Pulmonary arterial hypertension therapies in patients with obesity hypoventilation syndrome: a case series

Abstract

Obesity hypoventilation syndrome is caused by complex interactions between multiple pathological processes, including diminished respiratory drive and sleep-related breathing alterations, leading to structural and functional respiratory impairment and ultimately, pulmonary hypertension. Because pulmonary hypertension is closely associated with obesity hypoventilation syndrome, thoroughly evaluating its etiology is essential, and individualized treatments must be considered. We describe 2 patients with obesity hypoventilation syndrome exhibiting severe pulmonary hypertension with pulmonary vascular resistance exceeding 5 Wood units; both were classified as Group 1 pulmonary hypertension, ie, pulmonary arterial hypertension. Initially admitted to our hospital complaining of dyspnea, both patients commenced pulmonary arterial hypertension therapies in addition to positive airway pressure therapy and diuretics, improving their hemodynamic status, dyspnea, and exercise capacity, and finally enabling their discharge. These findings suggest that pulmonary arterial hypertension can coexist with obesity hypoventilation syndrome, and pulmonary arterial hypertension therapies, introduced with careful consideration, may provide substantial benefits for select patients.

Citation:

Daigo K, Hiraide T, Momoi M, et al. Pulmonary arterial hypertension therapies in patients with obesity hypoventilation syndrome: a case series. J Clin Sleep Med. 2025;21(4):723–732.

INTRODUCTION

Obesity hypoventilation syndrome (OHS) is defined as the combination of obesity (body mass index [BMI] > 30 kg/m²), daytime hypoventilation and hypercapnia (partial pressure of arterial carbon dioxide > 45 mmHg), and sleep-disordered breathing.¹ In patients with OHS, multiple factors including upper-airway obstruction, increased work of breathing, and blunted central respiratory drive result in structural and functional respiratory impairment and ultimately, pulmonary hypertension (PH).² Notably, 58% of patients with OHS are complicated by PH.³

The 2022 European Society of Cardiology and European Respiratory Society Guidelines for the Diagnosis and Treatment of PH provide 5 clinical classifications for PH. These include pulmonary arterial hypertension (PAH; Group 1), PH associated with left heart disease (Group 2), PH associated with lung disease with or without hypoxia (Group 3), PH associated with pulmonary artery obstructions (Group 4), PH with unclear or multifactorial mechanisms (Group 5).⁴ Patients with PAH are hemodynamically characterized by precapillary PH in the absence of other causes of precapillary PH. As PH is closely associated with OHS, a thorough evaluation of its etiology is essential, and individualized treatments must be considered for each patient.

Although PH can lead to right ventricular (RV) dysfunction and generally poor prognosis,⁵ treatments for PH have improved significantly over the years, including the development of PAH therapies. However, studies regarding the implementation and efficacy of PAH therapies for PAH accompanying OHS remain limited. Here, we report 2 patients with OHS and severe PAH who were successfully treated with PAH therapies, in conjunction with a multidisciplinary approach to OHS.

REPORT OF CASES

Case 1

A 60-year-old female was diagnosed with obstructive sleep apnea (OSA) in 2016 by polysomnography revealing an apnea-hypopnea index of 41.1 events/h. At that time, she weighed 145 kg and her BMI was 57.3 kg/m². She had been on nasal continuous positive airway pressure (CPAP) with auto CPAP mode and a 90% inhalation pressure was 7.4 cmH₂O at night. She was admitted to a hospital complaining of progressive dyspnea on exertion in June 2021. Her BMI was 44 kg/m², and an echocardiogram at the time of admission demonstrated severe PH. Thus, she was referred to our hospital for further management. At the time of transfer, her symptoms were classified as World Health Organization Function class IV.

