Uncommon cause of paradoxical low-flow low-gradient severe aortic stenosis due to pulmonary arterial hypertension

Abstract

A 74-year-old female presented with dyspnea [New York Heart Association (NYHA) class IV and 94 % percutaneous oxygen saturation at room air]. She was diagnosed with pre-capillary pulmonary arterial hypertension (PAH) due to connective tissue disease [mean pulmonary arterial wedge pressure (mPAWP): 6 mmHg; pulmonary arterial pressure (PAP): 93/36 [59] mmHg; pulmonary vascular resistance (PVR): 12.2 Wood units; cardiac index (CI): 2.95 L/min/m²] and paradoxical low-flow low-gradient severe aortic stenosis (AS) [mean gradient: 16.7 mmHg; max jet velocity: 2.87 m/s; aortic valve area: 0.70 cm²; left ventricular ejection fraction (LVEF): 65 %; stroke volume index (SVi): 31.1 mL/m²]. The patient was treated for PAH, which was considered to be the underlying cause of the paradoxical low-flow low-gradient severe AS. After 10-month titration of riociguat (7.5 mg/day) and selexipag (1.6 mg/day), PAH [mPAWP: 9 mmHg; PAP: 55/23 (36) mmHg; PVR: 5.9 Wood units; CI: 3.10 L/min/m²] improved and normal-flow high-gradient severe AS became evident (mean gradient: 41.9 mmHg; max jet velocity: 4.04 m/s; aortic valve area: 0.70 cm²; LVEF: 65 %; SVi: 41.7 mL/m²). Although symptoms improved to NYHA class II, exertional dyspnea persisted. Accordingly, medication dosages were further increased, and transcatheter aortic valve replacement was successfully performed 12 months after treatment initiation.

Learning objective

We aimed to understand how group 1 pulmonary arterial hypertension (PAH) can lead to paradoxical low-flow low-gradient severe aortic stenosis (AS), recognize its key clinical and hemodynamic features, and differentiate it from group 2 pulmonary hypertension (PH) associated with left heart disease, including isolated post-capillary PH and combined post- and pre-capillary PH. We also explored hemodynamic changes after PAH therapy, including transition to normal-flow high-gradient severe AS.

Introduction

Paradoxical low-flow (LF) low-gradient (LG) severe aortic stenosis (AS) is defined as follows: mean pressure gradient of aortic valve <40 mmHg, aortic valve area (AVA) ≤1.0 cm², preserved left ventricular ejection fraction (LVEF) ≥50 %, and stroke volume index (SVi) ≤35 mL/m² [1,2]. In a Western study, LF-LG patients had worse outcomes after transcatheter aortic valve replacement (TAVR) than normal-flow high-gradient patients [2]. Similarly, in Japanese patients, who typically have smaller bodies, paradoxical LF-LG severe AS was associated with poor outcomes following TAVR [1].

Various causes for paradoxical LF-LG severe AS have been proposed, including a smaller left ventricular chamber size due to left ventricle hypertrophy, mitral regurgitation, tricuspid regurgitation (TR), constrictive pericarditis in certain rare cases, and others [3,4]. However, there is a lack of data on pulmonary arterial hypertension (PAH) as a cause of paradoxical LF-LG severe AS and the relevant treatment outcomes in patients.

Case report

A 74-year-old female came to the emergency department complaining of dyspnea at rest [New York Heart Association (NYHA) class IV symptoms]. The patient's height and weight were 159 cm and 52 kg, respectively. Physical examination revealed a regular pulse (94 beats/min), normal blood pressure (125/75 mmHg), and low percutaneous oxygen saturation (94 %, room air). She had a history of autoimmune hepatitis at the age of 70 years; thus, she was receiving steroid treatment (4 mg).

Chest X-rays showed pulmonary arterial enlargement (Fig. 1A). B-type natriuretic peptide (BNP) levels were elevated (517 pg/mL). Antinuclear antibody (640 times: normal range <40) and anticentromere antibody (108 times: normal range <10) levels were also elevated; therefore, she was diagnosed with CREST syndrome, a subtype of systemic sclerosis. Levels for aspartate aminotransferase (33 U/L), alanine aminotransferase (31 U/L), serum creatinine (0.87 mg/dL), and KL-6 (280 U/mL) were within the normal range. Transthoracic echocardiography (TTE) revealed left ventricular end-diastolic diameter (LVDd) of 32 mm, left ventricular end-systolic diameter (LVDs) of 21 mm, dilated right ventricle (Fig. 1C), mild TR, tricuspid regurgitation pressure gradient (TRPG) of 45 mmHg, and paradoxical LF-LG severe AS (mean pressure gradient: 16.7 mmHg; max jet velocity: 2.87 m/s; AVA: 0.70 cm²; LVEF: 65 %; and SVi: 31.1 mL/m²).

