1 Taukinos

Phtn Classification Essay


Pulmonary hypertension (PH) is defined as a resting mean pulmonary artery pressure greater than 25 mmHg. The World Health Organization (WHO) classifies PH into five categories. The WHO nomenclature assumes shared histology and pathophysiology within categories and implies category-specific treatment. Imaging of the heart and pulmonary vasculature is critical to assigning a patient's PH syndrome to the correct WHO category and is also important in predicting outcomes. Imaging studies often reveal that the etiology of PH in a patient reflects contributions from several categories. Overlap between Categories 2 and 3 (left heart disease and lung disease) is particularly common, reflecting shared risk factors. Correct classification of PH patients requires the combination of standard imaging (chest roentgenograms, ventilation-perfusion scans, echocardiography, and the lead electrocardiogram) and advanced imaging (computed tomography, cardiac magnetic resonance imaging, and positron emission tomography). Despite the value of imaging, cardiac catheterization remains the gold standard for quantification of hemodynamics and is required before initiation of PH-specific therapy. These cases illustrate the use of imaging in classifying patients into WHO PH Categories

Keywords: CREST, Eisenmenger's syndrome, late gadolinium enhancement, pulmonary artery acceleration time, pulmonary capillary hemangiomatosis, pulmonary veno-occlusive disease, right ventricular hypertrophy


Reviews of pulmonary hypertension (PH) almost invariably begin with a hemodynamic definition accompanied by a reference to the five categories or groups of PH.[1,2] The hemodynamic definition of PH (mean pulmonary artery pressure, mPAP, at rest greater than 25 mmHg) is relatively straightforward, although estimations of PA pressures by echocardiography can be unreliable.[3] The clinician's challenge arises when reviewing the differential diagnosis to place the PH patient into one of the five WHO categories (Table 1). This classification has practical importance because there are category-specific treatments, such as medical therapies for pulmonary arterial hypertension (PAH) (Category 1 PH),[4,5] supplemental oxygen or continuous positive airway pressure (CPAP) for Category 3, and pulmonary artery endarterectomy for Category 4 PH, chronic thromboembolic PH (CTEPH).

Table 1

Updated WHO PH classification

Despite the importance of imaging to the categorization of PH, there is a paucity of articles showing representative diagnostic images for the WHO categories of PH. This visual compendium of images obtained in patients in each of the PH categories is meant to illustrate key diagnostic imaging features of each PH category and demonstrates the role of multimodality imaging in the categorization of PH. Conventional imaging (computed tomography (CT), echocardiography and Ventilation-perfusion scans (VQ scans)) are used to identify cardiac shunts, pulmonary emboli and to characterize parenchymal lung disease. Doppler echocardiography is used to estimate pulmonary artery pressure (PAP). Although the ECG is technically not an imaging tool, it offers a noninvasive assessment of the status of the RV. Advanced imaging can monitor pulmonary vascular density and compliance and evaluate the metabolism, function, and vascularity of the hypertrophied right ventricle (RV). Although pulmonary angiography is largely reserved for Category 4 PH, the role of left and right heart catheterization in achieving correct categorization remains paramount.


Category 1 PH (PAH) is diverse and is unified by histological similarities amongst the represented diseases and the shared elevation of pulmonary vascular resistance (PVR). Category 1 includes idiopathic and familial PH, as well as PH associated with conditions such as collagen vascular disease, congenital shunts, cirrhosis and portal hypertension, HIV, hemoglobinopathies, and schistosomiasis. It also includes PH associated with drugs, such as anorexigens or amphetamines.[2] The diagnosis of Category 1 PH is largely a diagnosis of exclusion (i.e., excluding Categories PH), a process in which imaging is crucial. Images of idiopathic PAH and PAH due to atrial septal defect (ASD) with Eisenmenger's physiology are shown (Figs. 1&#x;7). In addition, complications of severe Category 1 PH are illustrated, including compression of the left main coronary artery (Fig. 5) and calcification of the proximal pulmonary artery (PA) (Fig. 3). Imaging can also provide clues to the subcategory of Category 1 PH, as illustrated in a patient with pulmonary capillary hemangiomatosis (PCH) (Figs. 6 and 7). Cardiac magnetic resonance imaging (CMR) can quantify RV volumes and size and, when performed using gadolinium as a contrast agent, provides prognostic information.

Figure 1

Images obtained in a year-old female with idiopathic PAH. (A) S1Q3T3 pattern noted consistent with right ventricle strain. T-wave inversion on anterior leads and ST depression is also suggestive of RVH with strain (note early R wave predominance in

Figure 3

Calcified PAs in a patient with atrial septal defect (ASD) and Eisenmenger's physiology. (A) ECG shows first-degree AV block, right bundle branch block. (B, C) Chest X-ray showing enlarged and calcified pulmonary artery. (D, E) Axial CT scan below the

Figure 5

Patient with ASD and left main coronary artery compression. (A) ECG showing right atrial enlargement and severe RVH. (B) Chest X-ray showing severely enlarged PA. (C) Lateral chest X-ray showing filling of the retrosternal space. (D, E) Coronary angiogram

Figure 6

Category 1 PH diagnosed postmortem as secondary to pulmonary capillary hemangiomatosis (PCH). (A) ECG shows mild left ventricular hypertrophy and right atrial enlargement. (B, C) Chest X-ray shows PA enlargement and cephalization with Kerly B lines. (D)

Figure 7

Category 1 PH due to a second case of pulmonary capillary hemangiomatosis. (A) ECG showing sinus tachycardia and right atrial enlargement. (B) Chest X-ray on presentation with cardiomegaly and clear lung fields. (C) Chest X-ray after initiation of sildenafil

Classification into Category 1 is not as simple as identifying that a patient has a Category 1-associated disease. For example, while sickle cell disease is in Category 1 (because some patients develop pulmonary vascular remodeling), sickle cell patients can often develop Category 2 PH, due to secondary hemochromatosis and a secondary restrictive cardiomyopathy. Certain subsets of Category 1 PH have significant lung disease that can complicate attribution of their PH to a single category (notably scleroderma patients who often have parenchymal lung disease, Category 3).