The patient’s percutaneous oxygen saturation was 88% under 3 L/min oxygen administration via nasal cannula. Bilateral jugular vein distention and lower limbs edema were apparent. Her lung sounds were normal, but heart auscultation revealed gallops with a loud P2 component of the second heart sound. Chest x-ray demonstrated cardiomegaly and a notably enlarged pulmonary trunk (Figure 1A). An electrocardiogram showed sinus rhythm with a heart rate of 70 beats/min, while right axis deviation, clockwise rotation, and a deep S wave in the V5 lead suggested RV hypertrophy (Figure 1B). Serum B-type natriuretic peptide level was elevated to 871.3 pg/mL, and high sensitivity cardiac muscle troponin T level was 0.025 ng/mL. Endocrinologic investigations of serum and 24-hour pooled urine were performed, but there was no evidence of secondary causes of obesity such as Cushing’s disease or hypothyroidism. Laboratory tests for human immunodeficiency virus antigen and autoantibody screening were negative. An echocardiogram showed a normal left ventricular ejection fraction of 64.4%. The RV was dilated with a base diameter of 60 mm, and RV function was reduced, represented by a tricuspid valve annulus peak systolic velocity of 8.0 cm/s (Figure 1C, Table 1). Arterial blood gas analysis under 5 L/min oxygen administration revealed a pH of 7.44, partial pressure of arterial oxygen of 94.4 mmHg, partial pressure of arterial carbon dioxide of 45.5 mmHg, and bicarbonate of 30.9 mmol/L, which was taken as evidence of metabolic alkalosis caused by the loop diuretics she was taking (Table 1). She had no history of apnea beginning in childhood, thus excluding the possibility of congenital central hypoventilation syndrome. There were no episodes of progressive muscle weakness, making neuromuscular junction disorders, such as myasthenia gravis, unlikely. Additionally, a computed tomography scan revealed no distinct abnormalities in her lungs. Although her hypercapnia was mild probably due to the CPAP therapy, with the presence of obesity, hypercapnia, and OSA, she was diagnosed with OHS.

Figure 1. Images of patient in case 1.

(A) Chest x-ray, (B) electrocardiogram, and (C) echocardiogram at the time of admission. (D) Chest x-ray, (E) electrocardiogram, and (F) echocardiogram after the treatment. (G) A graphical summary of body weight, renal function, pulmonary pressures, and the use of medications throughout the patients’ hospital stay. BW = body weight, Cre = creatinine, mPAP = mean pulmonary artery pressure, RAP = right atrial pressure, RV = right ventricle, UN = urea nitrogen.

Table 1.

BMI, SpO₂, lists of medications, and results of key examinations throughout each patient’s treatment course.

