Pulmonary Hypertension: Controversial and Emerging Topics

This book is a clinical guide to controversial and emerging topics in pulmonary hypertension. There are multiple challenges and unanswered questions encountered by clinicians that evaluate, diagnose and treat patients with suspected or confirmed pulmonary vascular disease. This book provides a deep dive into the diagnosis and therapeutics of pulmonary hypertension supported by the literature and balanced with personal clinical experience. Expert authors have chosen these specific topics to address issues where uncertainty and/or controversy exists as well as highlight areas that are just being incorporated into clinical practice. These topics include: exercise pulmonary hypertension, sickle cell disease and pulmonary hypertension, and sarcoid pulmonary hypertension, among many others. Chapters address the diagnostic and treatment dilemmas posed by these various clinical entities through literature review, sharing of expert opinion, and review of recent guidelines and their applicability to the multiple different nuanced presentations of pulmonary hypertension. This is an ideal guide for pulmonologists, cardiologists, and other specialty practitioners caring for patients with pulmonary hypertension.

• Language: English
• Publisher: Springer International Publishing
• Release date: Oct 13, 2020
• ISBN: 9783030527877

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© Springer Nature Switzerland AG 2020

H. J. Ford et al. (eds.)Pulmonary HypertensionRespiratory Medicinehttps://doi.org/10.1007/978-3-030-52787-7_1

1. Exercise Pulmonary Hypertension

Michael G. Risbano¹  

(1)

Division of Pulmonary Allergy and Critical Care Medicine Pittsburgh Heart, Lung, Blood and Vascular Medicine Institute, University of Pittsburgh Medical Center, Pittsburgh, PA, USA

Michael G. Risbano

Email: [e-mail]

Keywords

Exercise pulmonary hypertensionPulmonary hypertensioniCPETExercise right heart catheterizationExercise hemodynamics

Introduction

Exercise pulmonary hypertension (ePH) is an underappreciated form of exertional limitation that results in symptoms with physical activity and a reduction in aerobic exercise capacity [1–4]. ePH is a clinical syndrome that may reside on a continuum between normal resting hemodynamics and manifest pulmonary arterial hypertension (PAH). An abnormal pulmonary vascular response during exercise delineates ePH from normal resting hemodynamics. At the present time there are no uniformly established definitions of ePH; however, there has been a recent interest in reviving a definition of ePH.

At the fourth World Symposium on Pulmonary Hypertension in Dana Point (CA, USA) in 2008 the definition of exercise-induced pulmonary hypertension of mean pulmonary artery pressure (mPAP) >30 mmHg was abandoned due to the lack of a unified diagnostic approach, concerns pertaining to normal aging and changes in hemodynamics, as well as the need for more precise hemodynamic cutoffs [5, 6]. The subsequent fifth and sixth World Symposium on Pulmonary Hypertension both held in Nice, France, in 2013 and 2018 did not provide a working definition of ePH. The task force concluded that exercise challenge is beneficial methodology to unmask pulmonary vascular disease in patients with normal resting hemodynamics that are early in the disease state or well-compensated. They recommended that additional studies be performed to further refine the clinical syndrome of ePH [7, 8].

Exercise pulmonary hypertension (ePH) describes elevated right-sided filling pressures during exertion and is preferred to the older terminology exercise-induced pulmonary hypertension. The latter has implications that exercise has a causative role in the pulmonary vascular disease [9]. It may make sense to use the term exercise pulmonary arterial hypertension (ePAH) to primarily distinguish abnormally elevated right-sided filling pressures during exercise from exercise pulmonary venous hypertension (ePVH); however, this terminology has not been widely adopted in recent statement on pulmonary hemodynamics during exercise [9].