Category 2 is the collection of PH syndromes resulting from left ventricular (LV) or left-sided valvular disease. Whether due to mitral stenosis, cardiomyopathy or LV diastolic dysfunction, Category 2 patients have PH due in large part to increased left atrial pressure. Category 2 is the most common form of PH and while there is no approved PH-specific therapy for this category, PH does confer adverse prognosis to these patients (as is the case in Categories 3 and 5). Classically, Category 2 patients are defined at catheterization by an elevated pulmonary-wedge pressure and a modest transpulmonary gradient (usually 10 mmHg difference between mean PA and wedge pressure). However, increasingly cases are identified where the transpulmonary gradient is increased disproportionately.[6] In such cases, there is likely pulmonary vascular remodeling. Such a case of disproportionate Category 2 PH is illustrated in Figure 8. In Figures 9 and 10, we present cases of restrictive physiology causing PH.

Figure 8

Category 2 PH after mitral valve repair. (A) Normal sinus rhythm with lateral T wave flattening. (B) Chest X-ray showing splaying of carina and left atrial enlargement. (C) Lateral chest X-ray showing mitral ring in place and RV enlargement. (D) Representative

Figure 9

Category 2 PH secondary to restrictive physiology. (A) ECG showing diffuse T wave inversion. (B) Chest X-ray with right-sided pleural effusion on presentation. (C) Chest X-ray after pleurocentesis left-sided heart enlargement is apparent. (D) Apical 4-chamber

Figure 10

(A) ECG showing left ventricular hypertrophy. (B, C) Chest X-ray showing cardiomegaly. (D) T2 Star Cardiac MRI short axis images demonstrating reduced T2 star time 10 ms suggesting significant iron overload and no signal from dark liver (white

Category 3 PH is PH secondary to chronic lung diseases, hypoxia or both (e.g., sleep apnea). This category of PH is characterized by mild elevations in PAP.[7] As with Category 2, however, there are Category 3 patients in whom the PH is disproportionately severe, as compared to their lung disease. We present a case of obstructive sleep apnea with severe PH (Fig. 11).

Figure 11

Images obtained in year-old male with cor pulmonale. (A) S1Q3T3 pattern noted consistent with right ventricle strain. RVH is evident from the prominent R wave in the early precordial leads. Evidence of pulmonary disease, with failure of R wave transition

Category 4 PH (CTEPH) is unique because it represents the form of PH that is curable without transplantation.[8] In this review, we present a severe case of CTEPH (Fig. 12). Perfusion lung scanning can be helpful for the diagnosis, but will not reveal the proximal extent of the thromboemboli. In addition, patients with nonocclusive thrombi may have normal distal lung perfusion in those segments giving a false negative impression. While noninvasive imaging is key to the diagnosis of CTEPH, there are cases in which the CT angiography fails to detect the intimately incorporated thrombus, which forms a neointima.[9] This reminds one of the need for pulmonary angiography when the index of suspicion is high.

Figure 12

WHO Group 4 &#x; chronic thromboembolic pulmonary hypertension. (A) Twelve-lead electrocardiogram showing S1Q3T3 suggestive of right ventricular strain, and right axis deviation. (B, C) Chest X-ray: Massively enlarged central pulmonary arteries.

Category 5 PH represents a heterogeneous collection of PH syndromes secondary to systemic diseases (i.e., sarcoidosis, histiocytosis X), hematological disorders (such as polycythemia vera or chronic myeloid leukemia) and extrinsic compression of the pulmonary artery. Two Category 5 PH cases due to examples of extrinsic PA compression, one caused by mediastinal calcification and the other by nonsmall cell lung cancer, are shown (Figs. 13 and 14), respectively).

Figure 13

WHO Group 5 &#x; Pulmonary hypertension with unclear or multifactorial etiologies. (A) ECG showing left ventricular hypertrophy. (B, C) Chest X-ray, PA and lateral with no edema or cardiomegaly. (D) Computerized tomographic scan of the chest showing

Figure 14

Category 5 PH. (A) ECG showed non-specific TW flattening. (B, C) Chest X-ray showed left-sided pleural effusion. (D, E) CT scan showed extensive confluent mediastinal and bihilar lymphadenopathy, compressing both pulmonary arteries, right more so than


Category 1 PH: year-old female with pulmonary arterial hypertension

A year-old female was referred for management of PH. She had initially presented 1 year prior for evaluation of progressive dyspnea and fatigue. Her ECG showed right axis deviation with right ventricular hypertrophy (RVH) and a strain pattern (manifest as early R-wave transition in V1-V2 with ST depression in V1-V4). She also had the S1Q3T3 pattern, defined as a prominent S wave in lead I, Q wave in lead III and T wave inversion in lead III. S1Q3T3 is more commonly seen with pulmonary embolism but can reflect RV strain of any cause, as shown in Figure 1A.[10]

Chest X-ray was consistent with PH with enlarged pulmonary arteries bilaterally, distal pruning of the pulmonary blood vessels and filling-in of the retrosternal airspace on the lateral film, consistent with right ventricular enlargement (Fig. 1B and C). Enlargement of the right descending PA 20 mm is quite specific for PH.[11]

Her transthoracic echocardiogram showed severe RV dilatation with flattening of the interventricular septum and LV compression consistent with RV pressure and volume overload (Fig. 1D and E). Flattening of the interventricular septum that occurs only in diastole reflects right-sided volume overload; however, systolic septal flattening indicates that there is also right-sided pressure overload with right-sided systolic pressures approximating left ventricular systolic pressures.

The tricuspid regurgitation (TR) velocity, obtained using continuous-wave Doppler (Fig. 1F), is used to estimate RV systolic pressure, which is equal to the PA systolic pressure in the absence of pulmonic stenosis, by applying Bernoulli's equation (PAPsystolic=4V2+estimated RA pressure; where V is the average peak TR velocity). Difficulties in aligning the Doppler parallel to the TR jet or the paucity of TR may preclude accurate assessment of PA systolic pressures.[3] Moreover, although TR velocity can quantify PA pressure, the morphology of the TR jet does not vary with changes in the compliance of the pulmonary vasculature, unlike PAAT, and thus the TR signal does not help categorize PH.