Case 1	Admission (First RHC)	Day 27 (Second RHC)	Discharge (Third RHC)
BMI	45.7	42.6	34.5
SpO2	95	95	98
Oxygen administration	5 L/min, NC	2 L/min, NC	5 L/min, NC
Medications	Furosemide 80 mg	Furosemide 60 mg (iv)	Selexipag 2.4 mg
	Spironolactone 50 mg	Dobutamine 2.5 γ (div)	Riociguat 3 mg
	Bisoprolol 1.25 mg	Riociguat 3 mg	Macitentan 10 mg
	Tolvaptan 15 mg	Macitentan 10 mg	Azosemide 30 mg
		Azosemide 60 mg	Spironolactone 25 mg
		Spironolactone 50 mg	Tolvaptan 15 mg
		Tolvaptan 15 mg	Pimobendan 2.5 mg
		Trichlormethiazide 1 mg	Potassium L-aspartate 6.3 g
			Sodium chloride 1 g
ABG
pH	7.440	7.560	7.527
PaO2 (mmHg)	94.4	67.8	101.0
PaCO2 (mmHg)	45.5	36.3	33.7
HCO3− (mmol/L)	30.9	32.5	27.9
SaO2 (%)	97.4	95.1	98.7
BE (mmol/L)	6.7	10.3	5.1
Laboratory data
UN (mg/dL)	33.5	50.3	19.4
Cre (mg/dL)	1.19	1.73	1.81
Sodium (mmol/L)	139.7	126.4	127.6
Potassium (mmol/L)	4.3	3.7	4.1
Cl (mmol/L)	99	85	91
WBC (/µL)	4,100	4,000	4,300
RBC (/µL)	468 × 104	500 × 104	302 × 104
Hb (g/dL)	16.1	16.5	10.3
Plt (/µL)	11.4 × 104	11.5 × 104	18.3 × 104
BNP (pg/mL)	871.3	N/A	144.3
Troponin T (ng/mL)	0.025	N/A	N/A
Right heart catheterization
RAP (mmHg)	12	7	4
RVP (mmHg)	101/18	50/12	33/6
PAP (mmHg)	100/51 (67)	58/25 (40)	33/10 (22)
PAWP (mmHg)	14	6	13
CO (L/min)	2.97	4.15	4.87
CI (L/min/m2)	1.32	1.90	2.47
PVR (WU)	17.85	8.20	1.85
Echocardiography
LVDd (mm)	35	—	38
LVDs (mm)	23	—	25
LVEF (%)	64.4	—	70.0
E/e’	13.6	—	7.0
RVD (base) (mm)	60	—	41
TRPG (mmHg)	102	—	N/A
RV s’ (cm/s)	8.0	—	12.9
TAPSE (cm)	N/A	—	2.0
IVC (mm)	26	—	16
Spirometry
VC (L)	2.08	—	2.40
%VC	73.5	—	87.0
FVC (L)	1.96	—	2.28
FEV1 (L)	1.30	—	1.68
FEV1% (%)	66.3	—	73.7
%FEV1	59.6	—	79.2
DLco (mL/min/mmHg)	7.51	—	8.07
%DLco	31.6	—	34.8

Case 2	Admission	Day 8 (First RHC)	Discharge (Second RHC)
BMI	56.1	48.6	44.6
SpO2	85 | 94	85 | 92	95
Oxygen administration	None | 4 L/min, NC	None | 3 L/min, NC	None
Medications	Furosemide 20 mg	Furosemide 40 mg (iv)	Furosemide 40 mg
	Azosemide 30 mg	Furosemide 20 mg	Azosemide 30 mg
	Spironolactone 50 mg	Azosemide 30 mg	Spironolactone 50 mg
	Dapagliflozin 10 mg	Spironolactone 50 mg	Dapagliflozin 10 mg
		Tolvaptan 3.75 mg	Macitentan 10 mg
		Dapagliflozin 10 mg	Tadalafil 40 mg
		Potassium chloride 2.2 g
ABG*
pH	7.465	7.431	7.458
PaO2 (mmHg)	51.2	44.2	55.1
PaCO2 (mmHg)	45.0	54.4	43.7
HCO3− (mmol/L)	32.3	36.2	30.9
SaO2 (%)	84.3	78.4	88.5
BE (mmol/L)	8.6	11.9	7.0
Laboratory data
UN (mg/dL)	21.6	16.5	15.4
Cre (mg/dL)	1.07	0.96	0.80
Na (mmol/L)	138.8	139.4	133.6
K (mmol/L)	3.4	3.4	3.6
Cl (mmol/L)	96	94	95
WBC (/µL)	6,200	4,300	4,900
RBC (/µL)	5.03 × 104	5.14 × 104	5.28 × 104
Hb (g/dL)	16.3	16.9	17.1
Plt (/µL)	13.0 × 104	11.7 × 104	13.0 × 104
BNP (pg/mL)	368.1	192.0	86.0
Troponin T (ng/mL)	0.029	0.024	0.021
Right heart catheterization
RAP (mmHg)	—	21	6
RVP (mmHg)	—	95/22	76/8
PAP (mmHg)	—	101/51 (70)	79/39 (53)
PAWP (mmHg)	—	13	11
CO (L/min)	—	5.81	7.80
CI (L/min/m2)	—	2.46	3.44
PVR (WU)	—	9.82	5.38
Echocardiography
LVDd (mm)	40	—	40
LVDs (mm)	26	—	24
LVEF (%)	63	—	71
E/e’	10.2	—	11.0
RVD (base) (mm)	72	—	66
TRPG (mmHg)	57.4**	—	103.4
RV s’ (cm/s)	6.7	—	7.1
TAPSE (cm)	1.9	—	1.2
IVC (mm)	30	—	23
Spirometry
VC (L)	2.97	—	2.47
%VC	71.1	—	59.5
FVC (L)	2.86	—	2.20
FEV1 (L)	2.00	—	1.39
FEV1% (%)	69.9	—	63.2
%FEV1	54.8	—	38.4
DLco (mL/min/mmHg)	17.4	—	17.0
%DLco	52.8	—	52.0