Patients at risk for developing ePH include systemic sclerosis [10, 11], chronic PE [12, 13], parenchymal lung disease (including ILD [3] and COPD [14, 15]), HFpEF [16, 17], HFrEF [18, 19], atrial septal defects [20], valve disease [21, 22], family members of patients with iPAH [17], and asymptomatic carriers of the BMPR2 gene mutation [23]. These groups are representative of the types of patients that may benefit from confrontational exercise testing, especially when resting supine invasive hemodynamics are either normal or borderline elevated. There is irony that the workup of patients with symptomatic exertion includes a majority of procedures performed at rest. It is therefore intuitive that the workup of symptomatic dyspnea may include exercise stress testing. Our preference is to perform invasive cardiopulmonary exercise testing (iCPET) , which in the vast majority of cases provides real pathophysiological insight into the condition contributing to patient’s symptoms and helps make a diagnosis. There have been significant scientific contributions in the literature that have helped define normal and abnormal values in ePH to help move the field of invasive exercise testing forward [1, 3, 12, 18, 24–26]. Ongoing work in the field may ultimately result in the restitution of a definition of ePH.

This chapter will focus on the controversial topic of exercise pulmonary hypertension, in particular the precapillary (arterial) syndrome measured by invasive cardiopulmonary hemodynamics. Normal resting hemodynamic values and borderline pressures will be addressed. The specifics of ePH and the clinical impact of ePH will be discussed. Unresolved questions and controversies regarding ePH will be covered. The evidence for treatment of ePH will be presented. Finally, methods to assess invasive exercise hemodynamics will be discussed. Topics of exercise pulmonary hypertension in the setting of specific disease states such as parenchymal lung disease, parenchymal lung disease, and left heart disease will be touched upon in this chapter but will not be completely addressed.

Normal Resting and Exercise Pulmonary Hemodynamics

What Is the Normal Pulmonary Vascular Response to Exercise?

One of the initial impediments to defining ePH was the lack of consensus for a normal resting pulmonary artery pressure. This concern has since been reconciled. At rest under normal conditions the pulmonary vasculature is a low-pressure high capacitance system. A landmark systematic review of the available literature by Kovacs et al. included 1187 healthy individuals with invasively measured hemodynamics and showed that normal resting mPAP ± SD is 14 ± 3.3 mmHg in the supine position and 13.6 ± 3.1 mmHg in the upright position [6]. In the supine position the upper limit of normal was 20.6 mmHg and 19.8 mmHg in the upright position. Resting mPAP was independent of gender. Based upon these findings, the sixth World Symposium on Pulmonary Hypertension redefined resting pulmonary arterial hypertension as mPAP >20 mmHg, PVR >3 WU with a pulmonary artery wedge pressure (PAWP) ≤15 mmHg [8].

The same review by Kovacs and colleagues showed that the upper limit of normal during exercise stress testing was dependent on the intensity of exercise with mPAP of 28.8 mmHg in the upright position with slight exercise and 36.8 mmHg at maximal exercise [6]. This amounted to 47% of the 91 normal subjects aged >50 years with an mPAP >30 mmHg in the slight exercise category. Of the 193 subjects with more than one level of exercise performed the mPAP was >30 mmHg in 21% of subjects aged <50 years at maximal exercise. Thus, it was concluded that the previous definition of mPAP >30 mmHg was not valid and there was no established upper limit of normal mPAP during exercise. As a result, the fifth World Symposium on Pulmonary Hypertension in 2013 removed the definition of ePH as an mPAP >30 mmHg, which had been in place for over 30 years [7].

Exercise Pulmonary Hypertension

What Are the Hemodynamic Criteria to Define ePH?

Other impediments to defining ePH have included the lack of a unified diagnostic approach, concerns regarding age-related changes in hemodynamics, and the need for more precise hemodynamic cutoffs [5, 6]. A variety of hemodynamic thresholds have been proposed to describe an abnormal pulmonary vascular response to exercise [9, 12, 18, 25–29]. These methods emphasize the pressure-flow relationship of mPAP to CO to delineate normal from abnormal exercise hemodynamics, underscoring mPAP as a flow-dependent variable. For example, highly trained athletes can generate an mPAP that may exceed 30 mmHg at peak exercise. The elevated mPAP is largely due to a conditioned increase in CO and stroke volume (SV) [30] rather than pulmonary vascular disease or diastolic dysfunction, for example, in an exceptionally healthy individual. Therefore, it is reasonable that ePH is not defined by mPAP alone. The conceptual basis of the mPAP-CO relationship is that disproportionate increases in mPAP are related to either remodeling of the pulmonary vasculature or transmission of the left atrial pressure to the pulmonary vasculature due to left heart disease as CO increases during exercise [25]. This pressure-flow approach alleviates some of the difficulties ascribed to the former ePH definition that solely employed mPAP >30 mmHg. Healthy individuals should not have an mPAP exceed 30 mmHg when CO is <10 L/min [25].

