associated with connective tissue disease (APAH-CTD) were retrospectively included (Table 1). Standard, short-axis balanced steady-state free precession cine images were acquired at 1.5 T (Philips Achieva, Best, The Netherlands, or Siemens MAGNETOM Aera, Forchheim, Germany). The software Segment [4] was used to delineate the endocardium of both atria and ventricles at the start of diastole and at end diastole. The largest cross-sectional area (A) of each ventricle and atrium was determined, with AVAD defined as A_ventricle – A_atrium, for the left and right side of the heart, respectively, at both the start and end of diastole. Events were defined as lung transplantation or death within a 5-year follow-up period. The Mann-Whitney U test was used to compare the AVAD of patients with and without events. Kaplan-Meier curves and the logrank test were used to compare transplantation-free survival for those with infra- or supra-median AVAD values.

Results: Seventy-one patients were included (39 with IPAH/HPAH, and 32 with APAH-CTD) (Table 1). Forty of the 71 patients (56%) experienced an event during the 5-year follow-up. Left- or right-sided AVAD at either diastolic time point did not differ between patients that experienced an event or not (Figure 1). There was no difference in transplantation-free survival between the patients with infra- or supra-median AVAD, independent of ventricle or diastolic time point (Figure 2).

Conclusion: Left- and right-sided AVAD did not predict 5-year transplantation-free survival in patients with PAH.

Table 1. Subject characteristics and results. Data is expressed as median (Q1, Q3) unless otherwise specified. APAH-CTD, pulmonary arterial hypertension associated with connective tissue disease; AVAD, atrioventricular area difference; CMR, cardiovascular magnetic resonance imaging; HPAH, hereditable pulmonary arterial hypertension; IPAH, idiopathic pulmonary arterial hypertension.

	All	No event	Event	p-value
N, total (%)	71	31 (44%)	40 (56%)	-
IPAH/HPAH, n	39	21	18	-
APAH-CTD, n	32	10	22	-
Age at CMR, years	65 (42, 73)	55 (32, 68)	71 (58, 75)	0.002
Women, n (%)	54 (76%)	25 (81%)	29 (73%)	0.58
Mean pulmonary arterial pressure (mmHg)	44 (37, 52)	46 (38, 52)	43 (36, 52)	0.93
Pulmonary vascular resistance(Wood units)	7.9 (5.5, 12.1)	9.4 (5.0, 11.8)	7.8 (6.0, 12.9)	0.68
Pulmonary artery wedge pressure (mmHg)	8 (5, 11)	8 (5, 10)	8 (5, 11)	0.59
AVAD (cm2) Left side start of diastole	-2.2 (-6.1, 0.4)	-1.5 (-5.3, 0.5)	-2.8 (-7.6, 0.1)	0.25
AVAD (cm2) Left side end diastole	9.8 (6.7, 14.2)	11.9 (7.0, 14.9)	9.7 (6.5, 14.0)	0.51
AVAD (cm2) Right side start of diastole	0.9 (-5.2, 4.6)	1.8 (-4.6, 4.6)	-0.8 (-5.7, 4.9)	0.42
AVAD (cm2) Right side end diastole	18.6 (9.8, 23.7)	20.4 (12.2, 24.1)	18.5 (8.9, 23.2)	0.49

Figure 1. Atrioventricular area difference (AVAD) in patients with pulmonary arterial hypertension (PAH). AVAD was calculated on the left side (top panels) and the right side (bottom panels), at the start and end of diastole. AVAD was compared between patients who did not experience an event (green) and those who experienced an event (purple). Events were defined as lung transplantation or death. The p-values are derived from the Mann-Whitney U test.
Figure 2. Transplantation-free survival in patients with PAH in groups of infra- and supra-median atrioventricular area difference (AVAD), for the left side (top panels) and the right side (bottom panels), at the start and end of diastole. The p-values are derived from the logrank test. The reported hazard ratios (HR) correspond to infra-median vs. supra-median AVAD.