RVP was demonstrated as systolic or end-diastolic pressure and PAP was demonstrated as systolic or diastolic (mean) pressure. *ABG analysis was performed with room air in case 2. **TRPG was underestimated due to poor scanning and trivial TR. — = data not available, ABG = arterial blood gas, BE = base excess, BMI = body mass index, BNP = brain natriuretic peptide, CI = cardiac index, Cl = chloride, CO = cardiac output, Cre = creatinine, DLco = diffusing capacity of the lungs for carbon monoxide, E/e’ = peak early mitral inflow velocity/peak early diastolic mitral annular velocity, FEV1 = forced expiratory volume in 1 second, FVC = forced vital capacity, Hb = hemoglobin, HCO₃⁻ = bicarbonate, iv = intravenous injection, IVC = inferior vena cava, LVDd = left ventricular end-diastolic diameter, LVDs = left ventricular end-systolic diameter, LVEF = left ventricular ejection fraction, N/A = not available, NC = nasal cannula; PaCO₂ = partial pressure of arterial carbon dioxide, PaO₂ = partial pressure of arterial oxygen, PAP = pulmonary artery pressure, PAWP = pulmonary artery wedge pressure, Plt = platelet, PVR = pulmonary vascular resistance, RAP = right atrium pressure, RBC = red blood cell, RHC = right heart catheterization, RVD = right ventricular diameter, RVP = right ventricular pressure, RV s’ = tricuspid valve annulus peak systolic velocity, SaO₂ = arterial oxygen saturation, SpO₂ = percutaneous oxygen saturation, TAPSE = tricuspid annular plane systolic excursion, TRPG = tricuspid regurgitation pressure gradient, UN = urea nitrogen, VC = vital capacity, WBC = white blood cell, WU = wood units.

Right heart catheterization (RHC) on day 3 showed a mean pulmonary artery pressure (PAP) of 67 mmHg, cardiac output (CO) of 2.97 L/min measured by the Fick method, cardiac index (CI) of 1.32 L/min/m², mean right atrial pressure of 12 mmHg, mean pulmonary artery wedge pressure of 14 mmHg, and pulmonary vascular resistance (PVR) of 17.85 Wood units (Table 1). These outcomes suggest high-risk PH according to the 2022 European Society of Cardiology and European Respiratory Society guideline.⁴ A pulmonary ventilation and perfusion scan did not exhibit an apparent mismatch. Pulmonary function tests showed both mild restrictive and obstructive disorders with a forced expiratory volume in 1 second of 66.3% and a vital capacity of 73.5% (Table 1), but the computed tomography scan did not show any findings of specific lung disease. Abdominal ultrasonography showed no evidence of cirrhosis or portal hypertension. Considering the highly elevated PAP without a significant increase in pulmonary artery wedge pressure, we assessed the hemodynamics and classified her with precapillary PH. Because she had no other signs of PH causes, we concluded that this patient had Group 1 PH, ie, PAH.