Possible hemodynamic criteria to describe the mPAP-CO relationship include:

1.

Single-point measurement where ePH is defined as mPAPmax >30 mmHg and TPRmax >3.0 WU at maximum exercise [12]

2.

Multipoint measurement where multiple mPAP and CO (4–5 data points are needed) are measured from start of exercise to peak exercise and the mPAP-COslope is defined as ≥3 WU [18]

3.

Two-point measurement of the mPAP-CO slope that includes the difference in maximal and resting ∆mPAP/∆CO >3.0 WU [28, 29]

4.

An age-based definition with age ≤50 years mPAPmax >30 mmHg, PVRmax >1.34 WU, or age >50 years mPAPmax >33 mmHg, PVRmax >2.11 WU [27]

The European Respiratory Society issued a statement on exercise hemodynamics in 2018 and although no official definition of ePH was recognized the single-point criteria seem to have been favored based upon previously reported findings [9, 12]. Herve and colleagues compared patients with an mPAPmax >30 mmHg to those with an mPAPmax >30 mmHg and TPRmax >3.0 WU to evaluate whether measuring mPAPmax >30 mmHg alone at maximum exercise overdiagnosed ePH [12]. The authors found that the addition of TPR to the ePH definition improved the specificity without significantly compromising sensitivity. They demonstrated that mPAPmax alone had lower specificity (0.77) and higher sensitivity (0.98) when compared to mPAPmax >30 and TPRmax >3.0 WU which had a specificity (1.0) and sensitivity (0.93).

The single-point method may outperform mPAP >30 mmHg threshold; however, how do the individual ePH definitions compare? A small trial by Godinas and colleagues compared the single-point, multipoint, and two-point measurements in 49 patients with pulmonary vascular disease with non-PH controls demonstrated diagnostic concordance of 78% among the three criteria [26]. The sensitivity and specificity of the single-point definition mPAPmax >30 mmHg and TPRmax >3.0 WU for ePH were reported as 0.94 and 1.0, respectively. This outperformed the sensitivity and specificity of the mPAP-COslope of 0.67 and 0.88 and ∆mPAP/∆CO >3.0 WU of 0.88 and 0.87, respectively. Additionally, the single-point definition reduced the misclassification of healthy controls diagnosed with ePH compared to mPAP >30 mmHg alone [31]. The value of an age-driven definition of ePH is unclear as the sensitivity and specificity has not been compared to the other three ePH definitions.

Should Age Be Considered in the Definition of ePH?

As the pulmonary vasculature ages, there is deterioration of the vascular structure and function due to remodeling with increases in pulmonary vascular stiffness that cause increases in pulmonary artery pressures and resistance [32]. The intrinsic pulmonary vascular changes of normal aging result in lower pulmonary artery compliance (PAC) and reduced pulmonary vascular reserve in humans aged >50 years [33]. In addition, alpha (𝛼), a mechanical descriptor of the pulmonary vasculature and a measure of vascular distensibility, is reduced in older patients [34–36]. The exact cause of the vascular stiffness in senescence remains unclear. Although age-related pulmonary vascular changes do not limit exercise in the majority of older healthy patients, identifying the limits of normal in aging is important when defining an abnormal pulmonary vascular response to exercise.