In contrast, a less frequently used measure, the pulmonary artery acceleration time (PAAT), can be readily obtained in most patients and provides evidence of the state of pulmonary vascular remodeling (Fig. 1G).[12] To obtain the PAAT, defined as the time from the onset of flow to the peak of the ejection flow velocity (Fig. 1G), the pulsed-wave Doppler sample volume is placed parallel to flow in the main PA. Because the difference in PAAT between normal PA pressure and severe PH is small, it is crucial to record the signal at high sweep speed and optimize the filtering and velocity scale. The shorter the acceleration time, the more severe the PH with a value of 80 ms being regarded as abnormal.[13] In order to estimate mean PAP using PAAT, each echocardiography laboratory should determine a regression equation correlating mean PAP, measured by catheterization, with PAAT. In PH due to pulmonary vascular disease the PA Doppler envelope develops systolic notching. This notch results from a reflection wave from the noncompliant pulmonary vasculature that cancels forward velocity. In rodent models, shortening of the PAAT with notching routinely develops as PAH progresses and these changes resolve with experimental therapies.[14]

A nuclear ventilation/perfusion (VQ) scan which shows some patchy perfusion defects is consistent with Category 1 PH (Fig. 1H). Both this moth-eaten appearance on the perfusion scan and the pruning on chest X-ray (loss of arterial markings in the lung periphery) reflect the small vessel obliteration that typifies Category 1 PH. These are the imaging correlates of the histological changes seen in PAH (Fig. 1I and J). Hemodynamic measurements by right heart catheterization (RHC) at the time of diagnosis are shown in the table in Figure 1. The patient was started on sildenafil and subcutaneous treprostinil and ultimately transitioned to intravenous prostaglandins. This therapy was maintained for 6 years before the patient succumbed to RV failure.

Imaging lesson

The vascular remodeling of the distal resistance pulmonary arterioles, which is a hallmark of Category 1 PH, can be detected by the notching observed in PA Doppler at echocardiogram as well as the vascular pruning seen in chest X-ray and the moth-eaten appearance of the VQ scan. The RVH and strain pattern on ECG and RV pressure-volume overload, on transthoracic echocardiogram, help quantify the disease severity but are not specific for Category 1 PH.

Category 1 PH: CMR imaging to assess the RV

In Figure 2, we present two patients with PAH who have dilated right ventricles. Panel A is a year-old female with WHO functional class IV PAH on intravenous (IV) treprostinil. Panel 2B-C is a year-old male with PAH who was WHO functional class II on sildenafil. In Figure 2A, the late gadolinium enhancement at the RV insertion is shown. In Figure 2B and C, a severely dilated RV is seen.

Figure 2

(A) Cardiac MRI image showing late gadolinium enhancement in the RV insertion site (thick white arrow). (B, C) Cardiac MRI showing dilated right ventricle.

Imaging lesson

CMR has contributed greatly to the evaluation of PH patients. RV morphology on CMR can predict the extent of PAP elevation.[15] Also, late gadolinium enhancement at the insertion point of the RV has been studied as a prognostic indicator in PH patients.[16] CMR permits reproducible measurements of RV volumes.[17] Arguably, CMR should be a routine part of the diagnosis and follow-up of PH patients.

Category 1 PH: ASD with paradoxical embolization and calcified pulmonary arteries

This year-old female has Category 1 PH secondary to an ostium secundum atrial septal defect (ASD) and Eisenmenger's physiology, with bidirectional interatrial flow after a failed pericardial patch repair 12 years prior. She had a paradoxical embolism causing a right hemispheric stroke 1 year prior to admission. ECG shows first-degree atrial-ventricular and right bundle branch block, both common in ASD (Fig. 3A). Chest X-ray (Fig. 3B and C) shows enlargement and calcification of the proximal PAs and pruning of the peripheral PAs. PA calcification reflects long-standing PAH typically associated with congenital heart disease with shunt lesions.[18,19] Extensive calcification within both pulmonary arteries was also confirmed on chest CT (Fig. 3D and E). Echocardiogram showed an atrial septal defect with bidirectional flow and concentric RVH with preserved RV systolic function (Fig. 3F and G). Her RHC confirmed that the PH was pulmonary vascular in origin (i.e., high transpulmonary gradient and PVR, table in Fig. 3) and demonstrated that she was a vasodilator nonresponder. Despite declining IV epoprostenol, the patient remains WHO functional class II on sildenafil and bosentan after 7 years.

Imaging lesson

This patient's concentric RVH and preserved RV systolic function portend a good outcome, as does the etiology of her subcategory of PH 1 (congenital heart disease). The essential role of echocardiography in assessing the interatrial septum and evaluating RV function is illustrated. Calcified PAs are most commonly seen with Category 1 PH associated with congenital heart diseases (patent ductus or ASD), although calcified PA thrombi have been reported in Category 4 PH.[20]

Category 1 PH: Cardiac arrest in Eisenmenger's syndrome

In contrast to Figure 3, whose subject was WHO functional class II despite severe PAH, Figure 4 shows the autopsy findings of a female in her third decade. This patient also had a secundum ASD and Eisenmenger's physiology but suffered out-of-hospital cardiac arrest. An ECG obtained shortly before her death shows severe right axis deviation and RVH (Fig. 4A). This is consistent with the dilated right ventricle with focal thinning noted at autopsy (Fig. 4B). Figure 4C and D shows the anatomy of the ostium secundum ASD.

Figure 4

Congenital heart disease patient (ASD) with out-of-hospital sudden cardiac death. (A) ECG showing severe RVH. (B) Severe RV hypertrophy and dilatation. (C, D) Ostium secundum atrial septal defect.

Imaging lesson

Most PH patients develop symptoms or die when the RV thins, dilates and/or becomes hypokinetic.

Category 1 PH: Compression of the left main coronary artery by hypertensive PAs

This case demonstrates an uncommon but well-described clinical complication of severe PH secondary to ASD. This WHO functional class IV year-old female was referred for evaluation of PH. She had been doing well until 4 years prior to presentation when she developed progressive dyspnea and syncope. Transthoracic echocardiogram at that time showed severe RV dilatation and ASD. The ASD was deemed unsuitable for closure due to systemic desaturation and elevation in RV pressures on transient occlusion of the ASD. Transthoracic echocardiography confirmed the presence of ASD and RV dilatation. The patient underwent RHC (Table 2). Based on the negative response to vasodilator therapy (a rise in PAP and fall in cardiac output), the patient was referred for evaluation for lung transplantation. As part of the evaluation, the patient underwent coronary angiography and was found to have left main compression resulting from severe enlargement of her main PA (Fig. 5D and E). CT scan confirmed this and the proximity of the PA to left main coronary artery is illustrated (Fig. 5F and G).