The standard approach to treating obesity, calorie restriction and an optimized rehabilitation program was adopted. Intravenous administration of dobutamine (2.0 μg/kg/min) and diuretics (furosemide 120 mg/d), in addition to oral diuretics including spironolactone (25 mg/d) and tolvaptan (15 mg/d), were initiated given the patient’s decreased RV function and significant PH. Furthermore, considering the PH etiology, introduction of PAH therapies was required, although they needed to be initiated from a low dose because of a concern for pulmonary edema induced by increased CO from the right to the left side of the heart. As vasodilators for PAH, we started macitentan (10 mg/d) on day 4 and riociguat (initiated with 3 mg/d and titrated to 7.5 mg/d) on day 8. These approaches improved the patient’s condition to some extent, but follow-up RHC on day 27 revealed a high mean PAP of 40 mmHg and PVR of 8.20 Wood units despite improvements in volume status represented by improved right atrial pressure and concordant elevation in renal function (Table 1 and Figure 1G). These findings led us to continue titrating PAH therapies. From day 40, dobutamine was reduced using a step-by-step approach. However, she subsequently experienced low output syndrome on day 45, including fatigue, hypotension, and worsened renal function, so the dobutamine dose was increased to 2.5 μg/kg/min. Considering the echocardiogram on admission, which exhibited significant RV dilatation and reduced RV function, it had been estimated that it would take prolonged time to terminate dobutamine, waiting until her PH improved. In addition, fluid administration for low output syndrome worsened her respiratory condition, which led to the 24-hour use of CPAP with 5 L/min oxygen administration from day 48.

Along with these physical problems, her food intake significantly decreased during the hospitalization, and she became depressed about not being able to eat enough. Furthermore, she began to feel anxious about shortness of breath, and she was reluctant to wean herself from daytime CPAP. Following a neuropsychiatric consultation, treatment was continued with supportive care from psychiatrists, mainly thorough counseling. On day 62, dobutamine was gradually reduced again since riociguat was successfully titrated to the maximum dose of 7.5 mg/d. An improvement in PH was pivotal to enable her to wean off CPAP and dobutamine and ultimately be discharged. Therefore, we added selexipag (initiated with 0.8 mg/d and titrated to 2.4 mg/d) on day 65 to strengthen the treatment for PAH. As a result of this multidisciplinary therapy, dobutamine was finally terminated on day 166 with the assistance of oral inotropes, pimobendan. Her body weight decreased from 116.9–87.3 kg and her BMI from 45.7–34.5 kg/m². An RHC on day 174 showed significant improvement in hemodynamic status (mean PAP of 22 mmHg, CO of 4.87 L/min, CI of 2.47 L/min/m², and PVR of 1.85 Wood units [Table 1]). Chest x-ray showed cardiomegaly improvement (Figure 1D), and the deep S wave in the V5 electrocardiogram lead became insignificant (Figure 1E). Echocardiogram revealed a reduced RV size (41 mm) compared with pretreatment (60 mm) (Figure 1F, Table 1). As her dyspnea improved, she was able to wean from CPAP during daytime on day 159 and thereafter used 5 L/min oxygen administration via nasal cannula instead. Finally, on day 175, she was discharged from the hospital.

Case 2

A 34-year-old male was referred to our department in October 2023 for gradually progressing systemic edema and dyspnea on exertion over several months. He was diagnosed with OHS in 2009, with a body weight of 153 kg, a BMI of 56.2 kg/m², and an apnea-hypoxia index of 108 events/h determined by polysomnography. Initially, he commenced CPAP treatment, but subsequently, it was switched to bilevel positive airway pressure (adaptive servo-ventilation autoset mode with 4–14 cmH₂O pressure support) in 2017.