Kovacs and colleagues have shown mPAP increased with age with individuals aged >50 years with significantly higher mPAP compared to younger subjects; the mean mPAP ± SD in individuals ≥50 years was 14.7 ± 4.0 mmHg, 30–50 years was 12.9 ± 3.0 mmHg, and <30 years was 12.8 ± 3.1 mmHg [6]. In subjects aged <50 years Kovacs showed a ~60% increase in mPAP from rest 13.8 to 21.8 mmHg during mild exercise and was associated with an oxygen consumption (⩒O2) of 1362 mL/min and a CO 15.6 L/min. In contrast subjects aged >50 years had a ~120% increase in mPAP from 14.9 to 32.4 mmHg with an associated ⩒O2 of 1464 mL/min and a CO 13.1 L/min. The metabolic demand was similar for similar exercise efforts; however, the exercise increase in mPAP was disproportionate to the increase in CO.

Oliveira and colleagues, on the other hand, showed that at peak exercise, subjects aged ≤50 compared to >50 had similar mPAP (mean ± SD 22 ± 4 vs. 23 ± 5 mmHg; p = 0.22) with an upper limit of normal of 30 and 33 mmHg, respectively [27]. The CO was reduced in subjects aged ≤50 compared to >50 16.2 vs. 12.1 L/min (p < 0.001) which resulted in a lower PVR in younger subjects (with a mean ± SD 0.82 ± 0.26 vs. 1.20 ± 0.45 WU and an upper limit of normal 1.34 vs 2.1 WU, respectively). The older healthy subjects had reduced peak ⩒O2 (18.1 vs. 26.7 mL/kg/min; p < 0.01) and peak work (103 vs. 148 W; p < 0.01). The authors concluded that a definition for ePH may reasonably include an mPAP >30 mmHg with a PVR >1.34 WU for age ≤50 and >33 mmHg with a PVR >2.10 for age >50 years and have utilized these cutoffs in subsequent publications [2, 37].

Given the available data an age-driven definition of ePH may be useful to identify patients with ePH due to a pathologic state rather than normal aging. It is unclear if PVR is superior to TPR to define ePH as a direct comparison has not been performed. The European Respiratory Society position paper did not address these controversies, but future studies may provide clarification on the issue [9].

Is There Any Benefit to Performing Confrontational Exercise Testing in Patients with an mPAP 21–24 mmHg?

Resting mPAP between 21 and 24 mmHg formerly represented borderline pulmonary artery pressures. As a result of the sixth World Symposium on Pulmonary Hypertension in 2018 the working definition of PAH was changed to include mPAP >20 mmHg as long as pulmonary vascular resistance (PVR) is greater than 3.0 Wood units (WU) [8]. Not all at-risk patients with an mPAP between 21 and 24 mmHg will meet the strict definition of resting PAH, as many patients will have a normal PVR.

The clinical characteristics of patients with borderline pulmonary hypertension was not well understood until recently [2, 4, 11, 28, 38]. In a study of 141 patients with resting and exercise hemodynamics, 32 patients had borderline pulmonary artery pressures [28]. These patients were older and had a history of cardiac and lung disease. Exercise capacity in borderline mPAP compared to normal patients is limited with shorter 6-minute walk distance (6MWD) (383 ± 120 vs. 448 ± 92 meters; p = 0.001) and a trend toward a reduced ⩒O2peak (16.9 ± 4.6 vs. 20.9 ± 4.7 mL/min/kg; p = 0.09) [28]. Max hemodynamic response during exercise was higher in the borderline group. In particular the pressure-flow relationship measured as the slope of the mPAP-cardiac output (defined as the change in mPAP divided by change in CO from rest to 50 Watts) was higher in the borderline compared to normal group (5.2 vs. 3.2 mmHg/L/min; p < 0.001). This indicates that higher resting pulmonary artery pressures may result in elevated pulmonary vascular response to exercise.