Table 2

Hemodynamics and shunt study in a patient with ASD and left main coronary artery compression by a dilated main pulmonary artery

Most cases of left main compression due to PA enlargement are complications of ASD, ventricular septal defect (VSD) or tetralogy of Fallot (TOF).[21] They can be an incidental finding or present with angina or dyspnea. Enlarged PAs in PH can also compress the proximal airways. The optimal management of this PH complication is uncertain with some proponents for left main stenting if LV ischemia is demonstrated.[22] In this case the patient was referred for consideration of combined heart and lung transplantation.

Imaging lesson

Mitsudo et al. reported narrowing of left main coronary artery in 44% of 16 ASD patients with PH,[23] indicating that it is not an uncommon complication.

Category 1 PH: Apparent mixture of categories 2 and 3 PH diagnosed as PCH on autopsy

A year-old male with a history of essential hypertension, coronary artery disease, and past smoking history developed worsening dyspnea and fatigue 1 year before presentation. He had a history of sleep apnea but was poorly compliant with CPAP. A drug-eluting stent was placed in his left circumflex coronary artery 1 year prior to his presentation. ECG showed right atrial hypertrophy (and mild left ventricular hypertrophy [Fig. 6A]). Chest X-ray (Fig. 6B and C) showed cephalization of pulmonary vasculature with bilateral PA enlargement and hyperinflated lungs. There were increased interstitial markings and Kerley B lines. Echocardiogram showed normal left ventricular function, dilated right ventricle and elevated left-sided filling pressures. Right heart catheterization showed elevated PAP and a pulmonary capillary wedge pressure of 19 mmHg (table in Fig. 6). The patient's DLCO was 43% of the predicted level on PFTs without significant evidence of obstructive or restrictive airway disease. Therapy included improved blood pressure control (using an angiotensin receptor blocker) and the off-label use of the phosphodiesterase-5 inhibitor, sildenafil, for presumptive Category 2 PH.[24] The patient's functional class improved from WHO IV to WHO II and he did well for 2 years but ultimately expired due to azotemia and decompensated RV failure (which persisted despite admission for diuresis and inotropic support). His autopsy revealed an enlarged heart weighing g with four-chamber dilatation (Fig. 6D). The RV wall thickness was at the upper limit of normal ( cm, consistent with the absence of RVH on ECG). Lung histology (Fig. 6E and F) revealed medial hypertrophy and muscularization of small PAs and surprisingly demonstrated PCH, highlighting the frequent overlap in categories that can occur within patients and also the limitations of imaging in definitive classification.

Imaging lesson

This case illustrates one of the persistent difficulties in appropriately categorizing patients and in turn determining the best treatment options for patients with a new diagnosis of PH. The interstitial changes seen on chest X-ray, although initially concerning for pulmonary edema, can also be seen with PCH or pulmonary veno-occlusive disease. This patient responded well both clinically and hemodynamically to off-label phosphodiesterase-5 inhibition. He satisfied clinical diagnostic criteria for diastolic dysfunction (Category 2 PH); however, post-mortem results showed features of PCH, illustrating the importance of obtaining an autopsy whenever possible in PH patients.

Category 1 PH: Pulmonary edema with vasodilators in a patient with post-mortem diagnosis of PCH

A year-old female presented with a 5-month history of dyspnea, orthopnea, lower leg swelling, and a recent lb weight gain. The patient had a history of CREST syndrome with limited scleroderma, an antiphospholipid antibody syndrome and a recent diagnosis of PAH by RHC. Chest X-ray on presentation (Fig. 7B and C) showed cardiomegaly and no interstitial disease. VQ scan (Fig. 7D) showed accentuation of basilar perfusion. RHC (table in Fig. 7) results classified the patient as a borderline vasodilator responder (mean PAP fell from 56 mmHg to 43 mmHg with adenosine). The right coronary artery (RCA) was also found to be stenotic and the 80% lesion in her relatively small RCA was stented. The patient was started on sildenafil. The following day the patient became hypotensive and dyspneic. Chest X-ray at that time (Fig. 7C) was significant for subtle signs of pulmonary edema. Pressures and PVR on a repeat RHC were increased (table in Fig. 7). The patient was managed supportively in the ICU with vasopressors and diuretics before being discharged home 1 week later. While at home, the patient experienced in-stent thrombosis of her RCA. On readmission, care was ultimately withdrawn and the patient expired.

On autopsy, the heart was enlarged ( g) with biventricular dilatation (Fig. 7E). In all lung sections, there were multifocal and patchy areas of pulmonary capillary proliferations engorged with red blood cells (Fig. 7F). There was marked and diffuse concentric intimal fibrosis and medial hypertrophy of the small PAs. Some vessels were almost entirely occluded (Fig. 7G). No plexiform lesions were identified. The extensive multifocal proliferation of capillaries along with arteriolar thickening supports a diagnosis of PCH.

Imaging lesson

PCH remains a very difficult diagnosis to make antemortem. In retrospect it was suggested in this case by the development of pulmonary edema and worsened pulmonary hypertension after the introduction of a vasodilator (sildenafil),[25] and the accentuation of basilar perfusion on the VQ scan.[26]


Category 2 PH: Persistent PH after correction of aortic stenosis and mitral insufficiency disease

A year-old female presented 1 month after an aortic valve replacement (AVR) for aortic stenosis (AS) with concomitant mitral and tricuspid valve repair for mitral regurgitation (MR) and TR. The accompanying chest X-ray showed left atrial enlargement, evident from flattening of the left heart border and splaying of the carina (Fig. 8B and C). The echocardiogram showed RV enlargement and LVH (Fig. 8D and E) as well as significant TR with elevated estimated RVSP (Fig. 8F and G). The aortic prosthesis functioned normally. Although there was mild gradient across the mitral valve prosthesis (Fig. 8H and I), the normal pressure half-time was indicative of a nonstenotic repaired valve (Fig. 8I). The pulmonary capillary wedge pressure was mildly elevated at 12 mmHg (Fig. 8J); however, the transpulmonary gradient was increased and was dynamic, decreasing with inhaled nitric oxide.

Imaging lesson

This patient's dyspnea and PH following mitral surgery reflect an elevated transpulmonary gradient as a result of a dynamic elevation in pulmonary vascular tone. The vasodilator responsiveness in this case suggests a possible role for therapy with sildenafil (off-label) and would only be identified if the noninvasive diagnosis of PH were investigated by a RHC.