Upon admission to our department, his body weight was 144.6 kg and his BMI was 56.1 kg/m². The P2 component of the second heart sound was loud, and his lower extremities exhibited apparent pitting edema. Chest x-ray revealed a dilated pulmonary artery and cardiomegaly (Figure 2A). Right axis deviation and complete right bundle branch block were observed in an electrocardiogram, suggesting clinical RV overload (Figure 2B). An echocardiogram revealed distinct RV enlargement with a 72-mm base diameter and apparent left ventricle compression (Figure 2C). The percutaneous oxygen saturation was 85% in room air, and arterial blood gas analysis showed a pH of 7.46, partial pressure of arterial oxygen of 51.2 mmHg, partial pressure of arterial carbon dioxide of 45.0 mmHg, and bicarbonate of 32.3 mmol/L, which was inferred as evidence of metabolic alkalosis caused by diuretics he was taking regularly (Table 1). After 4 L/min oxygen administration via nasal cannula, the percutaneous oxygen saturation increased to 94%. A computed tomography scan showed no signs of lung disease, and perfusion scintigraphy of the lungs did not reveal any defects.

Figure 2. Images of patient from case 2.

(A) Chest x-ray, (B) electrocardiogram, and (C) echocardiogram at the time of admission. (D) Chest x-ray, (E) electrocardiogram, and (F) echocardiogram after the treatment. (G) A graphical summary of body weight, renal function, pulmonary pressures, and the use of medications throughout the patients’ hospital stay. BW = body weight, Cre = creatinine, mPAP = mean pulmonary artery pressure, RAP = right atrial pressure, RV = right ventricle, UN = urea nitrogen.

Because volume overload was obvious from his present illness and examinations, we initiated intravenous diuretics administration (furosemide 60 mg/d) in combination with spironolactone (50 mg/d) and tolvaptan (7.5 mg/d). He subsequently lost approximately 20 kg of body weight within a week. On day 8, mean PAP measured by RHC was 70 mmHg, CO was 5.81 L/min measured by the Fick method, CI was 2.46 L/min/m², mean right atrial pressure was 21 mm Hg, mean pulmonary artery wedge pressure was 13 mm Hg, and PVR was 9.82 Wood units (Table 1), suggesting severe PH and residual congestion. Continued diuresis was considered pivotal on the basis of the RHC result, but pulmonary artery wedge pressure did not exceed 15 mmHg, which indicated precapillary PH. Since he had no other apparent cause of PH, we concluded that he had comorbid severe PAH with OHS. As such, normalizing his hemodynamics would be difficult by diuresis or weight loss alone. Based on these assessments, we decided to introduce PAH therapies after modifying fluids valance. His response to diuretics was good, and oxygen administration was successfully terminated on day 15, with an percutaneous oxygen saturation level of approximately 95% in room air thereafter. Subsequently, we introduced macitentan (10 mg/d) on day 21 and tadalafil (40 mg/d) on day 24. He also underwent dietary adjustment and physical therapy with the support of a multidisciplinary team consisting of nurses, pharmacists, nutritionists, and physical therapists.

Four weeks after admission, RHC was repeated, and mean PAP was 53 mmHg, mean right atrial pressure was 6 mmHg, CO was 7.80 L/min, CI was 3.44 L/min/m², and PVR was 5.38 Wood units (Table 1). This result reflected preferential changes in congestion, but PAP and PVR remained high, which was concordant with the PAH diagnosis. Because PH required better management, we commenced treatment with selexipag (0.4 mg/d). After the course of the treatment, his dyspnea on exertion was ameliorated, and chest x-ray revealed improvements in pulmonary artery dilatation and cardiomegaly (Figure 2D), whereas an electrocardiogram exhibited no significant changes compared with the pretreatment phase (Figure 2E). Notably, an echocardiogram showed an apparently reduced RV size of 66 mm compared with the pretreatment (72 mm), which consequently attenuated left ventricle compression (Figure 2F, Table 1). He was discharged from the hospital on day 31 with a body weight of 114.4 kg and a BMI of 44.6 kg/m².

DISCUSSION

We report 2 patients with OHS and severe PH whose etiologies were classified as PAH. In both cases, PVR exceeded 5 Wood units at the first RHC, and precapillary PH persisted even after conventional heart failure therapy and optimal treatment for chronic respiratory failure, including positive airway pressure therapy. Introducing PAH therapies in both patients in combination with general approaches to OHS improved hemodynamics and symptoms.