What was unclear, however, was whether patients with resting mPAP 21–24 mmHg were associated with exercise pulmonary hypertension and if this impacted functional capacity. Lau and colleagues sought to answer these questions [4]. They studied 290 patients referred to a French pulmonary hypertension center where 86 patients had resting mPAP 21–24 mmHg by right heart catheterization. The resting hemodynamics including transpulmonary gradient (TPG), PVR, TPR, and PAWP were higher in the mPAP 21–24 population, likely due to increased resting pulmonary vascular tone. This population that underwent supine cycle ergometry had ePH defined as mPAPmax >30 mmHg and TPRmax >3.0 WU. Patients with mPAP 21–24 mmHg had peak exercise values mPAP, TPR, and PVR that were higher and CO lower compared to subjects with mPAP ≤20 mmHg. The mPAP 21–24 mmHg group had reduced peak exercise workload as well as reduced functional capacity with 6MWD (423 ± 110 vs 471 ± 109 meters; p = 0.002) and significantly worse New York Heart Association (NYHA) Functional Class compared to controls. With resting mPAP stratified into ranges <13, 13–16, 17–20, and 21–24 mmHg, there were significant stepwise increases in mPAP, TPR, PVR, and the mPAP/CO slope with an occurrence of ePH 7.7%, 38.7%, 60.3%, and 86%, respectively. This demonstrates that higher resting borderline pressures were associated with increased pulmonary vascular response during exercise. This work shows that high normal resting mPAP were associated with higher exercise cardiopulmonary hemodynamics, more patients meeting criteria for ePH, worse functional capacity, and increased exertional symptoms.

A 2017 study by Oliveira et al. [2] evaluated the same mPAP intervals as Lau et al. [4]; however, ePH was defined as mPAPmax ≥30 mmHg, PVRmax ≥120 dyne s cm−5, and PAWPmax <20 mmHg. Interestingly, the Lau study defined a prevalence of ePH as 65%, whereas Oliveira found the prevalence to be much lower at 27% (20 out of 74 patients) in patients with borderline mPAP. This discrepancy between the prevalence of ePH in borderline mPAP patients may be due to differing definitions of ePH and source of referral populations (PH center vs. dyspnea center). Oliveira demonstrated that the presence of ePH had a negative impact on exercise capacity on ⩒O2peak compared with non-PH patients. Those patients diagnosed with ePH had similar functional limitation as resting PH patients (⩒O2peak 67 ± 15 vs. 68 ± 17% predicted; p > 0.05) as well as associated chronotropic incompetence, increased right ventricular (RV) afterload, and evidence of RV-PA uncoupling. Patients with a resting mPAP 21–24 mmHg represent a population at risk for progression to resting pulmonary artery hypertension [2, 4, 39].

Disease states that are associated with borderline mPAP are heterogenous and include early pulmonary vascular disease (i.e., scleroderma, BMPR2 gene mutations), pulmonary parenchymal disease (COPD, ILD), left heart disease (HFpEF, HFrEF), or sleep-disordered breathing [28, 39–41]. Patients with these underlying disease states and borderline mPAP may benefit from further hemodynamic screening with confrontational exercise testing. This is particularly important as patients with chronic exertional dyspnea and ePH unmasked by exercise testing have increased mortality [42]. Therefore, symptomatic at-risk patients may benefit from a hemodynamic evaluation during confrontational invasive exercise testing to identify whether the exercise limitation is ePH. A borderline mPAP is prognostically worse compared to patients with normal pressures and is associated with not only a reduced exercise capacity, but increased risk for hospitalization and reduced survival at 1, 3, and 5 years [28, 41, 43].

What About the Wedge?

The proposed definitions of ePH describe an abnormal pulmonary vascular response to exercise, but do not discern whether an mPAP increase is related to the transmission of the left atrial pressure to the pulmonary vasculature due to left heart disease (Fig. 1.1). An abnormal PAWP >25 mmHg at maximum exercise may identify heart failure with preserved ejection fraction (HFpEF) [44]; however, some experts have identified 20 mmHg as the upper limit of normal [2, 45]. We utilize a lower limit of normal of PAWP >25 mmHg in the supine position [46] and PAWP >20 mmHg during iCPET studies in the upright position. Oliveira et al. showed that the peak PAWP during exercise in healthy adults aged >50 is similar to those aged ≤50 using a cutoff of 20 mmHg [27], though other authors have shown that PAWP may rely on age and exercise training in healthy controls [47]. The so-called left ventricular filling resistance represented by the PAWP/CO relationship has been proposed by Kovacs and colleagues [48]. This ratio may discriminate the pathologic from physiologic during exercise. Lewis and colleagues identified that a PAWP/CO slope >2 WU predicted reduced peak exercise capacity (⩒O2peak) and adverse composite cardiac outcomes such as cardiac death, incident resting PAWP elevation, or heart failure hospitalization at a mean of 5.3-year follow-up [49].