Category 2 PH: Restrictive cardiomyopathy caused by tumor infiltration

This year-old male had non-Hodgkin's lymphoma presenting as a neck mass 20 years prior to presentation. He was treated with chemotherapy and local radiation therapy. Six months prior to presentation, he developed a large mass on his right neck which on biopsy was found to be recurrent non-Hodgkin's lymphoma and he was treated with local radiation therapy. One month prior to admission he developed dyspnea, pedal edema, and ascites, with a lb weight gain. On exam, the patient had a JVP 18 cm above the manubrio-sternal angle with a steep Y descent, 2+ pitting edema to shin, ascites, hepatomegaly, and decreased breath sounds on the right lung with dullness to percussion and decreased vocal fremitus. Chest X-ray confirmed right-sided pleural effusion (Fig. 9B), which after pleurocentesis showed cardiomegaly (Fig. 9C). Echocardiogram was significant for right ventricular enlargement, flattening of interventricular septum, and thickening of the lateral wall of the left ventricle (Fig. 9D). CT chest showed fibrotic lung disease likely secondary to radiation therapy, pleural effusion, but most importantly, a left ventricular wall mass (Fig. 9E). On CMR, the mass was extrinsic to the heart and deformed the inferior wall of the LV (Fig. 9F). The patient underwent left ventriculography (Fig. 9G) confirming that the mass impinged upon and distorted the inferior wall of the left ventricle. Simultaneous right and left heart catheterization confirmed that the PH reflected restrictive physiology diagnosed by the near equalization of diastolic pressures, the steep Y descent and the square root sign of the RV diastolic pressure trace (Fig. 9H). This PH resulted from recurrent non-Hodgkin's Lymphoma causing LV restrictive physiology. Upon receiving therapy for his tumor, the mass shrank and the RV failure signs and symptoms resolved.

Imaging lesson

This case illustrates the utility of imaging in identifying the PH as Category 2 based on the presence of an extracardiac mass. However, the key role of hemodynamics in confirming that the etiology of the PH and right heart failure reflected restrictive physiology is paramount.

Category 2 PH: The complexities of categorization of PH &#x; not all Sickle cell PH is Category 1 PH

A year-old African-American female with sickle cell disease was admitted to the coronary care unit with a diagnosis of RV failure. She had multiple hospital admissions for dyspnea and volume overload, and Doppler echocardiography had identified elevated PAP. She had previously been presumptively classified as Category 1 PH (without a RHC), based on the history of sickle cell disease. During the current admission, she had hepatic encephalopathy with hyperammonemia (ammonia: mcg/dl. normal values mcg/dl) and was found to have hepatomegaly on CT (Fig. 10E). Her ferritin level was ng/ml (normal values: ng/ml). Invasive hemodynamics confirmed PH (table in Fig. 10) but showed near-equalization of diastolic pressures consistent with the restrictive physiology of an infiltrative cardiomyopathy (Fig. 10G). Ultimately, myocardial iron overload secondary to chronic blood transfusion was confirmed by CMR (Fig. 10D). In the CMR, the T2-star short axis images should retain an intense ( bright ) myocardial signal for the entirety of the series of images presented here. T2-star time in the normal myocardium is 20 ms. This patient's T2-star time is 10 ms, consistent with significant iron overload and has been associated with a very poor prognosis and ventricular arrhythmia independently of liver iron content and serum ferritin.[27,28] Also, on T2-star imaging, the liver appears very dark, again consistent with severe iron overload (Fig. 10F). The patient was subsequently initiated on IV desferrioxamine therapy, which has been shown to improve LV function in patients with secondary hemochromatosis.[29]

Image lesson

This case reinforces the fact that the presence of a PH-associated disease is insufficient to categorize a patient. PH is prevalent among patients with sickle cell disease, recently shown to be present in 6% of patients.[30] While the presumed etiology of PH associated with hemolytic anemias such as thalassemia is pulmonary vascular disease, histologically similar to other disease entities within Category 1 PH,[31] a RHC is required to accurately categorize PH and in this case dramatically altered therapy.


Category 3 PH: The Pickwick Papers redux

A year-old welder with Class IV obesity (BMI 65 kg/m2) presented to the emergency room for a 3-month history of weight gain, dyspnea and edema. His family reported he had periods of apnea and daytime hypersomnolence. He had cirrhosis and thrombocytopenia with portal hypertension, possibly secondary to alcohol use. ECG showed right axis deviation, incomplete right bundle branch, S1Q3T3 pattern and delayed R wave transition consistent with lung disease (Fig. 11A). Initial chest X-ray showed severe four-chamber cardiomegaly with pulmonary vascular redistribution (Fig. 11B and C). Transthoracic echocardiogram showed a severely dilated RV and severely reduced RV performance but normal left ventricular systolic function. A Swan-Ganz catheter revealed PA pressures of 80/40 mmHg (table in Fig. 11). The wedge pressure could not be obtained due to patient size. A VQ scan was low probability for pulmonary emboli (Fig. 11D and E). His CT angiogram showed moderate to severe cardiomegaly with evidence of elevated right heart pressures and normal lung parenchyma other than mild dependent hypoventilation (Fig. 11F&#x;H). The patient, however, did exhibit daytime hypoxemia and hypercapnia on room air as evidenced by an arterial blood gas, which showed pH , PaCO2 49 mmHg, PaO270 mmHg, and SaO2 93%. Given the patient's extreme obesity and evidence of daytime alveolar hypoventilation, his case is consistent with obesity hypoventilation syndrome (OHS) causing cor pulmonale. With diuresis, ultrafiltration and nocturnal positive airway pressure his PH was reduced and he lost 65 lbs of fluid over 25 days (Fig. 11I).

In classic Pickwickian syndrome,[32] an early description of what is now characterized as OHS, overall daytime hypoventilation related to markedly restricted lung volumes is coupled with significant nocturnal hypoxemia and episodes of obstructive sleep apnea (OSA). Episodic and eventually chronic hypoxia induces vasoconstriction of the small pulmonary arteries, leading to transient but repetitive elevations of PAP and RVH.[33]

Imaging lesson

Imaging (and RHC) in obese patients is challenging. Elevations in PAP from obesity, OHS, and respiratory disease are typically milder than in other forms of PH;[34] however the chamber dilation and volume overload that ensues can be dramatic, as in this case. In addition, patients often have risk factors for PH that ultimately contribute to their PH syndrome. This patient did have portal hypertension; however, his PH decreased substantially with CPAP, suggesting sleep apnea was the predominant cause.