The pathophysiologic mechanisms of PH in OHS include chronic hypoxemia that induces vasoconstriction and remodeling of the pulmonary artery, resulting in endothelial dysfunction, arterial wall thickening, and fibrosis. Additionally, severe obesity contributes to the development of PH through restrictive ventilatory impairment and wide intrathoracic pressure shifts in the respiratory cycle caused by increased upper airway resistance.⁶ Furthermore, OHS is associated with both systemic inflammation and endothelial dysfunction secondary to the morbidly obese state.⁷ In a previous study that analyzed 246 patients with OHS, BMI was an independent risk factor for PH in a multivariate model with an adjusted odds ratio of 1.07, suggesting that interventions targeting weight loss to ameliorate PH play a critical role.⁸ Given these underlying mechanisms, it is widely accepted that weight loss has beneficial effects on patient with OHS.⁹

Positive airway pressure therapy is another important therapeutic approach to OHS. In the long-term Pickwick randomized controlled trial comparing the effectiveness of noninvasive ventilation and CPAP on echocardiographic changes in 196 patients with OHS, approximately 50% of patients had PH (defined as pulmonary artery systolic pressure ≥ 40 mmHg at baseline), and both noninvasive ventilation and CPAP significantly improved pulmonary artery systolic pressure over 3 years.¹⁰ Of note, especially in the subgroup of those with PH at baseline, noninvasive ventilation and CPAP improved pulmonary artery systolic pressure by 9–10 mmHg at the 1-year follow-up.¹⁰ Another study also demonstrated significant improvements in hemodynamics and exercise capacity following 3 months of noninvasive ventilation in patients with PH (Group 3) due to hypoventilation.¹¹

Contrary to these findings previous studies, the 2 patients described here consistently exhibited precapillary PH despite years of positive airway pressure therapy. This underscores the importance of a comprehensive assessment of PH etiology and classification to provide individualized treatments. It is worth noting that a recent review article indicated that OSA was present in 23.5% of patients with PAH.¹² It can be asserted that PAH coexists in a proportion of patients with OSA or OHS. Moreover, Javaheri et al recently summarized findings from the Pickwick trial and showed that PH (defined as pulmonary artery systolic pressure ≥ 40 mmHg measured by echocardiography) prevalence was 52% in the entire cohort at baseline, which declined to 28% at the 1-year follow-up and remained around 25–30% at the 2- or 3-year follow-up.¹³ A possible explanation for these findings is that the underlying etiology of PH in some of these patients may be attributable to not only OHS but also other causes of PH, such as precapillary PH (Group 1). Considering the etiology of PH in the 2 present cases, left heart disease was excluded on the basis of findings from RHC and echocardiography. No other causes of PH, such as lung diseases, pulmonary artery obstructions, connective tissue diseases, congenital heart diseases, portal hypertension, or PH-inducing medications, were identified. Although differentiating Group 3 PH, specifically PH secondary to alveolar hypoventilation, from Group 1 PH can be challenging in patients with obesity, characteristic findings—including severe precapillary PH, a high alveolocapillary difference estimated from arterial blood gas analysis, decreased DLco, and markedly elevated RVP with low CI—supported the Group 1 PH diagnosis in both cases.