../images/473496_1_En_1_Chapter/473496_1_En_1_Fig1_HTML.png

Fig. 1.1

Relationship between exercise mean pulmonary artery pressure (mPAP) and cardiac output (CO). The data points represent mPAP and CO measured at maximal exercise. The mPAP to CO relationship split by total pulmonary resistance (TPR) discriminates patients with an abnormal pulmonary vascular response to exercise from control subjects and historical healthy volunteers. However, an mPAP >30 mmHg and TPR >3.0 WU does not discriminate patients with pulmonary vascular disease (PVD) from those with left heart disease (LHD). (This figure has been used with permission from reference [12])

Borlaug and colleagues showed that patients with HFpEF had a significant elevation in PAWP during passive leg elevation compared to patients without cardiac disease (+7 ± 3 vs. +2 ± 3 mmHg; p < 0.0001) [16]. With exercise, there was an early increase (1.5 min into low-level exercise at 20 W); the PAWP increased from baseline value in the HFpEF group to +16 ± 6 mmHg [80% of peak value] vs. noncardiac dyspnea patients to +5 ± 3 mmHg [80% of peak value], p < 0.0001 (Fig. 1.2). At peak exercise all HFpEF patients (n = 32) had a PAWP ≥20 mmHg vs. ≤18 mmHg in 96% of noncardiac dyspnea patients. Of the HFpEF patients, approximately 88% met criteria for ePH using mPAP >30 mmHg, which was primarily due to elevations in PAWP; PVR decreased in this group indicating ability to recruit pulmonary vasculature during exercise.

../images/473496_1_En_1_Chapter/473496_1_En_1_Fig2_HTML.png

Fig. 1.2

PCWP increases in patients with HFpEF from baseline to feet up and continues to increase with exercise compared to noncardiac dyspnea (NCD). The resting PCWP remains elevated at 1 min recovery. (This figure has been modified and used with permission from reference [16])

Interestingly Borlaug and colleagues evaluated 61 compensated HFpEF patients that performed iCPET testing at rest and submaximal exercise [50]. Using high-fidelity micromanometers with simultaneous lung ultrasound and echocardiography the group found that during exercise 54% of patients developed extravascular lung water associated with higher PAWP and a higher incidence of RV dysfunction by echocardiogram. The authors concluded that even at submaximal exercise the acute accumulation of extravascular lung water is related to elevations in central venous pressures secondary to RV abnormalities and RV-PA coupling. The mPAP, RAP, and PAWP, but not the PVR, were significantly higher in the increased extravascular lung water group. Identification of patients that develop extravascular lung water during exercise may help target therapy. However, the type of therapy is still subject to debate, but targeting extravascular lung water as well as elevated right-sided filling pressures may be warranted. Further studies are needed to understand different treatment modalities, and research is needed to understand the mechanisms driving the differences in lung water accumulation.

Obtaining a PAWP at rest and during exercise can be challenging and fraught with inaccuracy in spite of the best of intentions. An increase in PAWP may be related to left heart dysfunction (systolic, diastolic, or valve disease); however, in some patients (i.e., obstructive lung disease) increases in intrathoracic pressure may contribute to abnormally elevated PAWP during exercise. This is limitation that may restrict the generalizability of the PAWP/CO ratio [9]. In order to limit respiratory effects during exercise an averaging of the PAWP over several respiratory cycles and not at end expiration leads to a more accurate PAWP assessment [51].