Category 4 PH: Chronic thromboembolic pulmonary hypertension

This year-old male presented to an outside hospital with exertional dyspnea, and was referred to our institution for further evaluation of PH. He has a history of chronic liver disease secondary to hepatitis C infection and chronic obstructive lung disease. His ECG showed right axis deviation and an S1Q3T3 pattern (Fig. 12A). His chest X-ray showed an enlarged RV, a severely dilated main pulmonary artery, and dilated bilateral pulmonary arteries, consistent with long-standing PH (Fig. 12B and C). Echocardiogram showed severe RV dilatation and dysfunction and a flattened interventricular septum, consistent with RV volume and pressure overload. RHC (table in Fig. 12) revealed severely elevated PAP. Pulmonary function testing was consistent with severe obstructive lung disease with a FEV1/FVC ratio of 49%, total lung capacity of %, residual volume of % and a DLCO of ml/min/mmHg (72% predicted). Although he had risk factors for Category 1 and 3 PH (i.e., chronic liver disease and chronic obstructive pulmonary disease), adherence to the recommended diagnostic algorithm[35] led to a VQ scan that showed small unmatched perfusion defect in the left lower lobe (Fig. 12D and E). Subsequently, a CT pulmonary angiogram showed a filling defect in the right main pulmonary artery and the right middle lobe branch suggestive of pulmonary embolism (Fig. 12F&#x;H). The thrombus in the right main PA had recanalized, evident from the contrast within the thrombus and the absence of right-sided perfusion defect on the VQ scan. The CT scan also confirmed the massive enlargement of the pulmonary arteries. The patient was started on warfarin and sildenafil. Although pulmonary endarterectomy (PEA) represents a definitive cure of CTEPH,[8] this patient was not referred for PEA due to his other significant co-morbidities (liver disease and thrombocytopenia).

Imaging lesson

This case demonstrates the complementary role of CT pulmonary angiography and VQ scans in detecting CTEPH (both modalities being fallible).


Category 5 PH: PH due to extrinsic PA obstruction

A year-old male who was recently diagnosed with testicular cancer was referred for a radical orchiectomy and abdominal lymph node dissection. On post-operative day 1, he developed sudden dyspnea and hypoxemia. ECG and chest X-ray were unremarkable (Fig. 13A&#x;E). Echocardiography showed normal left ventricular function with moderately dilated and reduced RV function. Pulmonary artery systolic pressure was estimated at 40 mmHg+RA pressure. A CT pulmonary angiogram revealed a calcified mediastinal mass compressing the right main PA (Fig. 13D and E). There was a filling defect adherent to the vessel wall extending from the right main PA to the right lower lobe PA suggestive of a thrombus (Fig. 13E and F). The VQ scan showed normal ventilation in both lungs (Fig. 13G) with absence of perfusion in the right lung, consistent with right PA compression (Fig. 13H).

Figure 14 shows the case of a year-old male with non-small cell lung cancer. He presented to a clinic with worsening dyspnea and cough. Chest X-ray showed pleural effusion (Fig. 14B and C). CT scan showed extensive confluent mediastinal and bihilar lymphadenopathy, compressing both pulmonary arteries and involving the pericardium (Fig. 14D and E). Obstruction to RV outflow was visualized on the echocardiogram as flow acceleration detected by color- and pulsed-wave Doppler (Fig. 14F and G).

Imaging lesson

CT scan and MRI are the usual modes of imaging by which Category 5 PH is detected. Extrinsic compression of the PA can obstruct flow, causing RV hypertension. However, if the obstruction is proximal (as in these cases) it is probable that there will be no PH and that PVR will be normal.


These cases offer representative examples of each category of PH in the WHO classification.


The authors are grateful to the family of Mr. Ernie Nafpliotis, who supported our PH research with a generous donation, and to Dr. Mardi Gomberg-Maitland for providing access to patient images in Figure 3.


Source of Support: Nil,

Conflict of Interest: None declared.


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Hypoxia-inducible factor and downstream metabolic effectors relevant to the Warburg effect

Hypoxia-inducible factor (HIF) is a transcription factor and master hypoxic regulator, controlling metabolic reprogramming in response to low oxygen levels. HIF has a well-described role in the pathogenesis of PAH and hypoxia-induced PH with probable contributions to other PH subtypes [17]. In all metazoan cells, exposure to low oxygen tension inhibits the proteasomal degradation of the HIF-1α/HIF-2α subunit via alteration of proline hydroxylation within HIF. This stabilised HIF-1α/HIF-2α subunit then translocates to the nucleus, heterodimerises with HIF-1β and binds to the promoters of hundreds of genes. Additionally, HIF-dependent processes, both directly and indirectly, are integrally related to numerous proliferative and survival genes and pathways implicated in PAH, including p53, leptin, caveolin-1 and PTEN, among others [18]. Evidence of the pathogenic importance of HIF in PH has been derived from several animal models, as previously reviewed [19]. For example, mice with heterozygous genetic deficiencies for either the HIF-1α or HIF-2α subunit display resistance to the development of hypoxia-induced PH. More recently, it was reported that constitutive activation of HIF-2α in pulmonary arterial endothelial cells via genetic knockout of prolyl-4 hydroxylase 2 (Egln1) resulted in profound obliterative PAH in mice [20]. In humans, HIF activation under normal oxygen tension has been observed in pulmonary vascular cells from PAH patients. Recently, a genetic variant of HIF-2α has been identified that displays increased prevalence in high-altitude PH cattle compared with unaffected cattle [21], thus providing rare genetic evidence of the importance of HIF in the development of PH.

Among the first HIF-responsive genes implicated in the Warburg effect in PH is the mitochondrial enzyme pyruvate dehydrogenase kinase (PDK). This enzyme is well established as a gatekeeper of oxidative metabolism, and its expression is known to be increased in response to hypoxia and in PAH [4]. Elevated levels of PDK lead to phosphorylation and inhibition of the enzyme pyruvate dehydrogenase, which in turn shunts pyruvate into glycolysis and induces the conversion of glucose to lactate by anaerobic respiration. In order to reverse the Warburg effect and thus improve PH manifestations, the drug dichloroacetate (DCA), an inhibitor of PDK originally developed as a cancer treatment, has been evaluated. In a number of animal models of PH, the use of DCA has demonstrated robust efficacy [22–25]. The effects of DCA in advanced human PAH have yet to be reported.