Fig. 1.

X-rays, computed tomography, echocardiography, and pressure waveform during transcatheter aortic valve replacement. (A) X-rays showing pulmonary artery enlargement. (B) Contrast computed tomography showing no pulmonary embolism and pulmonary artery obstructions. (C) Four-chamber view of echocardiography at baseline showing dilated right ventricle. (D) Four-chamber view of echocardiography after 10 months of pulmonary arterial hypertension drug treatment showing improvement of dilated right ventricle from baseline. (E) Computed tomography showing no parenchymal lung diseases and minimal interstitial lung disease. (F) Pressure waveform of left ventricle (red line) and aorta (yellow line) before transcatheter aortic valve replacement, suggesting aortic stenosis. (G) Pressure waveform of left ventricle (red line) and aorta (yellow line) after transcatheter aortic valve replacement, suggesting improvement of aortic stenosis.

The baseline hemodynamic data obtained by right heart catheterization (RHC) are shown in Table 1. The mean pulmonary arterial wedge pressure (PAWP) and pulmonary arterial pressure (PAP) were 6 mmHg and 93/36 (59) mmHg, respectively. The pulmonary vascular resistance (PVR) was elevated to 12.2 WU, while the cardiac index (CI) (2.95 L/min/m²) was within the normal range. The SVi measured by catheterization was 32.9 mL/m², which was consistent with TTE findings. The systemic blood pressure (149/75 mmHg) and left ventricle pressure (183/10 mmHg) were also measured, further indicating AS. The AVA measured by catheterization was 0.70 cm², which was consistent with TTE findings. In addition, coronary angiography did not show any significant stenosis. Based on the low mean PAWP, we diagnosed the patient with group 1 PAH and not group 2 pulmonary hypertension (PH) associated with left heart disease (LHD). PAH was also considered to be the cause of the paradoxical LF-LG severe AS. Furthermore, we excluded common causes of PH. For example, group 3 PH due to lung disease was excluded by no parenchymal lung diseases and minimal interstitial lung disease on computed tomography scans (Fig. 1E), normal pulmonary function [forced vital capacity 2.82 L (126 % predicted), forced expiratory volume in 1 s 1.98 L (120 % predicted)], and a markedly reduced lung diffusion capacity for carbon monoxide [4.62 mL/min/mmHg (30.6 % predicted)]. Group 4 PH (chronic thromboembolic PH) was excluded using contrast-enhanced computed tomography (Fig. 1B).

Table 1.

Hemodynamic data by right heart catheterization.

	Baseline	1 week after introducing therapy	2 weeks after introducing therapy	10 months after introducing therapy	1 week after TAVR
PAP (mmHg)	93 / 36 (59)	79 / 33 (51)	74 / 24 (45)	55 / 23 (36)	56 / 20 (36)
Mean PAWP (mmHg)	6	12	13	9	13
PVR (Wood units)	12.2	9.4	6.2	5.9	3.5
CI (L/min/m2)	2.95	2.83	3.09	3.10	3.90
SVi (mL/m2)	32.9	35.8	40.2	42.8	45.5
SvO2 (%)	79.5	78.1	80.4	80.2	83.8
PAH drugs	none	Riociguat 3.0 mg	Riociguat 4.5 mg Selexipag 0.4 mg	Riociguat 7.5 mg Selexipag 1.6 mg	Riociguat 7.5 mg Selexipag 3.2 mg Macitentan 10 mg

PAP; pulmonary arterial pressure (systolic / diastolic / mean), PAWP; pulmonary arterial wedge pressure, PVR; pulmonary vascular resistance, CI; cardiac index, SVi; stroke volume index, SvO₂; mixed venous oxygen saturation, PAH; pulmonary arterial hypertension, TAVR; transcatheter aortic valve replacement.

Management

The patient required emergency admission and was started on 2 L oxygen to prevent hypoxia; 6-minute walking distance (6MWD) under oxygen was 140 m. Riociguat (1.5 mg/day) was introduced in small doses for maximum capacity to prevent hemodynamic collapse and was well tolerated, thus enabling up-titration to 3.0 mg/day. After 1 week, RHC data showed improvement (Table 1). The riociguat dose was further increased to 4.5 mg/day, and selexipag (0.4 mg/day) was added. At 2 weeks, additional hemodynamic improvement was observed, with BNP decreasing to 63 pg/mL and the 6MWD increasing to 300 m. The patient was discharged with 24-hour oxygen and PAH medications.