The Clinical Impact of ePH

Exercise Pulmonary Hypertension, Who Cares?

Exercise pulmonary hypertension is a clinical syndrome marked by abnormalities in invasive exercise hemodynamics in at-risk individuals and accompanied by exercise limitation. Tolle and colleagues demonstrated that patients with a primary complaint of dyspnea studied during invasive cardiopulmonary exercise testing (iCPET) in the upright position had reduced ⩒O2peak and CO compared to normal controls [1]. Patients were defined as having ePH with normal resting hemodynamics (mPAP <25 mmHg) but abnormal pulmonary vascular response to exercise (mPAPmax ≥30 mmHg, PVRmax ≥80 dyne s cm−5, and PAWPmax <20 mmHg). The ePH patients had a reduced predicted ⩒O2peak 66.5 ± 16.3 vs. 91.7 ± 13.7%, p < 0.05, and CO 11.4 ± 3.0 vs. 15.5 ± 3.2 L/min, p < 0.05.

A 2016 study by Oliveira and colleagues evaluated pulmonary hemodynamics during iCPET and also found that patients diagnosed with ePH (n = 36, defined as an mPAPmax ≥30 mmHg, PVRmax ≥120 dyne s cm−5, and PAWPmax <20 mmHg) achieved a lower work rate of 87 ± 36 vs. 124 ± 43 Watts (W), p < 0.05, and a lower ⩒O2 peak of 76 ± 18 vs. 95 ± 10%, p < 0.05, compared to unaffected controls (n = 31) [52]. There was a trend toward reduced CO in the ePH group. A follow-up study by Oliveira et al. in 2017 demonstrated that regardless of the range of borderline mPAPs identified at rest, patients with ePH have a reduced exercise capacity [2]. This study compared 35 ePH with 224 non-PH patients that underwent iCPET which demonstrated similar reduction in ⩒O2 peak 67 ± 15 vs. 88 ± 19%, p < 0.05, and CO 10.2 ± 2.7 vs. 12.8 ± 3.9 L/min, p < 0.05. The cutoff values to define ePH were PAWPmax <20 mmHg with mPAPmax ≥30 mmHg and PVRmax ≥1.34 WU for age <50 years and mPAPmax ≥33 mmHg and PVRmax ≥2.1 WU for age >50 years. Additionally, peak oxygen delivery (DO2) was significantly reduced, with increased right ventricular load measured by right ventricular stroke work index (RVSWI) in the ePH vs. non-PH group. These studies reflect a reduced cardiopulmonary fitness and exercise capacity in individuals with ePH. Exercise limitation may be a result of inappropriate oxygen delivery due to lower CO related to reduced RV output. Finally, a study of scleroderma subjects with borderline pulmonary artery pressures (n = 29) demonstrated that resting mPAP >17 mmHg (n = 14) was associated with reduced 6-minute walk distance (6MWD) and ⩒O2 max [53].

Is There Evidence of Pulmonary Vasculature Pathology in ePH?

Our understanding that ePH may be a precursor to resting pulmonary hypertension has been made through hemodynamic associations and case series [2, 10, 12, 15, 25, 27, 34, 52, 54, 55]. Evidence demonstrating physical findings of early pulmonary vascular involvement has been shown in a single case study [56]. Bhatti and colleagues presented a case of a 42-year-old male with a past medical history of Raynaud’s and family history of idiopathic PAH and pulmonary fibrosis who presented with a complaint of dyspnea with very strenuous exercise. His workup including chest and cardiac imaging was unrevealing, though there was an isolated reduction in the diffusing capacity for carbon monoxide, and his 6MWD was >600 meters. iCPET revealed normal resting right-sided filling pressures. However, the ⩒E/⩒CO2 slope (a measure of ventilatory inefficiency) was abnormally increased, the ⩒O2 predicted was reduced, and the mPAP and TPR were elevated consistent with ePAH. In an attempt to rule out early idiopathic pulmonary fibrosis the patient underwent lung biopsy which showed early occlusive microvasculopathy