Alterations to the tricyclic acid (TCA) cycle and its intermediates can stabilise HIF. For example, α-ketoglutarate (KG) is a cofactor for prolyl hydroxylation and HIF degradation [26]. In addition, the TCA enzyme isocitrate dehydrogenase (IDH) has been reported to be elevated in the serum of PAH patients and in pulmonary microvascular endothelial cells derived from individuals carrying BMPR2 mutations [27]. IDH converts α-KG into isocitrate, with increased IDH activity leading to reduced availability of α-KG for HIF hydroxylation. This reduces the rate of HIF degradation and increases the expression of HIF-responsive genes. Other TCA metabolites can inhibit prolyl hydroxylation and activate HIF. For example, hypoxia increases the rate at which α-KG is reduced to 2-hydroxyglutarate (2HG), and the enantiomers l2HG and d2HG can inhibit prolyl hydroxylation of HIF [28]. In human pulmonary vascular cell types, hypoxia increases l2HG levels, thus controlling glycolysis and oxidative phosphorylation [29]. The influence of TCA cycle intermediates has epigenetic implications, as acetylation and methylation of nuclear histones are regulated by citrate and α-KG, respectively [28, 30]. Notably, the epigenetic inhibitors valproic acid and suberoylanilide hydroxamic acid (vorinostat) ameliorated PH in a rat model [31], supporting the concept that downstream metabolic pathways are potential therapeutic targets for PH, at least in part.

Control of iron handling has also emerged as a key pathway implicated in HIF biology and the Warburg effect, and iron deficiency has previously been reported in PAH populations [32, 33]. Specifically, microRNA (miR), a transcriptional target of HIF, was found to downregulate expression of the iron-sulfur (Fe-S) cluster assembly proteins (ISCU) 1 and 2 [34]. These are involved in the assembly of Fe-S clusters, which are prosthetic groups incorporated into enzymes involved in cellular redox signalling [35]. Hypoxic repression of ISCU1/2 via miR decreased Fe-S-dependent mitochondrial respiration in favour of glycolysis in pulmonary arterial endothelial cells, thereby promoting PH in rodent models [36]. Importantly, a female with a genetic deficiency in ISCU1/2 was found to suffer from exercise-induced PH, offering evidence to support a role for Fe-S clusters in the development of PH. This relationship between Fe-S deficiency and PH is also supported by epidemiological data showing that histological manifestations of PAH occur in infants with a genetic deficiency in NFU1, another Fe-S cluster assembly protein [37]. More than 30 Fe-S biogenesis genes have been identified in mammalian cells [35], and it is likely that several others also contribute to the Warburg effect in PH.

Iron can directly regulate expression of HIF-1α and HIF-2α. Prolyl hydroxylases that regulate HIF protein stability are dependent upon iron and oxygen as cofactors. Iron deficiency decreases such hydroxylase activity and promotes HIF stability [38, 39]. In vivo, iron-deficient rats have been found to display HIF upregulation, accompanied by decreased mitochondrial activity, increased glycolytic activity and substantial pulmonary vascular remodelling. These alterations were reversed with iron replacement therapy [40]. Iron deficiency also was found to be associated with elevated hepcidin [33], which in turn can predispose to PAH and could serve as an additional therapeutic target. Furthermore, iron-regulatory proteins such as Irp1 are known to be influenced by both iron levels and hypoxia. Irp1-deficient mice develop PH and in pulmonary endothelial cells from these animals, increased HIF-2α protein levels were observed compared with cells from wild-type animals [41]. Notably, iron-specific biology may be context-specific and/or dose-dependent, given the reported predisposition to PH in sickle-cell patients with iron overload [42]. Nonetheless, iron replacement therapy is currently under study as a therapy for PAH (NCT), and drugs that inhibit miR or Fe-S cluster biogenesis, or activate Irp1 (i.e. tempol) [43], could represent future PH therapies.

Independent of HIF, additional molecules have been identified that control glucose metabolism in the remodelled arteries of PH. Peroxisome proliferator-activated receptor (PPAR)γ is a nuclear hormone receptor and transcription factor. In pulmonary vessels, PPARγ is vasoprotective [44]. Furthermore, in pulmonary artery smooth muscle cells (PASMCs) from PAH patients and in PH rodents, decreased BMPR2-PPARγ signalling has been reported [45, 46] and has led to PH and right ventricular (RV) hypertrophy in animals [46]. This metabolic connection of PPARγ with BMP signalling further correlated with studies of BMPR2 activity in regulating mitochondrial biogenesis and membrane potential, thus promoting a pro-proliferative state [7]. PPARγ was identified as a target of the microRNA family miR/, a systems-level regulator of cell proliferation, vascular stiffness, vasomotor tone and metabolism [47]. Most recently, PPARγ was found to regulate key enzymes controlling glucose utilisation in vascular smooth muscle cells (SMCs) [48]. Despite these encouraging findings, the clinical use of older PPARγ agonists has been tempered by indications of adverse myocardial events [49] and has stymied advances in PH. Nonetheless, the weight of evidence regarding the activity of PPARγ in PH indicates its potential as a future drug target, particularly for newer PPARγ agonists [50].

Emerging metabolic and mitochondrial pathways in PH beyond the Warburg effect

The preference for glycolysis over oxidative phosphorylation is unlikely to represent the only metabolic shift required for vascular cell proliferation in PH. Beyond the requisite ATP production, sufficient biomass must be generated to support proliferation. Anaplerosis is the replenishing of TCA carbon intermediates via either the glutaminase (GLS1)-mediated deamidation of glutamine or the carboxylation of pyruvate. In multiple subtypes of PH, it has been reported that two transcriptional coactivators, yes-associated protein (YAP)-1 and transcriptional coactivator with a PDZ-binding motif (TAZ), are required for GLS1 upregulation and subsequent glutaminolysis to sustain vascular cell proliferation and migration within stiff pulmonary vessels [16], and is reviewed in the article by Hemnes and Humbert [51] in this issue.