During out-patient follow-up, medication doses were gradually increased, leading to further improvements in BNP and 6MWD (Fig. 2). RHC data at 10 months post-therapy initiation showed improved hemodynamics (Table 1), and the patient's NYHA class improved from IV to II. At the same time, TTE revealed LVDd of 44 mm, LVDs of 21 mm, improvement of the dilated right ventricle from baseline (Fig. 1D), mild TR, TRPG of 37 mmHg, and normal-flow high-gradient severe AS (mean pressure gradient: 41.9 mmHg; max jet velocity: 4.04 m/s; AVA: 0.70 cm²; LVEF: 65 %; and SVi: 41.7 mL/m²).

Fig. 2.

Time course of therapeutic effects after introduction of pulmonary arterial hypertension drugs.

BNP, B-type natriuretic peptide; 6MWD, 6-minute walking distance.

We considered that intervention for AS was necessary, since the patient's exertional symptoms persisted despite PAH improvement, suggesting that AS was a contributing factor. Surgical aortic valve replacement (SAVR) was considered to be a high-risk procedure because of the PAH and steroid use; thus, TAVR was selected. We successfully performed TAVR at 12 months after treatment initiation with riociguat (7.5 mg/day) and selexipag (3.2 mg/day) (Fig. 1F and G). Macitentan (10 mg/day) was then administered on the day after TAVR, and RHC data obtained 1 week after TAVR (Table 1) showed further improvement.

Discussion

Based on the clinical classification of PH established by the 2022 European Society of Cardiology/European Respiratory Society guidelines, PAH associated with connective tissue disease belongs to group 1 and PH associated with LHD belongs to group 2 [5]. Group 1 PAH is defined as pre-capillary PH in the absence of LHD or lung disease, with a mean PAP >20 mmHg, PAWP ≤15 mmHg, and PVR >2 WU.

Group 2 PH is further classified into two distinct hemodynamic phenotypes: isolated post-capillary pulmonary hypertension (IpcPH: mean PAP >20 mmHg, PAWP >15 mmHg, and PVR ≤2 WU) and combined post- and pre-capillary pulmonary hypertension (CpcPH: mean PAP >20 mmHg, PAWP >15 mmHg, and PVR >2 WU]. Our patient was diagnosed as group 1 PAH with complications of paradoxical LF-LG severe AS.

PH has been reported in a substantial proportion of severe AS patients, with a prevalence ranging from approximately 30 % to 50 %, and is associated with increased mortality after both TAVR and SAVR [[6], [7], [8]]. In these studies, PH was diagnosed using either TTE or RHC. However, without RHC, it is impossible to determine whether the patient has group 2 PH. Thus, these previous reports would not have been able to distinguish between group 1 PAH and group 2 PH. On the other hand, prognostic stratification was reportedly conducted for patients before TAVR based on pre-capillary PH, IpcPH, and CpcPH, using RHC data in all cases [9]. The authors concluded that early improvement in PH occurred only in patients with IpcPH and was associated with a survival benefit, while those with pre-capillary PH or CpcPH showed significantly higher risk for mortality after TAVR.

Reportedly, TAVR induces several changes (decreased afterload; reduced mitral regurgitation, pulmonary pressures, and TR; increased right ventricular function as measured by tricuspid annular plane systolic excursion) that can provide further insight into the potential mechanisms that contribute to improved outcomes [10]. Notably, any favorable changes are more likely to be present in patients with IpcPH. In contrast, these favorable events are unlikely to be present in AS patients with complications of pre-capillary PH and CpcPH following TAVR due to the progression of pulmonary vasculopathy. Thus, patients with pre-capillary PH and severe AS, such as this case, will require medication for pre-capillary PH and intervention for the aortic valve. Therefore, accurate hemodynamic classification using RHC will be crucial for guiding appropriate management and differentiating pre-capillary PH from post-capillary PH, including its subtypes IpcPH and CpcPH, in patients with severe AS.

We considered that her symptoms and hypoxia were primarily caused by PAH and selected riociguat as the initial medication, because it is a short-acting drug and can be started in small doses. We also thought that it would be easier to monitor the time course of hemodynamic changes in AS after the introduction of the PAH drug. Moreover, we carefully added a small amount of selexipag to the dose, since it is also a short-acting drug. Ten months after the introduction of PAH drugs, the LF caused by the PAH had improved, indicating that the patient's hemodynamics had changed to those of normal-flow high-gradient severe AS. Although the CI increased to 3.10 L/min/m² after PAH therapy, there were no signs of high-output heart failure such as bounding pulses or widened pulse pressure. Mixed venous oxygen saturation remained consistently high from baseline under oxygen therapy (Table 1), likely reflecting a physiologic response rather than a true high-output state.

Additional studies are needed to evaluate the efficacy of PAH therapy and TAVR or SAVR in patients with paradoxical LF-LG AS due to pre-capillary PH. The management of CpcPH patients with more severe hemodynamic conditions also warrants further investigation.

Consent statement

Permission for publication was obtained from the patient.

Declaration of competing interest

None.