After a comprehensive evaluation of the underlying PH etiology, we propose that introducing PAH therapies might be considered in cases where severe PAH coexists with OHS. In case 1, the key reason for commencing PAH therapies was PH severity. Given that PVR was at 17.85 Wood units and echocardiography revealed significant dilation, as well as RV dysfunction, the therapeutic approach included initiating PAH therapies in addition to conventional heart failure treatment, weight management, and positive airway pressure therapy. Consequently, we decided to introduce macitentan the day following the initial RHC. Riociguat was also initiated as early as day 8, because of the need for it to be titrated gradually. Following the initiation and adjustment of these medications, although there were both physical and psychiatric complication (represented by a failure of dobutamine weaning at the first attempt), her PVR eventually dropped below 3 Wood units as PAH therapies titrated. The resulting improvement in hemodynamic status allowed for the discontinuation of intravenous dobutamine. This favorable hemodynamic change also led to significant dyspnea relief, enabling her to walk short distances independently, which was crucial for her discharge. The effectiveness of PAH therapies in this patient further confirmed the diagnosis of PAH because these therapies are generally ineffective in Group 3 PH. The patient in case 2 responded well to initial diuresis after admission, represented by a decrease in body weight (from 144.6 kg on admission to 125.2 kg on the first RHC day). Nevertheless, he demonstrated severe PH with mPAP of 70 mmHg and PVR of 9.82 Wood units, which directed us to initiate PAH therapies. In this case, an important limitation was that the patient underwent repeated RHC only a few days after starting macitentan and tadalafil. This is likely to have obscured the extent to which PAH therapies contributed to improving PH. However, given the etiology of PH in both patients, we attribute their improvements to not only weight loss, diuresis, or CPAP and bilevel PAP, but also the introduction of PAH therapies. In summary, we suggest that PAH therapies can have a positive impact on hemodynamics, exercise capacity, and symptom relief in patients with PAH comorbid with OHS.

The downsides of this approach include difficulties in patient selection and side effects of PAH therapies. As in the cases here, assessing PH etiology is generally difficult, especially when differentiating Group 3 PH from Group 1 PH (PAH) in patients with obesity. Patients should be carefully evaluated, and select patients classified with PAH could be candidates for this approach. Another downside might be the side effects of PAH therapies. The use of vasodilators can cause hypotension, flushing, headache, nausea, and vomiting. It is difficult to anticipate these side effects, so prudent decisions should be made considering the risk and benefit of introducing these drugs.

Our study has several limitations. First, arterial blood gas analysis at the time of OSA diagnosis was unavailable for either patient. This made it difficult to assess baseline partial pressure of arterial carbon dioxide levels before undergoing positive airway pressure therapy. Second, measuring pulmonary pressures in patients with obesity is challenging. In our facility, when RHC is performed, the patient is placed in a supine position, and the catheter is inserted through the right internal jugular vein. The mean values of several stable waveforms cycles were measured in the 2 present cases because they had difficulty in holding breath. We did not correct for intrinsic positive end-expiratory pressure using esophageal manometry; thus, the possibility of measurement error remains. In addition, a reversibility test using inhaled nitric oxide was not conducted because it is unavailable at our institution. We acknowledge this as a significant limitation in our study. Third, a sleep study was not performed in either patient after weight loss was achieved. Therefore, the existence or severity of their OSA before discharge was unknown. Fourth, other causes of PH such as venous hypertension or capillary hemangiomatosis caused by obesity were not completely ruled out. This limitation is inevitable because these conditions are typically revealed by autopsy. Finally, it remains to be established whether PAH therapies should be introduced upfront, as in the present cases, or secondary to weight loss and heart failure stabilization. Further studies about introducing PAH therapies to patients with PAH coexisting with obesity are warranted.

In conclusion, PH is a clinically important comorbidity of OHS, and we describe 2 patients with PAH exhibiting PVR more than 5 Wood units. PAH therapies concomitant with a multidisciplinary approach to OHS successfully improved their symptoms and hemodynamic status. Our study underscores the fact that PAH therapies might be beneficial for specific patients with PAH comorbid with OHS. However, further case reports and studies are needed to generalize this approach.

DISCLOSURE STATEMENT

All authors have seen and approved the manuscript. The authors report no conflicts of interest.

ABBREVIATIONS

BMI

body mass index

CI

cardiac index

CO

cardiac output

CPAP

continuous positive airway pressure

OHS

obesity hypoventilation syndrome

OSA

obstructive sleep apnea

PAH

pulmonary arterial hypertension

PAP

pulmonary artery pressure

PH

pulmonary hypertension

PVR

pulmonary vascular resistance

RHC

right heart catheterization

RV

right ventricular