TCA cycle and electron transport chain modulations are associated with alterations in reactive oxygen species (ROS), which are known to regulate pulmonary vasodilation or vasoconstriction [52]. For example, the redox-sensitive nuclear factor erythroid 2-related factor 2 (Nrf2) is a transcription factor that decreases ROS generation and subsequent inflammation. In preclinical PH studies, Nrf2 activation improves mitochondrial dysregulation, decreases ROS and inflammatory signalling, and consequently improves arterial and RV remodelling [53]. A chemical inducer of Nrf2, bardoxolone methyl, is under investigation in a phase II clinical study in PAH patients (NCT) [54]. Although beyond the scope of this review and reviewed in detail elsewhere [55], ROS dynamics are further influenced in PH by various forms of superoxide dismutase [56], voltage gated potassium channels (Kv) [57], and L-type voltage gated calcium channels, to name but a few. In this regard, Kv channels are controlled by key upstream metabolic effectors such as the AMP-activated protein kinase (AMPK). As previously reviewed, the antidiabetic drug metformin, a known stimulator of AMPK, was found to protect against the development of PH in both hypoxia and monocrotaline (MCT) rat models, while also displaying antiremodelling properties. Other AMPK activators, such as salicylate and methotrexate may also be effective. A clinical trial to evaluate the effects of metformin on pulmonary vascular function in patients with PAH is currently recruiting patients (NCT).

Mitochondrial metabolic functions depend substantially on intramitochondrial calcium dynamics. Uncoupling protein (UCP)2 is a calcium uniporter which transports calcium from the endoplasmic reticulum into mitochondria [58]. Genetic ablation of UCP2 in cultured PASMCs resulted in mitochondrial hyperpolarisation and decreased activity of calcium-sensitive mitochondrial enzymes [59, 60]. In endothelial cells, loss of UCP2 promoted mitophagy and decreased mitochondrial synthesis [61]. Correspondingly, in mice, genetic deficiency of UCP2 increased pulmonary vascular remodelling and promoted the development of PH [59, 60]. Additionally, microRNA-dependent impairment of another calcium uniporter (the mitochondrial calcium uniporter complex) resulted in decreased mitochondrial calcium levels and a concomitant PAH phenotype in PASMCs as well as in MCT rats [62]. Further downstream, calcium dynamics are dysregulated at the level of the sarco-/endoplasmic reticulum calcium-ATPase (SERCA), a sarcoplasmic reticulum transporter that is downregulated in PAH. Gene transfer of SERCA2a in both rodent and porcine PH models rescued expression of SERCA2 in pulmonary arteries, resulting in decreased pulmonary artery pressure and improved RV function [63, 64]. Additionally, dysregulated calcium homeostasis can alter electrical dynamics within the cell and mitochondria. Studies have implicated glycolysis in the control of the mitochondrial permeability transition pore, a voltage- and redox-dependent channel that remains closed under hyperpolarised mitochondrial membrane potential and thus promotes cell survival [65]. Finally, the transfer of calcium from the endoplasmic reticulum to mitochondria, specifically dependent on the protein Nogo-B, has been studied in the pulmonary vasculature and found to be important in the development of PH [66]. Further work will be necessary to determine whether more substantial links exist between endoplasmic reticulum stress and metabolic dysregulation in PH.

Alterations of mitochondrial structure and biogenesis have been found to drive metabolic alterations in PH. Emerging studies have identified interconnected and dynamic sets of mitochondrial structures which exist within each cell and are controlled by an ever-changing balance of fission and fusion processes. Dynamin-related protein (Drp)1 is a GTPase that regulates mitochondrial fission and fragmentation [67, 68] and has been associated with the pro-proliferative vascular state in PH [69]. Decreased levels of mitofusin-2 in PAH have also been implicated in driving mitochondrial fragmentation and an imbalance of proliferation/apoptosis [70]. Pharmacological inhibition of mitochondrial fission and Drp1 with Mdivi-1 [71, 72] has been shown to ameliorate both pulmonary vascular and right ventricular dysfunction in animal models of PH. In parallel, decreased activation of peroxisome proliferator-activated receptor-γ coactivator (PGC)1α, a transcription factor mediating mitochondrial biogenesis and fission, has been linked to PH [70]. Additionally, deficient BMPR2 signalling has been implicated in the control of mitochondrial fission and a pro-inflammatory state [7]. In combination with PGC1α, Sirtuin 3 (SIRT3), a factor implicated in the control of mitochondrial structure via protein deacetylation [73], was recently reported to be repressed in rodent PH models, and SIRT3-null mice spontaneously developed PH [74]. Yet, due to their ubiquitous activity in other organ systems, it remains to be seen whether molecules involved in controlling mitochondrial structure can be useful therapeutic targets for PH.

Dysregulated fatty acid oxidation in the diseased right ventricle

Under non-diseased and baseline activity, fatty acid oxidation (FAO) generates 60–90% of energy production in cardiomyocytes, with the remaining 10–40% derived from glycolysis and glucose oxidation. A mutually competitive relationship, known as the Randle cycle, exists between these processes [75]. At baseline, increased production of citrate during FAO inhibits phosphofructokinase and leads to an accumulation of glucosephosphate. This inhibits hexokinase, resulting in a decrease in pyruvate production and further inhibiting glycolysis. Perhaps incited by increased pulmonary arterial pressures and impaired coronary perfusion as a result of advancing RV hypertrophy, initial RV injury in PH is thought to produce an inadequate oxygen supply. Consequently, HIF-1α is activated in cardiomyocytes thus driving upregulation of glycolytic genes [76]. Such reprogramming consequently leads to a reduction of FAO and worsens RV hypertrophy and cardiomyocyte contractile function. In fact, the upregulation of HIF-1α and glycolysis in hypertrophied RV has been demonstrated in both hypoxic and MCT PH rodent models [77, 78]. Correspondingly, inhibition of this process in mice via administration of DCA resulted in increased cardiac output and function [79]. Targeting the Randle cycle via FAO inhibitors may improve RV function by allowing more efficient use of glucose oxidation. For example, trimetazidine and ranolazine are FAO inhibitors that enhance glucose oxidation, and both compounds improved RV function in a pulmonary artery banding model of RV failure [80]. FAO inhibitors are under investigation in clinical trials, including one with trimetazidine (NCT) and a number of studies evaluating ranolazine, both published (NCT) [81] and ongoing (NCT, NCT and NCT). Targeting dysfunction at the RV separately from dysregulation of pulmonary vascular remodelling, if used in combination with classical therapeutic approaches, may provide another avenue in the treatment of PH.

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